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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. 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

  4. 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

  5. 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…

  6. Enhanced Patient Expectation and Antiemetic Drug Efficacy

    DTIC Science & Technology

    1999-07-01

    by the introduction of the 5-HT 3 receptor antagonist class of antiemetics ( ondansetron , granisetron, tropisitron) have greatly reduced chemotherapy...same materials plus specific information designed to enhance expectations of efficacy by pointing out that ondansetron can control emesis in a... ondansetron ( Ondansetron 20 mg IV infusion - over 15 min) and Dexamethasone (10 mg IV infusion - over 5-10 min). Patients are studied during the first

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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

  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. 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.

  17. 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

  18. 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

  19. 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…

  20. 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

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

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-11-1-0550 TITLE: Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer 5a. CONTRACT NUMBER W81XWH-11-1-0550 5b. GRANT NUMBER...new bc epitopes and mimotopes. 15. SUBJECT TERMS Breast cancer, tumor antigens, T cell receptor, cancer vaccine 16. SECURITY CLASSIFICATION OF: 17

  2. 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.

  3. 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…

  4. 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…

  5. 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…

  6. 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

  7. 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.

  8. 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.

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

    DTIC Science & Technology

    2015-10-01

    1 Award Number: W81XWH-11-1-0549 TITLE: Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-11-1-0549 Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer 5b. GRANT...and CD4 anti-tumor T cells in vivo, as CD4 T cells are needed to optimally sustain vaccine -elicited CD8 T cells in vivo [1]. Identified antigens

  10. 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.

  11. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

    PubMed Central

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

    2012-01-01

    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 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 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 inductive-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 5mg/kg 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. PMID:22275055

  12. Efficacy of an Unsaturated Soil Flushing/Enhanced Bioremediation Technology

    NASA Astrophysics Data System (ADS)

    Smith, J. E.; Badley, J. A.; Crowe, A. S.

    2003-12-01

    Undesirably high concentrations of DDT and its daughter products DDE and DDD in some soils at Point Pelee National Park (PPNP) in Leamington, Ontario, Canada has resulted in restricted access to relatively large areas of the park. The contamination occurs primarily within the upper 20 cm thick Ah horizon, and has been linked to elevated levels within numerous local fauna. The common solution of "dig-and-dump" is not practical in this case since it would destroy the local protected ecosystem. Field trials conducted by McMaster University in partnership with Environment Canada, and Parks Canada have indicated that the application of solutions of cyclodextrin as a low-impact soil flushing/enhanced biodegradation remediation technology can remove a large proportion of DDT, DDE and DDD from the soil within a few months. Based upon previous studies at PPNP, the naturally occurring degradation processes would take decades to achieve the same mass loss. The cyclodextrin solutions exhibited a strong "tailing-effect" after approximately ten pore-volumes had passed through the Ah. There was an effect on soil hydraulic properties with decreased hydraulic conductivities and higher soil water retention, particularly where the higher concentration solutions were applied. The results indicate that soil flushing with cyclodextrin is highly effective to remediate pesticide contaminated soils. Additional work will quantify the relative amount of enhanced degradation versus mobilisation.

  13. 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.

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

    DTIC Science & Technology

    2012-10-01

    vaccine antigens for her tumor. Another novel aspect of this project is the identification of altered peptides ( mimotopes ) that may more efficiently...Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Paul T. Spellman, PhD...2011 – 24 September 2012 4. TITLE AND SUBTITLE Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer 5a. CONTRACT NUMBER

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

    DTIC Science & Technology

    2012-10-01

    Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Peter P. Lee, MD...September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer 5b. GRANT...TERMS Breast cancer, immunotherapy, vaccine , antigens 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a

  16. 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

  17. 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…

  18. 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…

  19. 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 ...

  20. 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…

  1. "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)

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

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

    DTIC Science & Technology

    2012-10-01

    antigens  and  identify  novel  tumor   antigens/ mimotopes  as  candidates  for   vaccine   immunotherapy.       In  the...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

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

    DTIC Science & Technology

    2013-10-01

    Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Jill E. Slansky CONTRACTING ORGANIZATION: University of Colorado, REPORT...TITLE AND SUBTITLE Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer 5a. CONTRACT NUMBER W81XWH11-1-0550 5b. GRANT...receptor, cancer vaccine 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC

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

    DTIC Science & Technology

    2014-10-01

    of Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Paul T. Spellman, PhD CONTRACTING ORGANIZATION: REPORT DATE...SUBTITLE Enhancing the Breadth and Efficacy of Therapeutic Vaccines for 5a. CONTRACT NUMBER Breast Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...RESPONSIBLE PERSON USAMRMC a. REPORT U b . ABSTRACT U c. THIS PAGE U UU 12 19b. TELEPHONE NUMBER (include area code

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. Peptide-Mediated Liposomal Doxorubicin Enhances Drug Delivery Efficiency and Therapeutic Efficacy in Animal Models

    PubMed Central

    Chang, De-Kuan; Li, Pi-Chun; Lu, Ruei-Min; Jane, Wann-Neng; Wu, Han-Chung

    2013-01-01

    Lung cancer ranks among the most common malignancies, and is the leading cause of cancer-related mortality worldwide. Chemotherapy for lung cancer can be made more specific to tumor cells, and less toxic to normal tissues, through the use of ligand-mediated drug delivery systems. In this study, we investigated the targeting mechanism of the ligand-mediated drug delivery system using a peptide, SP5-2, which specifically binds to non-small cell lung cancer (NSCLC) cells. Conjugation of SP5-2 to liposomes enhanced the amount of drug delivered directly into NSCLC cells, through receptor-mediated endocytosis. Functional SP5-2 improved the therapeutic index of Lipo-Dox by enhancing therapeutic efficacy, reducing side effects, and increasing the survival rate of tumor-bearing mice in syngenic, metastatic and orthotopic animal models. Accumulation of SP5-2-conjugated liposomal doxorubicin (SP5-2-LD) in tumor tissues was 11.2-fold higher than that of free doxorubicin, and the area under the concentration-time curve (AUC0–72 hours) was increased 159.2-fold. Furthermore, the experiment of bioavailability was assessed to confirm that SP5-2 elevates the uptake of the liposomal drugs by the tumor cells in vivo. In conclusion, the use of SP5-2-conjugated liposomes enhances pharmacokinetic properties, improves efficacy and safety profiles, and allows for controlled biodistribution and drug release. PMID:24386166

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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.

  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. 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

  14. 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.

  15. 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

  16. 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%).

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. Novel Curcumin Diclofenac Conjugate Enhanced Curcumin Bioavailability and Efficacy in Streptococcal Cell Wall-induced Arthritis

    PubMed Central

    Jain, S. K.; Gill, M. S.; Pawar, H. S.; Suresh, Sarasija

    2014-01-01

    Curcumin-diclofenac conjugate as been synthesized by esterification of phenolic group of curcumin with the acid moiety of diclofenac, and characterized by mass spectrometry, NMR, FTIR, DSC, thermogravimetric analysis and X-ray diffraction analysis. The relative solubility of curcumin-diclofenac conjugate, curcumin and diclofenac; stability of curcumin-diclofenac conjugate in intestinal extract; permeability study of curcumin-diclofenac conjugate using the everted rat intestinal sac method; stability of curcumin-diclofenac conjugate in gastrointestinal fluids and in vitro efficacy have been evaluated. In vivo bioavailability of curcumin-diclofenac conjugate and curcumin in Sprague-Dawley rats, and antiarthritic activity of curcumin-diclofenac conjugate, curcumin and diclofenac in modified streptococcal cell wall-induced arthritis model in Balb/c mice to mimic rheumatoid arthritis in humans have also been studied. In all of the above studies, curcumin-diclofenac conjugate exhibited enhanced stability as compared to curcumin; its activity was twice that of diclofenac in inhibiting thermal protein denaturation taken as a measure of in vitro antiinflammatory activity; it enhanced the bioavailability of curcumin by more than five folds, and significantly (P<0.01) alleviated the symptoms of arthritis in streptococcal cell wall-induced arthritis model as compared to both diclofenac and curcumin. PMID:25425755

  4. 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

  5. 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.

  6. 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.

  7. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  9. 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…

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. [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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. Liposomal glucocorticosteroids in treatment of chronic autoimmune demyelination: long-term protective effects and enhanced efficacy of methylprednisolone formulations.

    PubMed

    Linker, Ralf A; Weller, Charlotte; Lühder, Fred; Mohr, Alexander; Schmidt, Jens; Knauth, Michael; Metselaar, Josbert M; Gold, Ralf

    2008-06-01

    Liposomal encapsulation leads to enhanced efficacy of glucocorticosteroids (GS) in treatment of autoimmune diseases. Here we compare liposomal prednisolone (PL) to liposomal methylprednisolone (MPL) in chronic-relapsing myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), a model closely reflecting aspects of multiple sclerosis (MS). At the maximum of the first relapse, a single dose of PL or MPL was applied at 10 mg/kg or at 4 mg/kg and compared to classical methylprednisolone (MP) pulse therapy. PL at 10 mg/kg was superior to free MP with long-term efficacy and a sustained protection even during the second and third relapse. At the same time, in vivo magnetic resonance imaging of rat brains revealed a significant reduction of T2-lesions after PL application. Comparison of PL and MPL at 10 mg/kg disclosed superior effects for MPL with an enhanced reduction of inflammatory infiltration as well as preservation of myelin and axons. Dose titration experiments underscored a dose-dependent efficacy of liposomal GS with a sustained efficacy especially of the higher dosage. In histological analyses, PL10 was superior in reducing macrophage and T cell infiltration as well as demyelination and axonal loss while the lower dosages were still at least as effective as free MP. FACS analyses revealed an effect of liposome formulations on T cell numbers, the CD4/CD8 ratio, frequencies of regulatory T cells and adhesion molecule expression. In summary, liposomal GS and especially methylprednisolone formulations display an enhanced efficacy not only in acute inflammatory, but also in chronic demyelinating models of MS and confer long-term protection from relapses. These findings lay the groundwork for applying liposomal GS in clinical MS trials in the near future.

  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. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Lipid-Coated Cisplatin Nanoparticles Induce Neighboring Effect and Exhibit Enhanced Anticancer Efficacy

    PubMed Central

    Guo, Shutao; Wang, Yuhua; Miao, Lei; Xu, Zhenghong; Lin, C. Michael; Zhang, Yuan; Huang, Leaf

    2014-01-01

    Encapsulation of cisplatin (CDDP) into nanoparticles (NPs) with high drug loading and encapsulation efficiency has been difficult due to the poor solubility of CDDP. However, this barrier has been overcome with a reverse microemulsion method appropriating CDDP’s poor solubility to our advantage promoting the synthesis of a pure cisplatin nanoparticle with a high drug loading capacity (approximately 80.8wt%). Actively targeted CDDP NPs exhibited significant accumulation in human A375M melanoma tumor cells in vivo. In addition, CDDP NPs achieved potent anti-tumor efficacy through the neighboring effect at a dose of 1 mg/kg when injected weekly via IV without inducing nephrotoxicity. The neighboring effect regards an observation made in vivo when the tumor cells that took up CDDP NPs released active drug following apoptosis. Via diffusion, surrounding cells that were previously unaffected showed intake of the released drug and their apoptosis soon followed. This observation was also made in vitro when A375M melanoma tumor cells incubated with CDDP NPs exhibited release of active drug and induced apoptosis on untreated neighboring cells. However, the neighboring effect was unique to rapidly proliferating tumor cells. Liver functional parameters and H&E staining of liver tissue in vivo failed to detect any difference between CDDP NP treated and control groups in terms of tissue health. By simultaneously promoting an increase in cytotoxicity and a lesser degree of side effects over free CDDP, CDDP NPs show great therapeutic potential with lower doses of drug while enhancing anti-cancer effectiveness. PMID:24083505

  13. 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.

  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. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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…

  8. 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…

  9. 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.…

  10. 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…

  11. 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…

  12. 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…

  13. 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…

  14. 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…

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. Combined Efficacy of Cediranib and Quinacrine in Glioma Is Enhanced by Hypoxia and Causally Linked to Autophagic Vacuole Accumulation

    PubMed Central

    Lobo, Merryl R.; Wang, Xiaoyan; Gillespie, G. Yancey; Woltjer, Randall L.; Pike, Martin M.

    2014-01-01

    We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia) vs. 31±3% (normoxia), p<0.05. Apoptosis was markedly increased for cediranib/quinacrine/hypoxia versus all other groups. Autophagic vacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine. Quinacrine's unique

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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…

  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. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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'.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  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. 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

  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. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  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. IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice

    PubMed Central

    Wang, Wei-qiang; Dong, Kui; Zhou, Lu; Jiao, Guo-hui; Zhu, Cong-zhong; Li, Wen-wen; Yu, Gang; Wu, Wan-tong; Chen, Song; Sun, Zhi-na; Wang, Yu-ming; Liu, Wen-tian; Zhang, Jie; Wang, Bang-mao; Feng, Xiao-ming

    2015-01-01

    Aim: To investigate whether the transfer of the IL-37b gene, a newly identified inhibitor of both innate and adaptive immunity, could improve the therapeutic efficacy of mesenchumal stromal cells (MSCs) in inflammatory bowel disease (IBD). Methods: The expression of IL-37 in biopsied specimens of the patients with active ulcerative colitis (UC) was detected using RT-PCR and immunohistochemistry. Mice were treated with 3% dextran sulfate sodium (DSS) for 8 days to induce colitis. Before DSS treatment, the mice were injected with MSCs, MSC-eGFP or MSC-IL37b. Their body weight was measured each day, and the colons and spleens were harvested on d 10 for pathological and biochemical analyses. Results: In biopsied specimens of the patients with active UC, the expression of IL-37 was dramatically elevated in inflamed mucosa, mainly in epithelial cells and infiltrating immune cells. Compared to MSC-eGFP or MSCs, MSC-IL37b administration significantly attenuated the body weight and colon length reduction, and decreased the histological score in DSS-induced colitis mice. Furthermore, MSC-IL37b administration increased the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells as well as the percentage of regulatory T cells (Tregs) among splenic CD4+ T cells in the mice. Moreover, MSC-IL37b administration increased the IL-2+ cells and decreased the IFN-γ+ cells among splenic CD4+ T cells. Conclusion: IL-37 is involved in the pathophysiology of UC. IL-37b gene transfer enhances the therapeutic efficacy of MSCs in DSS-induced colitis mice by inducing Tregs and MDSCs and regulating cytokine production. PMID:26190499

  20. Efficacy of oncolytic herpesvirus NV1020 can be enhanced by combination with chemotherapeutics in colon carcinoma cells.

    PubMed

    Gutermann, Anja; Mayer, Elfriede; von Dehn-Rothfelser, Karin; Breidenstein, Claudia; Weber, Mihaela; Muench, Martina; Gungor, Denis; Suehnel, Juergen; Moebius, Ulrich; Lechmann, Martin

    2006-12-01

    NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.

  1. 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…

  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. 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.

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  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. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  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. 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.

  11. 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.

  12. Nanoparticle conjugation and pulmonary delivery enhance the protective efficacy of Ag85B and CpG against tuberculosis.

    PubMed

    Ballester, Marie; Nembrini, Chiara; Dhar, Neeraj; de Titta, Alexandre; de Piano, Cyntia; Pasquier, Miriella; Simeoni, Eleonora; van der Vlies, André J; McKinney, John D; Hubbell, Jeffrey A; Swartz, Melody A

    2011-09-16

    Vaccines that drive robust T-cell immunity against Mycobacterium tuberculosis (Mtb) are needed both for prophylactic and therapeutic purposes. We have recently developed a synthetic vaccine delivery platform with Pluronic-stabilized polypropylene sulfide nanoparticles (NPs), which target lymphoid tissues by their small size (∼ 30 nm) and which activate the complement cascade by their surface chemistry. Here we conjugated the tuberculosis antigen Ag85B to the NPs (NP-Ag85B) and compared their efficacy in eliciting relevant immune responses in mice after intradermal or pulmonary administration. Pulmonary administration of NP-Ag85B with the adjuvant CpG led to enhanced induction of antigen-specific polyfunctional Th1 responses in the spleen, the lung and lung-draining lymph nodes as compared to soluble Ag85B with CpG and to the intradermally-delivered formulations. Mucosal and systemic Th17 responses were also observed with this adjuvanted NP formulation and vaccination route, especially in the lung. We then evaluated protection induced by the adjuvanted NP formulation following a Mtb aerosol challenge and found that vaccination with NP-Ag85B and CpG via the pulmonary route displayed a substantial reduction of the lung bacterial burden, both compared to soluble Ag85B with CpG and to the corresponding intradermally delivered formulations. These findings highlight the potential of administrating NP-based formulations by the pulmonary route for TB vaccination.

  13. 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

  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. 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…

  17. 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)…

  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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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…

  13. 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…

  14. 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…

  15. 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…

  16. 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…

  17. 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…

  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. 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.

  20. Enhanced Efficacy of the CDNF/MANF Family by Combined Intranigral Overexpression in the 6-OHDA Rat Model of Parkinson's Disease

    PubMed Central

    Cordero-Llana, Óscar; Houghton, Benjamin C; Rinaldi, Federica; Taylor, Hannah; Yáñez-Muñoz, Rafael J; Uney, James B; Wong, Liang-Fong; Caldwell, Maeve A

    2015-01-01

    Cerebral Dopamine Neurotrophic Factor (CDNF) and Mesencephalic Astrocyte-derived Neurotrophic factor (MANF) are members of a recently discovered family of neurotrophic factors (NTFs). Here, we used intranigral or intrastriatal lentiviral vector-mediated expression to evaluate their efficacy at protecting dopaminergic function in the 6-OHDA model of Parkinson's disease (PD). In contrast to the well-studied Glial-Derived Neurotrophic Factor (GDNF), no beneficial effects were demonstrated by striatal overexpression of either protein. Interestingly, nigral overexpression of CDNF decreased amphetamine-induced rotations and increased tyroxine hydroxylase (TH) striatal fiber density but had no effect on numbers of TH+ cells in the SN. Nigral MANF overexpression had no effect on amphetamine-induced rotations or TH striatal fiber density but resulted in a significant preservation of TH+ cells. Combined nigral overexpression of both factors led to a robust reduction in amphetamine-induced rotations, greater increase in striatal TH-fiber density and significant protection of TH+ cells in the SN. We conclude that nigral CDNF and MANF delivery is more efficacious than striatal delivery. This is also the first study to demonstrate that combined NTF can have synergistic effects that result in enhanced neuroprotection, suggesting that multiple NTF delivery may be more efficacious for the treatment of PD than the single NTF approaches attempted so far. PMID:25369767

  1. Colistin enhances therapeutic efficacy of daptomycin or teicoplanin in a murine model of multiresistant Acinetobacter baumannii sepsis.

    PubMed

    Cirioni, Oscar; Simonetti, Oriana; Pierpaoli, Elisa; Barucca, Alessandra; Ghiselli, Roberto; Orlando, Fiorenza; Pelloni, Maria; Trombettoni, Maria Michela Cappelletti; Guerrieri, Mario; Offidani, Annamaria; Giacometti, Andrea; Provinciali, Mauro

    2016-12-01

    We investigated the efficacy of colistin combined with teicoplanin or daptomycin in an experimental mouse model of multiresistant Acinetobacter baumannii infection. Animal received intraperitoneally 1ml saline containing 2×10(10)CFU of A. baumannii. Colistin, daptomycin, teicoplanin, and colistin plus daptomycin or teicoplanin were given by intraperitoneal administration 2h after bacterial challenge. A control group received sodium chloride solution. In the in vitro study A. baumannii showed to be susceptible only to colistin with MIC of 2mg/l. In the in vivo study, colistin alone showed a good antimicrobial efficacy. When combined with teicoplanin or daptomycin, colistin produced the lowest bacterial and the best survival rates. In immunological studies, when colistin was associated to daptomycin or teicoplanin, both the number and the cytotoxic activity of NK cells increased. In conclusion, colistin combined with teicoplanin or daptomycin may improve the therapy of multiresistant A. baumannii infection.

  2. Using Robotics and Game Design to Enhance Children's Self-Efficacy, STEM Attitudes, and Computational Thinking Skills

    NASA Astrophysics Data System (ADS)

    Leonard, Jacqueline; Buss, Alan; Gamboa, Ruben; Mitchell, Monica; Fashola, Olatokunbo S.; Hubert, Tarcia; Almughyirah, Sultan

    2016-12-01

    This paper describes the findings of a pilot study that used robotics and game design to develop middle school students' computational thinking strategies. One hundred and twenty-four students engaged in LEGO® EV3 robotics and created games using Scalable Game Design software. The results of the study revealed students' pre-post self-efficacy scores on the construct of computer use declined significantly, while the constructs of videogaming and computer gaming remained unchanged. When these constructs were analyzed by type of learning environment, self-efficacy on videogaming increased significantly in the combined robotics/gaming environment compared with the gaming-only context. Student attitudes toward STEM, however, did not change significantly as a result of the study. Finally, children's computational thinking (CT) strategies varied by method of instruction as students who participated in holistic game development (i.e., Project First) had higher CT ratings. This study contributes to the STEM education literature on the use of robotics and game design to influence self-efficacy in technology and CT, while informing the research team about the adaptations needed to ensure project fidelity during the remaining years of the study.

  3. Preparation of Hollow N-Chloramine-Functionalized Hemispherical Silica Particles with Enhanced Efficacy against Bacteria in the Presence of Organic Load: Synthesis, Characterization, and Antibacterial Activity.

    PubMed

    Rahma, Hakim; Asghari, Sogol; Logsetty, Sarvesh; Gu, Xiaochen; Liu, Song

    2015-06-03

    The fabrication of highly effective antimicrobial materials is an important strategy for coping with the growing concern of bacterial resistance. In this study, N-chloramine-functionalized hollow hemispherical structures were designed and prepared to examine possible enhancement of antimicrobial performance. Antimicrobial testing was carried out on Gram-negative (Escherichia coli) and Gram-positive (Baccilus Cereus) bacteria in the presence and absence of biological medium. The efficacy of the hollow hemispherical particles functionalized with various N-chloramines in killing bacteria was compared among themselves with that of small organic molecules and spherical particles to investigate the effect of the surface charge, chemical structure, and shape of the particles. Results demonstrated that quaternary ammonium salt or amine functions in the chemical structure enhanced the antimicrobial activity of the particles and made the particles more effective than the small molecules in the presence of biological medium. The importance of particle shape in the killing tests was also confirmed.

  4. The role of intrinsic motivation in a group of low vision patients participating in a self-management programme to enhance self-efficacy and quality of life.

    PubMed

    Tay, Kay Chai Peter; Drury, Vicki Blair; Mackey, Sandra

    2014-02-01

    Self-management programmes have previously been found to decrease health problems, enhance quality of life and increase independence. However, there is no literature that examines the influence of the participants' intrinsic motivation on the outcomes of such programmes. This study examined the role of intrinsic motivation in a pilot low vision self-management programme to enhance self-efficacy and quality of life of the programme participants. A positive association was observed between the female participants' perceived choice and perceived competence, two underlying dimensions of the Intrinsic Motivation Inventory. In addition, a positive correlation was observed between the younger participants' perceived competence and the change in their quality of life. The findings provide some support for consideration of participants' intrinsic motivation in the development of effective self-management programmes.

  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. Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues.

    PubMed

    Zhu, Charles; Bandekar, Amey; Sempkowski, Michelle; Banerjee, Sangeeta Ray; Pomper, Martin G; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2016-01-01

    This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of α-particle emitters by using different radionuclide carriers in the setting of targeted antivascular α-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the α-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four α-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of α-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of α-particle emitters.

  7. Nanoconjugation of PSMA-targeting ligands enhances perinuclear localization and improves efficacy of delivered alpha-particle emitters against tumor endothelial analogues

    PubMed Central

    Sempkowski, Michelle; Banerjee, Sangeeta Ray; Pomper, Martin G.; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2015-01-01

    This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of alpha-particle emitters by using different radionuclide carriers in the setting of targeted antivascular alpha-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific-membrane-antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the alpha-particle generator actinium-225 and were compared to a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four alpha-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb), and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of DNA double strand breaks per nucleus of treated cells compared to the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus increase the probability of alpha-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of alpha-particle emitters. PMID:26586724

  8. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy.

    PubMed

    Yeku, Oladapo O; Brentjens, Renier J

    2016-04-15

    Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the 'armor' agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.

  9. Induction of Indoleamine 2,3-dioxygenase by Pre-treatment with Poly(I:C) May Enhance the Efficacy of MSC Treatment in DSS-induced Colitis

    PubMed Central

    Ryu, Da-Bin; Lim, Ji-Young; Lee, Sung-Eun; Park, Gyeongsin

    2016-01-01

    Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly owing to their immunosuppressive properties. The goal of the study was to determine whether TLR ligands can enhance the therapeutic efficacy of bone marrow-derived MSCs for the treatment of inflammatory bowel disease. Mice (C57BL6) were administered with 4% dextran sulfate sodium (DSS) in drinking water for 7 days and injected with MSCs on days 1 and 3 following DSS ingestion. Our results demonstrated that among various TLR ligands, MSCs treated with polyinosinic-polycytidylic acid [poly(I:C)], which is a TLR3 ligand, more profoundly induced IDO, which is a therapeutically relevant immunosuppressive factor, without any observable phenotype change in vitro. The poly(I:C)-treated MSCs attenuated the pathologic severity of DSS-induced murine colitis when injected i.p. but not i.v. In summary, preconditioning MSCs with poly(I:C) might improve their efficacy in treating DSS-induced colitis, and this effect at least partly depends on the enhancement of their immunosuppressive activity through increasing their production of IDO. PMID:28035211

  10. C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer.

    PubMed

    Rapp, Moritz; Grassmann, Simon; Chaloupka, Michael; Layritz, Patrick; Kruger, Stephan; Ormanns, Steffen; Rataj, Felicitas; Janssen, Klaus-Peter; Endres, Stefan; Anz, David; Kobold, Sebastian

    2016-03-01

    T cell infiltration at the tumor site has been identified as a major predictor for the efficacy of adoptive T cell therapy. The chemokine C-C motif ligand 22 (CCL22) is highly expressed by immune cells in murine and human pancreatic cancer. Expression of its corresponding receptor, C-C chemokine receptor type 4 (CCR4), is restricted to regulatory T cells (Treg). We show that transduction of cytotoxic T cells (CTL) with CCR4 enhances their immigration into a pancreatic cancer model. Further, we show that binding of CCR4 with CCL22 strengthens the binding of T cell LFA-1 to dendritic cell (DC) ICAM-1 and increases CTL activation. In vivo, in a model of subcutaneous pancreatic cancer, treatment of tumor-bearing mice with CCR4-transduced CTL led to the eradication of established tumors in 40% of the mice. In conclusion, CCR4 overexpression in CTL is a promising therapeutic strategy to enhance the efficacy of adoptive T cell transfer (ACT).

  11. Poly-γ-glutamic acid/chitosan nanogel greatly enhances the efficacy and heterosubtypic cross-reactivity of H1N1 pandemic influenza vaccine

    PubMed Central

    Yang, Jihyun; Shim, Sang-Mu; Nguyen, Thi Quyen; Kim, Eun-Ha; Kim, Kwang; Lim, Yong Taik; Sung, Moon-Hee; Webby, Richard; Poo, Haryoung

    2017-01-01

    In 2009, the global outbreak of an influenza pandemic emphasized the need for an effective vaccine adjuvant. In this study, we examined the efficacy of poly-γ-glutamic acid/chitosan (PC) nanogel as an adjuvant for the influenza vaccine. PC nanogel significantly enhanced antigen-specific cross-presentation and cytotoxic T lymphocyte (CTL) activity. Compared with alum, the protective efficacy of the pandemic H1N1 influenza (pH1N1) vaccine was substantially increased by PC nanogel, with increased hemagglutination-inhibition titers, CTL activity, and earlier virus clearance after homologous and heterosubtypic [A/Philippines/2/82 (H3N2)] virus challenges. However, CD8+ T cell-depleted mice displayed no protection against the heterosubtypic virus challenge after immunization with PC nanogel-adjuvanted pH1N1 vaccine. We also observed that using PC nanogel as a vaccine adjuvant had a dose-sparing effect and significantly enhanced the long-lasting protection of the pH1N1 vaccine. Together, these results suggest that PC nanogel is a promising vaccine adjuvant that could broadly prevent influenza virus infection. PMID:28322289

  12. Enhanced Efficacy of 5-Fluorouracil in Combination with a Dual Histone Deacetylase and Phosphatidylinositide 3-Kinase Inhibitor (CUDC-907) in Colorectal Cancer Cells

    PubMed Central

    Hamam, Rimi; Ali, Dalia; Vishnubalaji, Radhakrishnan; Alsaaran, Zaid F.; Chalisserry, Elna Paul; Alfayez, Musaad; Aldahmash, Abdullah; Alajez, Nehad M.

    2017-01-01

    Background/Aims: 5-Fluorouracil (5-FU) is widely used in the treatment of patients with colorectal cancer (CRC). However, the efficacy of 5-FU as a single agent is limited, with multiple undesired side effects. Therefore, the aim of the current study was to assess the efficacy of CUDC-907 (a dual inhibitor of histone deacetylase and phosphatidylinositide 3-kinase) in combination with 5-FU against CRC cells. Materials and Methods: Cell viability was determined using AlamarBlue and colony formation assays. Acridine orange/ethidium bromide staining and flow cytometry were used to measure apoptotic and necrotic events, as well as cell cycle progression. Immunoblotting was used to assess acetylation of histone H3 and phosphorylation of AKT. Results: Our data revealed enhanced toxicity of CUDC-907 against HCT116, RKO, COLO-205, and HT-29 CRC cells when combined with 5-FU. Similarly, the colony formation capability of HCT116 cells was suppressed by the combination treatment. Cells treated with CUDC-907 and 5-FU underwent apoptosis and necrosis, and exhibited increased polyploidy. Furthermore, CRC cells treated with CUDC-907 exhibited a higher degree of histone H3 lysine 9 acetylation (H3K9ac) and reduced AKT phosphorylation (Ser473). Conclusion: Our data revealed, for the first time, the enhanced inhibitory effect of CUDC-907 against CRC cells when combined with 5-FU, supporting the application of this combination as a potential therapeutic strategy in CRC treatment. PMID:28139498

  13. Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

    PubMed Central

    Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

    2015-01-01

    Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

  14. Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.

    PubMed

    Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa; Leng, Yan; Liao, Hsiao-Mei; Maric, Dragan; Chuang, De-Maw

    2016-07-01

    Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells

  15. The combination of Pleurotus ferulae water extract and CpG-ODN enhances the immune responses and antitumor efficacy of HPV peptides pulsed dendritic cell-based vaccine.

    PubMed

    Li, Jinyu; Li, Jinyao; Aipire, Adila; Luo, JiaoJiao; Yuan, Pengfei; Zhang, Fuchun

    2016-06-30

    Our previous study reported that the combination of Pleurotus ferulae water extract (PFWE) and CpG (PFWE+CpG) enhanced the maturation and function of dendritic cells (DCs). Here, we investigated the effects of PFWE+CpG on the immune responses and antitumor efficacy of DC-based vaccine. We observed that all of HPV E6 and E7 peptides pulsed DCs (HPV-immature DCs, HPV+PFWE-, +CpG- or +PFWE+CpG-DCs) induced antigen-specific CD8(+) T cell responses and HPV+PFWE+CpG-DCs induced highest level of CD8(+) T cell responses. The antitumor efficacy of HPV-DCs vaccines was evaluated in TC-1 tumor mouse model. The early therapeutic study showed that HPV+PFWE-, +CpG- and +PFWE+CpG-DCs greatly inhibited tumor growth. Moreover, HPV+PFWE+CpG-DCs controlled tumor growth at a faster rate compared to other groups. These three groups induced HPV-specific CD8(+) T cell responses and significantly decreased the frequencies of induced regulatory T cells (iTregs: CD4(+)CD25(-)Fopx3(+)). However, only HPV+PFWE+CpG-DCs significantly decreased the frequency of natural Tregs (nTregs: CD4(+)CD25(+)Fopx3(+)). Furthermore, HPV+PFWE+CpG-DCs also significantly inhibited tumor growth in the late therapeutic study. The results showed that PFWE+CpG enhanced the immune responses and antitumor efficacy of DC-based vaccine, suggesting that PFWE+CpG might be the potential candidate for the generation of clinical-grade mature DCs.

  16. Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction.

    PubMed

    Han, Sang-Oh; Ronzitti, Giuseppe; Arnson, Benjamin; Leborgne, Christian; Li, Songtao; Mingozzi, Federico; Koeberl, Dwight

    2017-03-17

    Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 10(11) vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 × 10(10) vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA-mediated tolerogenic gene therapy in Pompe disease mice.

  17. Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcome drug resistance in myeloid leukemia

    PubMed Central

    Agarwal, Anupriya; MacKenzie, Ryan J.; Pippa, Raffaella; Eide, Christopher A.; Oddo, Jessica; Tyner, Jeffrey W.; Sears, Rosalie; Vitek, Michael P.; Odero, María D.; Christensen, Dale; Druker, Brian J.

    2014-01-01

    Purpose The SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A. Experimental Design In vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis and colonogenic assays. Efficacy of target inhibition by OP449 is evaluated by immunoblotting and PP2A assay. In vivo antitumor efficacy of OP449 was measured in human HL-60 xenografted murine model. Results We observed that OP449 inhibited growth of CML cells including those from patients with blastic phase disease and patients harboring highly drug-resistant BCR-ABL1 mutations. Combined treatment with OP449 and ABL1 tyrosine kinase inhibitors was significantly more cytotoxic to K562 cells and primary CD34+ CML cells. SET protein levels remained unchanged with OP449 treatment, but BCR-ABL1-mediated downstream signaling was significantly inhibited with the degradation of key signaling molecules such as BCR-ABL1, STAT5, and AKT. Similarly, AML cell lines and primary patient samples with various genetic lesions showed inhibition of cell growth after treatment with OP449 alone or in combination with respective kinase inhibitors. Finally, OP449 reduced the tumor burden of mice xenografted with human leukemia cells. Conclusions We demonstrate a novel therapeutic paradigm of SET antagonism using OP449 in combination with tyrosine kinase inhibitors for the treatment of CML and AML. PMID:24436473

  18. TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models

    PubMed Central

    Tougan, Takahiro; Aoshi, Taiki; Coban, Cevayir; Katakai, Yuko; Kai, Chieko; Yasutomi, Yasuhiro; Ishii, Ken J.; Horii, Toshihiro

    2013-01-01

    The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine. PMID:23291928

  19. EFFICACY OF COMMERCIAL INOCULA IN ENHANCING BIODEGRADATION OF WEATHERED CRUDE OIL CONTAMINATING A PRINCE WILLIAM SOUND BEACH

    EPA Science Inventory

    In a laboratory study evaluating the effectiveness of 10 commercial products in stimulating enhanced biodegradation of Alaska North Slope crude oil, two of the products provided significantly greater alkane degradation in closed flasks than indigenous Alaskan bacterial population...

  20. Ascorbic acid enhances oxidative stress tolerance and biological control efficacy of Pichia caribbica against postharvest blue mold decay of apples.

    PubMed

    Li, Chaolan; Zhang, Hongyin; Yang, Qiya; Komla, Mahunu Gustav; Zhang, Xiaoyun; Zhu, Shuyun

    2014-07-30

    The effect of ascorbic acid (VC) on improving oxidative stress tolerance of Pichia caribbica and biocontrol efficacy against blue mold caused by Penicillium expansum on apples was investigated. P. caribbica showed susceptibility to the oxidative stress in vitro test, and 250 μg/mL VC treatment improved its oxidative stress tolerance. The higher viability exhibited by VC-treated yeast was associated with a lower intracellular ROS level. The activities of antioxidant enzymes of P. caribbica were improved by VC treatment, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Additionally, VC-treated yeast exhibited greater biocontrol activity against P. expansum and faster growth when stored at 25 and 4 °C, respectively, compared to the performance of the non-VC-treated yeast. In response to the VC treatment under oxidative stress, several differentially expressed proteins were identified in P. caribbica, and most of the poteins were confirmed to be related to basic metabolism. Therefore, the application of ascorbic acid is a useful approach to improve oxidative stress tolerance of P. caribbica and its biocontrol efficacy on apples.

  1. Synergistic Enhancement of Antitumor Efficacy by PEGylated Multi-walled Carbon Nanotubes Modified with Cell-Penetrating Peptide TAT

    NASA Astrophysics Data System (ADS)

    Hu, Shanshan; Wang, Tong; Pei, Xibo; Cai, He; Chen, Junyu; Zhang, Xin; Wan, Qianbing; Wang, Jian

    2016-10-01

    In the present study, a cell-penetrating peptide, the transactivating transcriptional factor (TAT) domain from HIV, was linked to PEGylated multi-walled carbon nanotubes (MWCNTs) to develop a highly effective antitumor drug delivery system. FITC was conjugated on MWCNTs-polyethylene glycol (PEG) and MWCNTs-PEG-TAT to provide fluorescence signal for tracing the cellular uptake of the nanocarrier. After loaded with an anticancer agent, doxorubicin (DOX) via π - π stacking interaction, the physicochemical characteristics, release profile and biological evaluation of the obtained nano-sized drug carrier were investigated. The DOX loaded MWCNTs-PEG and MWCNTs-PEG-TAT drug carriers both displayed appropriate particle size, excellent stability, high drug loading, and pH-dependent drug release profile. Nevertheless, compared with DOX-MWCNTs-PEG, DOX-MWCNTs-PEG-TAT showed improved cell internalization, intracellular distribution and potentiated anticancer efficacy due to the TAT-mediated membrane translocation, endosomal escape and nuclear targeting. Furthermore, the therapeutic efficacy of DOX was not compromised after being conjugated with MWCNTs-PEG-TAT and the proposed nanocarrier was also confirmed to have a good biocompatibility. In conclusion, our results suggested that the unique combination of TAT and MWCNTs as a multifunctional drug delivery system might be a powerful tool for improved anticancer drug development.

  2. Novel Multiarm Polyethylene glycol-Dihydroartemisinin Conjugates Enhancing Therapeutic Efficacy in Non-Small-Cell Lung Cancer

    PubMed Central

    Dai, Lin; Wang, Luying; Deng, Lihong; Liu, Jing; Lei, Jiandu; Li, Dan; He, Jing

    2014-01-01

    The clinical application of dihydroartemisinin (DHA) has been hampered due to its poor water-solubility. To overcome this hurdle, we devised a novel polymer-drug conjugate, multiarm polyethylene glycol-dihydroartemisinin (PEG-DHA), made by linking DHA with multiarm polyethylene glycol. Herein, we investigated PEG-DHA on chemical structure, hydrolysis, solubility, hemolysis, cell cytotoxicity in vitro, and efficacy in vivo. The PEG-DHA conjugates have showed moderate drug loadings (2.82 ~ 8.14 wt%), significantly good water-solubilities (82- ~ 163-fold of DHA), excellent in vitro anticancer activities (at concentrations ≥8 μg/ml, showed only 15–20% cell viability) with potency similar to that of native DHA, and long blood circulation half-time (5.75- ~ 16.75-fold of DHA). Subsequent tumor xenograft assays demonstrated a superior therapeutic effect of PEG-DHA on inhibition of tumor growth compared with native DHA. The novel PEG-DHA conjugates can not only improve the solubility and efficacy of DHA but also show the potential of scale-up production and clinical application. PMID:25070490

  3. Novel Multiarm Polyethylene glycol-Dihydroartemisinin Conjugates Enhancing Therapeutic Efficacy in Non-Small-Cell Lung Cancer

    NASA Astrophysics Data System (ADS)

    Dai, Lin; Wang, Luying; Deng, Lihong; Liu, Jing; Lei, Jiandu; Li, Dan; He, Jing

    2014-07-01

    The clinical application of dihydroartemisinin (DHA) has been hampered due to its poor water-solubility. To overcome this hurdle, we devised a novel polymer-drug conjugate, multiarm polyethylene glycol-dihydroartemisinin (PEG-DHA), made by linking DHA with multiarm polyethylene glycol. Herein, we investigated PEG-DHA on chemical structure, hydrolysis, solubility, hemolysis, cell cytotoxicity in vitro, and efficacy in vivo. The PEG-DHA conjugates have showed moderate drug loadings (2.82 ~ 8.14 wt%), significantly good water-solubilities (82- ~ 163-fold of DHA), excellent in vitro anticancer activities (at concentrations >=8 μg/ml, showed only 15-20% cell viability) with potency similar to that of native DHA, and long blood circulation half-time (5.75- ~ 16.75-fold of DHA). Subsequent tumor xenograft assays demonstrated a superior therapeutic effect of PEG-DHA on inhibition of tumor growth compared with native DHA. The novel PEG-DHA conjugates can not only improve the solubility and efficacy of DHA but also show the potential of scale-up production and clinical application.

  4. Cystathionine-β-Synthase Inhibition for Colon Cancer: Enhancement of the Efficacy of Aminooxyacetic Acid via the Prodrug Approach

    PubMed Central

    Chao, Celia; Zatarain, John R; Ding, Ye; Coletta, Ciro; Mrazek, Amy A; Druzhyna, Nadiya; Johnson, Paul; Chen, Haiying; Hellmich, Judy L; Asimakopoulou, Antonia; Yanagi, Kazunori; Olah, Gabor; Szoleczky, Petra; Törö, Gabor; Bohanon, Fredrick J; Cheema, Minal; Lewis, Rachel; Eckelbarger, David; Ahmad, Akbar; Módis, Katalin; Untereiner, Ashley; Szczesny, Bartosz; Papapetropoulos, Andreas; Zhou, Jia; Hellmich, Mark R; Szabo, Csaba

    2016-01-01

    Colon cancer cells contain high levels of cystathionine-β-synthase (CBS). Its product, hydrogen sulfide (H2S), promotes the growth and proliferation of colorectal tumor cells. To improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory

  5. Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy.

    PubMed

    Mahran, Rama I; Hagras, Magda M; Sun, Duxin; Brenner, Dean E

    2017-01-01

    Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.

  6. Efficacy and durability of hyaluronic acid fillers for malar enhancement: a prospective, randomized, spilt-face clinical controlled trial.

    PubMed

    Jeong, Ki Heon; Gwak, Min Jae; Moon, Sung Kyung; Lee, Sang Jun; Shin, Min Kyung

    2017-01-31

    Various hyaluronic acid fillers can be used for facial attenuation and rejuvenation. The efficacy and durability of hyaluronic acid fillers are of major concern to dermatologists and patients. This study aimed to evaluate three dimensional morphology, tissue distribution, and changes in volume after injection of two different hyaluronic acid fillers. Ten Korean women were enrolled in this study. Each subject was injected with monophasic hyaluronic acid filler in one malar area and biphasic filler in the other. Clinical outcome was measured before and after injection, and after 2, 4, 6, 8, 12, and 24 weeks, using the Global Aesthetic Improvement Scale, photographs and Moire's topography. Facial magnetic resonance imaging (MRI) was performed twice over six months. Both products showed good results after injection and demonstrated good durability over time. MRI was a useful modality for assessing tissue distribution and volume changes. The effects and durability after injection of monophasic hyaluronic acid filler and biphasic hyaluronic acid filler are generally comparable.

  7. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides

    PubMed Central

    Sun, Jiawei; Jiang, Lei; Lin, Yi; Gerhard, Ethan Michael; Jiang, Xuehua; Li, Li; Yang, Jian; Gu, Zhongwei

    2017-01-01

    Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity. PMID:28280323

  8. Enhanced Protective Efficacy of Nonpathogenic Recombinant Leishmania tarentolae Expressing Cysteine Proteinases Combined with a Sand Fly Salivary Antigen

    PubMed Central

    Taheri, Tahereh; Taslimi, Yasaman; Doustdari, Fatemeh; Seyed, Negar; Torkashvand, Fatemeh; Meneses, Claudio; Papadopoulou, Barbara; Kamhawi, Shaden; Valenzuela, Jesus G.; Rafati, Sima

    2014-01-01

    Background Novel vaccination approaches are needed to prevent leishmaniasis. Live attenuated vaccines are the gold standard for protection against intracellular pathogens such as Leishmania and there have been new developments in this field. The nonpathogenic to humans lizard protozoan parasite, Leishmania (L) tarentolae, has been used effectively as a vaccine platform against visceral leishmaniasis in experimental animal models. Correspondingly, pre-exposure to sand fly saliva or immunization with a salivary protein has been shown to protect mice against cutaneous leishmaniasis. Methodology/Principal Findings Here, we tested the efficacy of a novel combination of established protective parasite antigens expressed by L. tarentolae together with a sand fly salivary antigen as a vaccine strategy against L. major infection. The immunogenicity and protective efficacy of different DNA/Live and Live/Live prime-boost vaccination modalities with live recombinant L. tarentolae stably expressing cysteine proteinases (type I and II, CPA/CPB) and PpSP15, an immunogenic salivary protein from Phlebotomus papatasi, a natural vector of L. major, were tested both in susceptible BALB/c and resistant C57BL/6 mice. Both humoral and cellular immune responses were assessed before challenge and at 3 and 10 weeks after Leishmania infection. In both strains of mice, the strongest protective effect was observed when priming with PpSP15 DNA and boosting with PpSP15 DNA and live recombinant L. tarentolae stably expressing cysteine proteinase genes. Conclusion/Significance The present study is the first to use a combination of recombinant L. tarentolae with a sand fly salivary antigen (PpSP15) and represents a novel promising vaccination approach against leishmaniasis. PMID:24675711

  9. Marine-Derived Quorum-Sensing Inhibitory Activities Enhance the Antibacterial Efficacy of Tobramycin against Pseudomonas aeruginosa

    PubMed Central

    Busetti, Alessandro; Shaw, George; Megaw, Julianne; Gorman, Sean P.; Maggs, Christine A.; Gilmore, Brendan F.

    2014-01-01

    Bacterial epiphytes isolated from marine eukaryotes were screened for the production of quorum sensing inhibitory compounds (QSIs). Marine isolate KS8, identified as a Pseudoalteromonas sp., was found to display strong quorum sensing inhibitory (QSI) activity against acyl homoserine lactone (AHL)-based reporter strains Chromobacterium violaceum ATCC 12472 and CV026. KS8 supernatant significantly reduced biofilm biomass during biofilm formation (−63%) and in pre-established, mature P. aeruginosa PAO1 biofilms (−33%). KS8 supernatant also caused a 0.97-log reduction (−89%) and a 2-log reduction (−99%) in PAO1 biofilm viable counts in the biofilm formation assay and the biofilm eradication assay respectively. The crude organic extract of KS8 had a minimum inhibitory concentration (MIC) of 2 mg/mL against PAO1 but no minimum bactericidal concentration (MBC) was observed over the concentration range tested (MBC > 16 mg/mL). Sub-MIC concentrations (1 mg/mL) of KS8 crude organic extract significantly reduced the quorum sensing (QS)-dependent production of both pyoverdin and pyocyanin in P. aeruginosa PAO1 without affecting growth. A combinatorial approach using tobramycin and the crude organic extract at 1 mg/mL against planktonic P. aeruginosa PAO1 was found to increase the efficacy of tobramycin ten-fold, decreasing the MIC from 0.75 to 0.075 µg/mL. These data support the validity of approaches combining conventional antibiotic therapy with non-antibiotic compounds to improve the efficacy of current treatments. PMID:25546516

  10. Targeting the glyoxalase pathway enhances TRAIL efficacy in cancer cells by downregulating the expression of antiapoptotic molecules.

    PubMed

    Taniguchi, Hiroya; Horinaka, Mano; Yoshida, Tatsushi; Yano, Kimihiro; Goda, Ahmed E; Yasuda, Shusuke; Wakada, Miki; Sakai, Toshiyuki

    2012-10-01

    Methylglyoxal is an essential component in glycolysis and is known to be an inducer of apoptosis. Glyoxalase I (GLO1) metabolizes and inactivates methylglyoxal. GLO1 is known to be overexpressed in cancer cells and causes resistance to anticancer agents. We show for the first time that methylglyoxal treatment or the silencing of GLO1 enhances sensitivity to the promising anticancer agent TRAIL in malignant tumor cells. Methylglyoxal suppressed the expression of antiapoptotic factors, X-linked inhibitor of apoptosis protein (XIAP), survivin, cIAP1, Bcl-2, and Bcl-xL, without affecting TRAIL receptors, DR4 and DR5. Knockdown of XIAP or survivin by siRNA also enhanced TRAIL-induced apoptosis, indicating that downregulation of XIAP and survivin expression by methylglyoxal contributes to the enhancement of TRAIL activity. Furthermore, methylglyoxal decreased NF-κB activity with or without TRAIL treatment. On the other hand, the knockdown of GLO1 by siRNA enhanced TRAIL-induced apoptosis via the downregulation of XIAP and survivin expression. In conclusion, our results strongly suggest that sensitivity to TRAIL is increased by inhibition of the glyoxalase pathway and that the combination of TRAIL with methylglyoxal or glyoxalase inhibitors may be useful for a novel combination chemotherapy.

  11. The Efficacy of Consulting Practicum in Enhancing Students' Readiness for Professional Career in Management Information Systems: An Empirical Analysis

    ERIC Educational Resources Information Center

    Akpan, Ikpe Justice

    2016-01-01

    Consulting practicum (CP) is a form of experiential learning technique to prepare students for professional careers. While CP has become a popular way to help students acquire the essential practical skills and experience to enhance career readiness and ensure a smooth transition from college to employment, there is a lack of empirical studies…

  12. Silencing of Foxp3 enhances the antitumor efficacy of GM-CSF genetically modified tumor cell vaccine against B16 melanoma

    PubMed Central

    Miguel, Antonio; Sendra, Luis; Noé, Verónica; Ciudad, Carles J; Dasí, Francisco; Hervas, David; Herrero, María José; Aliño, Salvador F

    2017-01-01

    The antitumor response after therapeutic vaccination has a limited effect and seems to be related to the presence of T regulatory cells (Treg), which express the immunoregulatory molecules CTLA4 and Foxp3. The blockage of CTLA4 using antibodies has shown an effective antitumor response conducing to the approval of the human anti-CTLA4 antibody ipilimumab by the US Food and Drug Administration. On the other hand, Foxp3 is crucial for Treg development. For this reason, it is an attractive target for cancer treatment. This study aims to evaluate whether combining therapeutic vaccination with CTLA4 or Foxp3 gene silencing enhances the antitumor response. First, the “in vitro” cell entrance and gene silencing efficacy of two tools, 2′-O-methyl phosphorotioate-modified oligonucleotides (2′-OMe-PS-ASOs) and polypurine reverse Hoogsteen hairpins (PPRHs), were evaluated in EL4 cells and cultured primary lymphocytes. Following B16 tumor transplant, C57BL6 mice were vaccinated with irradiated B16 tumor cells engineered to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and were intraperitoneally treated with CTLA4 and Foxp3 2′-OMe-PS-ASO before and after vaccination. Tumor growth, mice survival, and CTLA4 and Foxp3 expression in blood cells were measured. The following results were obtained: 1) only 2′-OMe-PS-ASO reached gene silencing efficacy “in vitro”; 2) an improved survival effect was achieved combining both therapeutic vaccine and Foxp3 antisense or CTLA4 antisense oligonucleotides (50% and 20%, respectively); 3) The blood CD4+CD25+Foxp3+ (Treg) and CD4+CTLA4+ cell counts were higher in mice that developed tumor on the day of sacrifice. Our data showed that tumor cell vaccine combined with Foxp3 or CTLA4 gene silencing can increase the efficacy of therapeutic antitumor vaccination. PMID:28176947

  13. Social support seeking and self-efficacy-building strategies in enhancing the emotional well-being of informal HIV/AIDS caregivers in Ibadan, Oyo state, Nigeria.

    PubMed

    Okeke, Bernedette Okwuchukwu

    2016-01-01

    This study examined the relative efficacy of social support seeking (SSS) and self-efficacy building (SEB) in the management of emotional well-being of caregivers of people suffering from HIV/AIDS. It was based at the United States President's Emergency Plan for AIDS Relief (PEPFAR) center in the University College Hospital, Ibadan, Oyo state, being the first and the largest teaching hospital in Nigeria. A 3 × 2 factorial design consisting of treatment and a control group was used. The columns have two levels of gender being male and female caregivers. One-hundred and sixty-five (165) caregivers who were taking care of people that are suffering from HIV/AIDS were purposively selected and randomly assigned to the treatment groups and control. The treatment was carried out for a period of eight weeks. Two null hypotheses were tested, both at .05 levels of significance. Data were collected with the use of standardized intruments rating scale; social support scale, general self-efficacy scale and emotional well-being scale. ANCOVA was used to establish significant treatment effects with the pretest as covariate. Even though SSS and SEB were both found to be effective in enhancing the emotional well-being of informal caregivers in this study when compared to the controls, SSS was significantly more effective than SEB in achieving this goal. Since the HIV/AIDS patients cannot be adequately cared for in the hospital settings due to severe shortages of material, personnel and time, serious efforts should be made by the three levels of the health care system viz: the primary, secondary and tertiary health care systems, to encourage the employment of the psychological management of caregivers of people suffering from HIV/AIDS. Also, the psychologists, clinical psychologists and the significant others should be encouraged to employ this psychological management in the care of HIV/AIDS informal caregivers.

  14. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

    PubMed

    Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

    2013-10-01

    Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high

  15. Efficacy of Standard Versus Enhanced Features in a Web-Based Commercial Weight-Loss Program for Obese Adults, Part 2: Randomized Controlled Trial

    PubMed Central

    Morgan, Philip J; Hutchesson, Melinda J; Callister, Robin

    2013-01-01

    Background Commercial Web-based weight-loss programs are becoming more popular and increasingly refined through the addition of enhanced features, yet few randomized controlled trials (RCTs) have independently and rigorously evaluated the efficacy of these commercial programs or additional features. Objective To determine whether overweight and obese adults randomized to an online weight-loss program with additional support features (enhanced) experienced a greater reduction in body mass index (BMI) and increased usage of program features after 12 and 24 weeks compared to those randomized to a standard online version (basic). Methods An assessor-blinded RCT comparing 301 adults (male: n=125, 41.5%; mean age: 41.9 years, SD 10.2; mean BMI: 32.2 kg/m2, SD 3.9) who were recruited and enrolled offline, and randomly allocated to basic or enhanced versions of a commercially available Web-based weight-loss program for 24 weeks. Results Retention at 24 weeks was greater in the enhanced group versus the basic group (basic 68.5%, enhanced 81.0%; P=.01). In the intention-to-treat analysis of covariance with imputation using last observation carried forward, after 24 weeks both intervention groups had reductions in key outcomes with no difference between groups: BMI (basic mean –1.1 kg/m2, SD 1.5; enhanced mean –1.3 kg/m2, SD 2.0; P=.29), weight (basic mean –3.3 kg, SD 4.7; enhanced mean –4.0 kg, SD 6.2; P=.27), waist circumference (basic mean –3.1 cm, SD 4.6; enhanced mean –4.0 cm, SD 6.2; P=.15), and waist-to-height ratio (basic mean –0.02, SD 0.03; enhanced mean –0.02, SD 0.04, P=.21). The enhanced group logged in more often at both 12 and 24 weeks, respectively (enhanced 12-week mean 34.1, SD 28.1 and 24-week mean 43.1, SD 34.0 vs basic 12-week mean 24.6, SD 25.5 and 24-week mean 31.8, SD 33.9; P=.002). Conclusions The addition of personalized e-feedback in the enhanced program provided limited additional benefits compared to a standard commercial Web

  16. Montanide IMS 1312 VG adjuvant enhances the efficacy of immersion vaccine of inactivated viral hemorrhagic septicemia virus (VHSV) in olive flounder, Paralichthys olivaceus.

    PubMed

    Hwang, Jee Youn; Kwon, Mun-Gyeong; Kim, Yu Jin; Jung, Sung-Hee; Park, Myoung-Ae; Son, Maeng-Hyun

    2017-01-01

    Vaccination by immersion is suitable for mass vaccination of small size fish. However, no viral vaccine has been developed for immersion applications, because of low efficacy. In this study, we evaluated the efficacy and safety of immersion vaccine against viral hemorrhagic septicemia (VHS) containing Montanide IMS 1312 VG adjuvant in olive flounder (Paralichthys olivaceus). Healthy fish were vaccinated by an immersion method with a heat-inactivated FP-VHS2010-1 strain of VHS virus (VHSV) in combination with Montanide IMS 1312 VG for 5 min at 20 ± 2 °C. The control group was vaccinated with sterile PBS. No toxicity of immersion vaccine with Montanide IMS 1312 VG adjuvant was observed by hematological and histopathological analysis. Immersion vaccine with adjuvant enhanced gene expression of immune-associated genes, i.e., genes encoding interleukin (IL)-1β, IL-6, IL-8, and Toll-like receptor (TLR) 3. Relative percent survival (RPS) of fish was measured on weeks 4 and 8 post vaccination. In fish vaccinated with adjuvant, RPS was significantly higher than that of fish vaccinated without adjuvant. The results of the present study provide evidence that the VHSV immersion vaccine with Montanide IMS 1312 VG induces protective immunity in olive flounder against VHS.

  17. Strontium-doped calcium polyphosphate/ultrahigh molecular weight polyethylene composites: A new class of artificial joint components with enhanced biological efficacy to aseptic loosening.

    PubMed

    Gu, Zhipeng; Huang, Bingxue; Li, Yiwen; Tian, Meng; Li, Li; Yu, Xixun

    2016-04-01

    To enhance implant stability and prolong the service life of artificial joint component, a new approach was proposed to improve the wear resistance of artificial joint component and endow artificial joint component with the biological efficacy of resistance to aseptic loosening. Strontium calcium polyphosphate (SCPP) were interfused in ultrahigh molecular weight polyethylene (UHMWPE) by a combination of liquid nitrogen ball-milling and flat-panel curing process to prepare the SCPP/UHMWPE composites. The micro-structure, mechanical characterization, tribological characterization and bioactivities of various SCPP/UHMWPE composites were investigated. The results suggested that this method could statistically improve the wear resistance of UHMWPE resulting from a good SCPP particle dispersion. Moreover, it is also observed that the SCPP/UHMWPE composites-wear particles could promote the production of OPG by osteoblasts and decrease the production of RANKL by osteoblasts, and then increase the OPG/RANKL ratio. This indicated that the SCPP/UHMWPE composites had potential efficacy to prevent and treat aseptic loosening. Above all, the SCPP/UHMWPE composites with a suitable SCPP content would be the promising materials for fabricating artificial joint component with ability to resist aseptic loosening.

  18. Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains

    PubMed Central

    Wang, Su; Doughtry, Julie; Xie, Jinfu; Miezeiewski, Matt; Rustandi, Richard R.; Horton, Melanie; Xoconostle, Rachel; Wang, Bei; Lancaster, Catherine; Kristopeit, Adam; Wang, Sheng-Ching; Christanti, Sianny; Vitelli, Salvatore; Gentile, Marie-Pierre; Goerke, Aaron; Skinner, Julie; Strable, Erica; Thiriot, David S.; Bodmer, Jean-Luc; Heinrichs, Jon H.

    2017-01-01

    Clostridium difficile infections (CDI) are a leading cause of nosocomial diarrhea in the developed world. The main virulence factors of the bacterium are the large clostridial toxins (LCTs), TcdA and TcdB, which are largely responsible for the symptoms of the disease. Recent outbreaks of CDI have been associated with the emergence of hypervirulent strains, such as NAP1/BI/027, many strains of which also produce a third toxin, binary toxin (CDTa and CDTb). These hypervirulent strains have been associated with increased morbidity and higher mortality. Here we present pre-clinical data describing a novel tetravalent vaccine composed of attenuated forms of TcdA, TcdB and binary toxin components CDTa and CDTb. We demonstrate, using the Syrian golden hamster model of CDI, that the inclusion of binary toxin components CDTa and CDTb significantly improves the efficacy of the vaccine against challenge with NAP1 strains in comparison to vaccines containing only TcdA and TcdB antigens, while providing comparable efficacy against challenge with the prototypic, non-epidemic strain VPI10463. This combination vaccine elicits high neutralizing antibody titers against TcdA, TcdB and binary toxin in both hamsters and rhesus macaques. Finally we present data that binary toxin alone can act as a virulence factor in animal models. Taken together, these data strongly support the inclusion of binary toxin in a vaccine against CDI to provide enhanced protection from epidemic strains of C. difficile. PMID:28125650

  19. Determination of efficacy of fingermark enhancement reagents; the use of propyl chloroformate for the derivatization of fingerprint amino acids extracted from paper.

    PubMed

    Mink, Tineke; Voorhaar, Annelies; Stoel, Reinoud; de Puit, Marcel

    2013-09-01

    The analysis of the constituents of fingerprints has been described numerous times, mainly with the purpose of determining the aging effect on fingerprints or showing the differences between donors or groups of donors. In this paper we describe the use of derivatized amino acids to determine the efficacy of the visualization reagents 1,8-diazafluoren-9-one (DFO) and ninhydrin. At present certain conditions are used for the application of these reagents, as determined by trial-and-error investigations, to the effect on fingerprints. The recovery of amino acids from a porous surface can be used as a measure for the efficacy of a visualization agent. In this paper we describe a method for the determination of the amount of amino acid left after reaction with well known fingerprint visualization reagents. This will allow a more scientific approach to method development for fingermark enhancement techniques. Furthermore, investigations on the influence of the concentration of fingermark amino acids, the order of application of and exposure time to reagents and the influence of age of the amino acids were carried out. These studies have resulted in a broader understanding of the mechanism involved in visualization of fingermarks using DFO and ninhydrin.

  20. Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.

    PubMed

    Secore, Susan; Wang, Su; Doughtry, Julie; Xie, Jinfu; Miezeiewski, Matt; Rustandi, Richard R; Horton, Melanie; Xoconostle, Rachel; Wang, Bei; Lancaster, Catherine; Kristopeit, Adam; Wang, Sheng-Ching; Christanti, Sianny; Vitelli, Salvatore; Gentile, Marie-Pierre; Goerke, Aaron; Skinner, Julie; Strable, Erica; Thiriot, David S; Bodmer, Jean-Luc; Heinrichs, Jon H

    2017-01-01

    Clostridium difficile infections (CDI) are a leading cause of nosocomial diarrhea in the developed world. The main virulence factors of the bacterium are the large clostridial toxins (LCTs), TcdA and TcdB, which are largely responsible for the symptoms of the disease. Recent outbreaks of CDI have been associated with the emergence of hypervirulent strains, such as NAP1/BI/027, many strains of which also produce a third toxin, binary toxin (CDTa and CDTb). These hypervirulent strains have been associated with increased morbidity and higher mortality. Here we present pre-clinical data describing a novel tetravalent vaccine composed of attenuated forms of TcdA, TcdB and binary toxin components CDTa and CDTb. We demonstrate, using the Syrian golden hamster model of CDI, that the inclusion of binary toxin components CDTa and CDTb significantly improves the efficacy of the vaccine against challenge with NAP1 strains in comparison to vaccines containing only TcdA and TcdB antigens, while providing comparable efficacy against challenge with the prototypic, non-epidemic strain VPI10463. This combination vaccine elicits high neutralizing antibody titers against TcdA, TcdB and binary toxin in both hamsters and rhesus macaques. Finally we present data that binary toxin alone can act as a virulence factor in animal models. Taken together, these data strongly support the inclusion of binary toxin in a vaccine against CDI to provide enhanced protection from epidemic strains of C. difficile.

  1. Influence of penetration enhancers and molecular weight in antifungals permeation through bovine hoof membranes and prediction of efficacy in human nails.

    PubMed

    Miron, D; Cornelio, R; Troleis, J; Mariath, J; Zimmer, A R; Mayorga, P; Schapoval, E E S

    2014-01-23

    This work aimed to evaluate the effect of different substances on the permeation of geraniol through bovine hoof membranes. Different penetration enhancers were able to increase the permeability up to 25 times compared to control. It was demonstrated that acetilcysteine in association with ascorbic acid increased the permeation, even in acid formulations. In addition, some antifungal drugs were incorporated into a gel formulation of HPMC containing acetylcysteine 5% and ascorbic acid 0.2% and then the permeation coefficient through bovine hoof membranes was evaluated. The relationship between permeability and molecular weight was established for fluconazole, miconazole, terbinafine, butenafine, geraniol and nerol. Geraniol and nerol, the antifungals with lower molecular weight, had the better permeability results. Permeability coefficients for nail plates were estimated and geraniol demonstrated similar or even better efficacy index values against T. rubrum, T. menthagrophytes and M. canis compared with terbinafine and miconazole.

  2. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

    DOE PAGES

    Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; ...

    2015-05-16

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6chi Ly6g₋monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection inmore » tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6chi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8+ T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.« less

  3. Oncolytic Adenoviral Mutants with E1B19K Gene Deletions Enhance Gemcitabine-induced Apoptosis in Pancreatic Carcinoma Cells and Anti-Tumor Efficacy In vivo

    PubMed Central

    Leitner, Stephan; Sweeney, Katrina; Öberg, Daniel; Davies, Derek; Miranda, Enrique; Lemoine, Nick R.; Halldén, Gunnel

    2010-01-01

    Purpose Pancreatic adenocarcinoma is a rapidly progressive malignancy that is highly resistant to current chemotherapeutic modalities and almost uniformly fatal.We show that a novel targeting strategy combining oncolytic adenoviral mutants with the standard cytotoxic treatment, gemcitabine, can markedly improve the anticancer potency. Experimental Design Adenoviral mutants with the E1B19K gene deleted with and without E3B gene expression (AdΔE1B19K and dl337 mutants, respectively) were assessed for synergistic interactions in combination with gemcitabine. Cell viability, mechanism of cell death, and antitumor efficacy in vivo were determined in the pancreatic carcinoma cells PT45 and Suit2, normal human bronchial epithelial cells, and in PT45 xenografts. Results The ΔE1B19K-deleted mutants synergized with gemcitabine to selectively kill cultured pancreatic cancer cells and xenografts in vivo with no effect in normal cells. The corresponding wild-type virus (Ad5) stimulated drug-induced cell killing to a lesser degree. Gemcitabine blocked replication of all viruses despite the enhanced cell killing activity due to gemcitabine-induced delay in G1/S-cell cycle progression, with repression of cyclin E and cdc25A, which was not abrogated by viral E1A-expression. Synergistic cell death occurred through enhancement of gemcitabine-induced apoptosis in the presence of both AdΔE1B19K and dl337 mutants, shown by increased cell membrane fragmentation, caspase-3 activation, and mitochondrial dysfunction. Conclusions Our data suggest that oncolytic mutants lacking the antiapoptotic E1B19K gene can improve efficacy of DNA-damaging drugs such as gemcitabine through convergence on cellular apoptosis pathways.These findings imply that less toxic doses than currently practicedin the clinic could efficiently target pancreatic adenocarcinomas when combined with adenoviral mutants. PMID:19223497

  4. Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate

    PubMed Central

    Calderon-Aparicio, Ali; Strasberg-Rieber, Mary; Rieber, Manuel

    2015-01-01

    Highlights exogenous SOD increases apoptosis by sub-toxic disulfiram without copper overload H2O2 generation from glucose oxidase also potentiates disulfiram toxicity N-acetylcysteine suppresses antitumor potentiation of DSF by H2O2 generation sub-toxic tetrathiomolybdate inhibits potentiation of DSF by SOD Background Cu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (•OH) by the Fenton reaction. Purpose To investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM) Results a) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF. Conclusions potentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non

  5. Efficacy of whey protein gel networks as potential viability-enhancing scaffolds for cell immobilization of Lactobacillus rhamnosus GG.

    PubMed

    Doherty, S B; Gee, V L; Ross, R P; Stanton, C; Fitzgerald, G F; Brodkorb, A

    2010-03-01

    This study investigated cell immobilization of Lactobacillus rhamnosus GG in three separate protein products: native, denatured and hydrolysed whey protein isolate (WPI). Treatments were assessed for their ability to enhance probiotic survival during storage, heat stress and ex vivo gastric incubation. Spatial distribution of probiotic cells within immobilized treatments was evaluated by atomic force and confocal scanning laser microscopy, while cell viability was enumerated by plate count and flow cytometry (FACS). Microscopic analysis of denatured treatments revealed an oasis of immobilized cells, phase-separated from the surrounding protein matrix; an environmental characteristic analogous to hydrolysed networks. Cell immobilization in hydrolysed and denatured WPI enhanced survival by 6.1+/-0.1 and 5.8+/-0.1 log10 cycles, respectively, following 14 day storage at 37 degrees C and both treatments generated thermal protection at 57 degrees C (7.3+/-0.1 and 6.5+/-0.1 log(10) cfu/ml). Furthermore, denatured WPI enhanced probiotic protection (8.9+/-0.2 log(10) cfu/ml) following 3h gastric incubation at 37 degrees C. In conclusion, hydrolysed or denatured WPI were the most suitable matrices for cell immobilization, while native protein provided the weakest safeguard against thermal and acid stress, thus making it possible to envision whey protein gel networks as protective substrates for cell immobilization applications.

  6. Immunotoxins Constructed with Ribosome-Inactivating Proteins and their Enhancers: A Lethal Cocktail with Tumor Specific Efficacy

    PubMed Central

    Gilabert-Oriol, Roger; Weng, Alexander; von Mallinckrodt, Benedicta; Melzig, Matthias F; Fuchs, Hendrik; Thakur, Mayank

    2014-01-01

    The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origin, which have N-glycosidase enzymatic activity leading to a complete destruction of the ribosomal function. The discovery of the RIPs was almost a century ago, but their usage has seen transition only in the last four decades. With the advent of antibody therapy, the RIPs have been a subject of extensive research especially in targeted tumor therapies, which is the primary focus of this review. In the present work we enumerate 250 RIPs, which have been identified so far. An attempt has been made to identify all the RIPs that have been used for the construction of immunotoxins, which are conjugates or fusion proteins of an antibody or ligand with a toxin. The data from 1960 onwards is reviewed in this paper and an extensive list of more than 450 immunotoxins is reported. The clinical reach of tumor-targeted toxins has been identified and detailed in the work as well. While there is a lot of potential that RIPs embrace for targeted tumor therapies, the success in preclinical and clinical evaluations has been limited mainly because of their inability to escape the endo/lysosomal degradation. Various strategies that can increase the efficacy and lower the required dose for targeted toxins have been compiled in this article. It is plausible that with the advancements in platform technologies or improved endosomal escape the usage of tumor targeted RIPs would see the daylight of clinical success. PMID:25341935

  7. Synthetic Toll-like receptor 4 agonist enhances vaccine efficacy in an experimental model of toxic shock syndrome.

    PubMed

    Morefield, Garry L; Hawkins, Lynn D; Ishizaka, Sally T; Kissner, Teri L; Ulrich, Robert G

    2007-11-01

    The development of new protein subunit vaccines has stimulated the search for improved adjuvants to replace traditional aluminum-containing products. We investigated the adjuvant effects of a synthetic Toll-like receptor 4 (TLR4) agonist on vaccine efficacy in an experimental model of toxic shock syndrome. The TLR4 agonist E6020 has a simplified structure consisting of a hexa-acylated acyclic backbone. The vaccine examined is a recombinantly attenuated form of staphylococcal enterotoxin B (STEBVax). Using cells stably transfected with TLRs, E6020 transduced signals only through TLR4, suggesting monospecificity, while Escherichia coli 055:B5 lipopolysaccharide activated both the TLR2/6 heterodimer and TLR4. Coadministration of E6020 with STEBVax, by the intramuscular or intranasal route, induced significant levels of immunoglobulin G (IgG) in BALB/c mice. Further, increased IgG production resulted from the combination of E6020 with aluminum hydroxide adjuvant (AH). The antibody response to the vaccine coadministered with E6020 was a mixed Th1/Th2 response, as opposed to the Th2-biased response obtained with AH. Mice vaccinated with STEBVax coadministered with AH, TLR4 agonists, or a combination of both adjuvants were protected from toxic shock. Our data demonstrate the effectiveness of the synthetic TLR4 agonist E6020 as an alternative adjuvant for protein subunit vaccines that may also be used in combination with traditional aluminum-containing adjuvants.

  8. Targeting of cancer-associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment

    PubMed Central

    LI, MINMIN; LI, MEI; YIN, TAO; SHI, HUASHAN; WEN, YUAN; ZHANG, BINGLAN; CHEN, MEIHUA; XU, GUANGCHAO; REN, KEXIN; WEI, YUQUAN

    2016-01-01

    Cancer-associated fibroblasts (CAFs), key components of the tumor stroma, can regulate tumorigenesis by altering the tumor microenvironment in variety of ways to promote angiogenesis, recruit inflammatory immune cells and remodel the extracellular matrix. Using a murine xenograft model of colon carcinoma, the present study observed that oxaliplatin increased the accumulation of CAFs and stimulated the production of cytokines associated with CAFs. When oxaliplatin was combined with the small-molecule dipeptidyl peptidase inhibitor PT-100, which inhibits CAFs by targeting fibroblast activation protein (FAP), the accumulation of CAFs was markedly reduced, xenograft tumor growth was significantly suppressed and the survival of the mice increased, compared to those of mice treated with oxaliplatin or PT-100 alone. Furthermore, the xenograft tumor tissues of mice treated with oxaliplatin and PT-100 contained lower numbers of tumor-associated macrophages and dendritic cells, expressed lower levels of cytokines associated with CAFs and had a lower density of CD31+ endothelial cells. The present study demonstrated that pharmacological inhibition of CAFs improved the response to chemotherapy, reduced the recruitment of immune tumor-promoting cells and inhibited angiogenesis. Combining chemotherapy with agents which target CAFs may represent a novel strategy for improving the efficacy of chemotherapy and reducing chemoresistance. PMID:26846566

  9. Fish oil supplementation enhanced CPT-11 (irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated intestinal side-effects

    PubMed Central

    Hardman, W E; Moyer, M P; Cameron, I L

    1999-01-01

    The cancer chemotherapeutic efficacy of the topoisomerase I inhibitor, CPT-11 (irinotecan) is often limited by the induction of severe delayed diarrhoea. In animal studies, CPT-11 use is associated with histopathological damage to the mucosa of the small and large intestines. Results from the present study demonstrate that 60 mg CPT-11 per kg body weight (i.v. q4d × 6) halted the growth, but did not cause significant regression, of MCF7 human breast carcinoma xenografts in mice fed a diet containing 7% corn oil. However, when the diet of the MCF7-bearing mice was supplemented with 3% or 6% fish oil, the same CPT-11 treatment caused significant regression of the MCF7 xenograft. Histomorphometric analyses of intestinal mucosa of mice treated with CPT-11 and fed the diet containing 7% corn oil indicated that treatment with CPT-11 induced structural changes in the intestinal mucosa which persisted at least 5 days after the last dose of CPT-11. The intestinal mucosal architecture of mice that were treated with CPT-11 and fed the diets containing fish oil was largely unchanged from the architecture of the group of mice which did not receive CPT-11. These findings indicate that fish oil supplements may be a useful adjunct to CPT-11 treatment. © 1999 Cancer Research Campaign PMID:10507768

  10. Enhanced anti-cancer efficacy on lymph node metastasis using peplomycin adsorbed on small activated carbon particles.

    PubMed

    Ito, M; Hagiwara, A; Iwamoto, A; Shimotsuma, M; Yoneyama, C; Sasabe, T; Takahashi, T

    1991-07-01

    A new dosage form (PEP-CH) of peplomycin was tested for therapeutic efficacy against lymph node metastasis in mice. PEP-CH is a suspension comprising 4 mg/ml of activated carbon, 2 mg/ml of peplomycin and 1.6 mg/ml of polyvinylpyrrolidone in saline. Mice were subcutaneously inoculated with 3 x 10(5) MH134 tumor cells into the left hind paw. Drugs were given on day 10 when cancer had been metastasized in the left popliteal lymph node. Mice were killed on day 17 and the left popliteal lymph node and the left deep inguinal lymph node were extirpated. Since the degree of the metastatic lesion and the lymph node weight correlated with a statistically high probability with each other, the degree of metastatic lesion was evaluated through comparison of lymph node weight. The left popliteal lymph node and the deep inguinal lymph node were 10.5 mg and 4.5 mg in average weight, respectively, in the mice given PEP-CH containing 0.1 mg of peplomycin subcutaneously into the left hind foot-pad. The weights were significantly smaller than those in the mice given an identical dose of peplomycin aqueous solution subcutaneously into the left hind foot-pad or intraperitoneally.

  11. Coadministration of black seeds and turmeric shows enhanced efficacy in preventing metabolic syndrome in fructose-fed rats.

    PubMed

    Amin, Faridah; Gilani, Anwarul-Hassan; Mehmood, Malik Hassan; Siddiqui, Bina S; Khatoon, Nasima

    2015-02-01

    Among noncommunicable diseases, metabolic syndrome (MS), a cluster of metabolic disorders including obesity, hyperglycemia, hyperlipidemia and hypertension, is highly prevalent in modern society. Its management requires lifestyle modifications and/or the life-long use of multiple medications, hence demanding development of safe alternative remedies. This study was aimed to establish the efficacy of combined use of black seeds and turmeric using fructose-fed rat model of MS. The high-performance liquid chromatographic fingerprints of turmeric and black seeds showed the presence of curcumin and thymoquinone, respectively, as their major constitutes. Different doses of black seeds and turmeric, individually and in combination, were administered to fructose-fed rats for up to 6 weeks representing characteristic features of MS. At 3 weeks of the treatment, black seeds and turmeric lowered (P < 0.01) high blood pressure and low-density lipoprotein cholesterol, respectively, whereas their coadministration reduced (P < 0.01) both high blood pressure and hypertriglyceridemia. At 6 weeks, the coadministration of both herbs, at half the doses of individual herbs, was the most effective (P < 0.001) in preventing hypertension, hyperglycemia, dyslipidemia, hyperinsulinemia, and endothelial dysfunction than the individual herbs. This study demonstrates the therapeutic superiority of the combination of black seeds and turmeric at low doses over individually tested herbs, in improving features of MS.

  12. Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

    PubMed Central

    Huang, Zhizhou; Zhou, Xueqiong; He, Yangfan; Ke, Xiangyu; Wen, Ying; Zou, Fei; Chen, Xuemei

    2016-01-01

    Due to the lack of effective treatment, hepatocellular carcinoma (HCC) is one of the malignancies with low survival rates worldwide. Combination of hyperthermia and chemotherapy has shown promising results in several abdominal tumours, but high expression of HSP90 in tumours attenuated the efficacy of hyperthermia. Thus a combination of hyperthermia and inhibition of HSP90 might be a feasible therapeutic strategy for HCC. One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). HCC cells of the combination group exhibited more G2/M arrest and higher apoptotic rates which might result from suffering from more reactive oxygen species and serious DNA damage. Heat shock/17-DMAG co-treatment of HCC cells also destabilized CDK1, Cyclin B1 and CDC25C with a concomitant decreased proportion of cells in the M phase. Furthermore, co-treatment impaired the interaction of HSP90α with CDC37 and with CDK1, accompanied with decreased soluble CDK1. Combination of 17-DMAG with a 1.5-h whole body hyperthermia treatment attenuated tumour growth in xenograft mice models. These results suggest hyperthermia sensitize HCC to 17-DMAG, and combination of hyperthermia with 17-DMAG might be a potential therapeutic strategy for HCC. PMID:27909289

  13. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

    PubMed Central

    Liu, Zuqiang; Ravindranathan, Roshni; Kalinski, Pawel; Guo, Z. Sheng; Bartlett, David L.

    2017-01-01

    Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1+ cells and facilitates non-redundant tumour infiltration of effector CD8+, CD4+ T cells, with increased IFN-γ, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1+CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients. PMID:28345650

  14. Subtype-specific binding peptides enhance the therapeutic efficacy of nanomedicine in the treatment of ovarian cancer.

    PubMed

    Shen, Yao-An; Liu, Chang-Sheng; Chang, Yen-Hou; Chen, Po-Hung; He, Chun-Lin; Wu, Han-Chung; Chuang, Chi-Mu

    2015-04-28

    Currently, epithelial ovarian cancer is viewed as a heterogeneous disease with five major histological subtypes. Clear cell carcinoma represents a specific histological subtype of epithelial ovarian cancer that demonstrates more aggressive clinical behavior and drug resistance compared with other subtypes. Nevertheless, clear cell carcinoma is treated in the same manner as the other subtypes without any particular consideration to its unique clinical characteristics. To improve the therapeutic efficacy of the current liposomal doxorubicin approach for the treatment of clear cell carcinoma, we aimed to develop a novel peptide-conjugated liposomal doxorubicin to actively target this subtype. Two phage clones (OC-6 and OC-26) that specifically bound to clear cell carcinoma were isolated from a phage peptide display library after biopanning procedures. The peptide sequences were translated and aligned (OCSP-6 for OC-6, and OCSP-26 for OC-26, respectively). Peptide-conjugated nanoparticles demonstrated better tumor endocytosis and time-dependent gradual increase of intracellular drug uptake than non-targeting liposomal nanoparticles. Furthermore, peptide-conjugated liposomal doxorubicin better controlled tumors than did non-targeting liposomal doxorubicin. The current work may pave a new way for the development of drugs that target each subtype of epithelial ovarian cancer in the future.

  15. Targeting of cancer‑associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment.

    PubMed

    Li, Minmin; Li, Mei; Yin, Tao; Shi, Huashan; Wen, Yuan; Zhang, Binglan; Chen, Meihua; Xu, Guangchao; Ren, Kexin; Wei, Yuquan

    2016-03-01

    Cancer‑associated fibroblasts (CAFs), key components of the tumor stroma, can regulate tumorigenesis by altering the tumor microenvironment in variety of ways to promote angiogenesis, recruit inflammatory immune cells and remodel the extracellular matrix. Using a murine xenograft model of colon carcinoma, the present study observed that oxaliplatin increased the accumulation of CAFs and stimulated the production of cytokines associated with CAFs. When oxaliplatin was combined with the small‑molecule dipeptidyl peptidase inhibitor PT‑100, which inhibits CAFs by targeting fibroblast activation protein (FAP), the accumulation of CAFs was markedly reduced, xenograft tumor growth was significantly suppressed and the survival of the mice increased, compared to those of mice treated with oxaliplatin or PT‑100 alone. Furthermore, the xenograft tumor tissues of mice treated with oxaliplatin and PT‑100 contained lower numbers of tumor‑associated macrophages and dendritic cells, expressed lower levels of cytokines associated with CAFs and had a lower density of CD31+ endothelial cells. The present study demonstrated that pharmacological inhibition of CAFs improved the response to chemotherapy, reduced the recruitment of immune tumor‑promoting cells and inhibited angiogenesis. Combining chemotherapy with agents which target CAFs may represent a novel strategy for improving the efficacy of chemotherapy and reducing chemoresistance.

  16. Chief Joseph Kokanee Enhancement Project; Strobe Light Deterrent Efficacy Test and Fish Behavior Determination at the Grand Coulee Dam Third Powerplant Forebay, 2004-2005 Annual Report.

    SciTech Connect

    Johnson, R.; McKinstry, C.; Cook, C.

    2005-02-01

    This report documents a four-year study(a) to assess the efficacy of a prototype strobe light system to elicit a negative phototactic response in kokanee (Oncorhynchus nerka kennerlyi) and rainbow trout (O. mykiss) at the entrance to the forebay of the third powerplant at Grand Coulee Dam. The work was conducted for the Bonneville Power Administration, U.S. Department of Energy, by Pacific Northwest National Laboratory (PNNL) in conjunction with the Confederated Tribes of the Colville Reservation (Colville Confederated Tribes). In this report, emphasis is placed on the methodology and results associated with the fourth project year and compared with findings from the previous years to provide an overall project summary. Since 1995, the Colville Confederated Tribes have managed the Chief Joseph Kokanee Enhancement Project as part of the Northwest Power and Conservation Council Fish and Wildlife Program. Project objectives have focused on understanding natural production of kokanee (a land-locked sockeye salmon) and other fish stocks in the area above Grand Coulee and Chief Joseph dams on the Columbia River (Figure S.1). A 42-month investigation from 1996 to 1999 determined that from 211,685 to 576,676 fish, including kokanee and rainbow trout, were entrained annually at Grand Coulee Dam. Analysis of the data found that 85% of the total entrainment occurred at the dam's third powerplant. Because these entrainment rates represent a significant loss to the tribal fisheries upstream of the dam, they have been judged unacceptable to fishery managers responsible for perpetuating the fishery in Lake Roosevelt. In an effort to reduce fish entrainment rates, the scope of work for the Chief Joseph Kokanee Enhancement Project was modified in 2001 to include a multiyear study of the efficacy of using strobe lights to deter fish from entering the third powerplant forebay. Pacific Northwest National Laboratory initiated the four-year study in collaboration with Colville Tribal

  17. Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells

    PubMed Central

    Thakur, Asmitananda; Zhang, Shuo; Wang, Ting; Liang, Yiqian; Shi, Puyu; Gao, Lei; Liu, Feng; Feng, Jing; Chen, Tianjun; Yang, Tian; Shang, Dong; Liu, Johnson J.; Xu, Feng; Chen, Mingwei

    2016-01-01

    NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120's growth-inhibitory activity. BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, predominantly in cell lines insensitive to BKM120, thereby inducing autophagy. The presence of lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II. BKM120 combined with chloroquine, enhanced growth-inhibitory effects including induction of apoptosis, suggesting that autophagy is a protective mechanism counteracting BKM120's growth-inhibitory activity. Interestingly, BKM120 increased p-ERK1/2 levels. When blocking the activation of this signaling with MEK inhibitors or with knockdown of ERK1/2, the ability of BKM120 to increase LC3-II was attenuated and the growth-inhibitory effects including induction of apoptosis were accordingly enhanced, suggesting that the MEK/ERK activation contributes to BKM120-induced authophagy. In mouse xenograft model, we also found that the combination of BKM120 and PD0325901 synergistically suppressed cell growth in human lung cancer cells. Thus, the current study not only reveals mechanisms accounting for BKM120-induced autophagy, but also suggests an alternative method to enhance BKM120's therapeutic efficacy against non-small cell lung cancer(NSCLC) by blocking autophagy with either a lysosomal protease inhibitor or MEK inhibitor. PMID:27572309

  18. Racial Differences in Selective Laser Trabeculoplasty Efficacy

    PubMed Central

    Goosen, Emil; Coleman, Kate; Visser, Linda

    2017-01-01

    ABSTRACT Aim Sub-Saharan Africa has a population of 1 billion, with one ophthalmologist per million people. Basic ophthalmic support services are virtually absent for all but a few urban populations. Minimally invasive laser treatment may help. This study reports our initial experience using selective laser trabeculoplasty (SLT) in a mixed-racial population of adult glaucoma patients in Durban, South Africa. Study design Institution Review Board approved the 5-year chart review. Materials and methods Consecutive glaucomatous adults underwent SLT (Lumenis Selecta) on one or both eyes applying 360° treatment of 120 to 140 closely spaced burns (400 urn spot size for 3 ns; range 1.1-1.4 mJ). Significance of change in intraocuar pressure (IOP) from baseline at 1, 3, 6, and 12 months was assessed by two-tailed paired t-test. Results Among 148 eyes of 84 patients (60 African, 21 Indian, 3 Caucasian), 69 had already undergone glaucoma therapy, and 15 untreated (de novo). Among all eyes, mean IOP was reduced by >32% with mean IOP < 15 mm Hg from baseline at all four study intervals (p < 0.0001). A 20% reduction in IOP was sustained at 12 months in 90% of African eyes but in only 50% of Indian eyes. Conclusion Selective laser trabeculoplasty was effective in producing clinically significant IOP reduction among South African adults with or without prior medical or surgical anti-glaucoma therapy. Socioeconomically comparable individuals of Indian ancestry showed good therapeutic responses, but significantly less efficacious than those observed among Black subjects. Programs to provide first-line SLT management of glaucoma in Africa, where 90% of patients are unable to sustain prescribed medical therapy, appear to be a very appropriate option. How to cite this article Goosen E, Coleman K, Visser L, Sponsel WE. Racial Differences in Selective Laser Trabeculoplasty Efficacy. J Curr Glaucoma Pract 2017;11(1):22-27. PMID:28138214

  19. Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study

    PubMed Central

    Cai, Xiao-Hong; Yao, Wen-Xiu; Xu, Yong; Liu, Xiao-Ke; Zhu, Wen-Jiang; Wang, Yan; Zhou, Jin; Lu, You; Wang, Yong-Sheng

    2016-01-01

    Background Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. Methods Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. Results Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). Conclusions Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases. PMID:26624882

  20. N-bromotaurine surrogates for loss of antiproliferative response and enhances cisplatin efficacy in cancer cells with impaired glucocorticoid receptor.

    PubMed

    Logotheti, Stella; Khoury, Nikolas; Vlahopoulos, Spiros A; Skourti, Elena; Papaevangeliou, Dimitra; Liloglou, Triantafyllos; Gorgoulis, Vassilis; Budunova, Irina; Kyriakopoulos, Anthony M; Zoumpourlis, Vassilis

    2016-07-01

    Glucocorticoids (GCs) are frequently used in anticancer combination regimens; however, their continuous use adds selective pressure on cancer cells to develop GC-resistance via impairment of the glucocorticoid receptor (GR), therefore creating a need for GC-alternatives. Based on the drug repurposing approach and the commonalities between inflammation and neoplasia, drugs that are either in late-stage clinical trials and/or already marketed for GC-refractory inflammatory diseases could be evaluated as GC-substitutes in the context of cancer. Advantageously, unlike new molecular entities currently being de novo developed to restore GC-responsiveness of cancer cells, such drugs have documented safety and efficacy profile, which overall simplifies their introduction in clinical cancer trials. In this study, we estimated the potential of a well-established, multistage, cell line-based, mouse skin carcinogenesis model to be exploited as an initial screening tool for unveiling covert GC-substitutes. First, we categorized the cell lines of this model to GC-sensitive and GC-resistant, in correlation with their corresponding GR status, localization, and functionality. We found that GC-resistance starts in papilloma stages, due to a dysfunctional GR, which is overexpressed, DNA binding-competent, but transactivation-incompetent in papilloma, squamous, and spindle stages of the model. Then, aided by this tool, we evaluated the ability of N-bromotaurine, a naturally occurring, small-molecule, nonsteroid anti-inflammatory drug which is under consideration for use interchangeably/in replacement to GCs in skin inflammations, to restore antiproliferative response of GC-resistant cancer cells. Unlike GCs, N-bromotaurine inhibited cell-cycle progression in GC-resistant cancer cells and efficiently synergized with cisplatin, thus indicating a potential to be exploited instead of GCs against cancer.

  1. A micronutrient-fortified food enhances iron and selenium status of Zambian infants but has limited efficacy on zinc.

    PubMed

    Gibson, Rosalind S; Kafwembe, Emmanuel; Mwanza, Sydney; Gosset, Laura; Bailey, Karl B; Mullen, Anne; Baisley, Kathy; Filteau, Suzanne

    2011-05-01

    Micronutrient-fortified, cereal-based infant foods are recommended for reducing multiple micronutrient deficiencies in low-income countries, but their nutritional quality is not always optimal. In a double-blind randomized trial, we compared the efficacy of a locally produced porridge based on maize, beans, bambaranuts, and groundnuts fortified with 19 (rich) or 9 (basal) micronutrients. Infants aged 6 mo from Lusaka, Zambia were randomized to receive the richly fortified (n = 373) or basal (n = 370) porridge daily for 12 mo along with routine vitamin A supplements. Baseline and final micronutrient status and inflammation (based on α-1-glycoprotein) were assessed using nonfasting blood samples. Baseline prevalence of anemia (39%) and zinc deficiency (51%) were a public health concern. There were overall treatment effects on hemoglobin (Hb) (P = 0.001), serum transferrin receptor (P < 0.001), serum ferritin (P < 0.001), and serum selenium (P = 0.009); biomarker responses for iron and zinc were modified by baseline concentrations, and for Hb and iron by socioeconomic status. At 18 mo, the adjusted odds of anemia, iron deficiency anemia (Hb <105 g/L and transferrin receptor > 11.0 mg/L), and iron deficiency were 0.37 (95% CI = 0.25, 0.55), 0.18 (0.09, 0.35), and 0.30 (0.18, 0.50) times those in the basal group, respectively. The rich level of fortification had no overall treatment effect on serum zinc (1.09; 0.66, 1.80) but improved serum zinc in children with lower Hb concentrations at baseline (P = 0.024). A locally produced cereal- and legume-based infant food richly fortified with micronutrients reduced anemia and improved iron and selenium status but may require reformulation to improve the biochemical zinc status of urban Zambian infants.

  2. Long-Term Efficacy of Methylphenidate in Enhancing Attention Regulation, Social Skills, and Academic Abilities of Childhood Cancer Survivors

    PubMed Central

    Conklin, Heather M.; Reddick, Wilburn E.; Ashford, Jason; Ogg, Susan; Howard, Scott C.; Morris, E. Brannon; Brown, Ronald; Bonner, Melanie; Christensen, Robbin; Wu, Shengjie; Xiong, Xiaoping; Khan, Raja B.

    2010-01-01

    Purpose Methylphenidate (MPH) ameliorates attention problems experienced by some cancer survivors in the short term, but its long-term efficacy is unproven. Patients and Methods This study investigates the long-term effectiveness of maintenance doses of MPH in survivors of childhood brain tumors (n = 35) and acute lymphoblastic leukemia (n = 33) participating in a 12-month MPH trial. Measures of attention (Conners' Continuous Performance Test [CPT], Conners' Rating Scales [CRS]), academic abilities (Wechsler Individual Achievement Test [WIAT]), social skills (Social Skills Rating System [SSRS]), and behavioral problems (Child Behavior Checklist [CBCL]) were administered at premedication baseline and at the end of the MPH trial while on medication. A cancer control group composed of patients who were not administered MPH (brain tumor = 31 and acute lymphoblastic leukemia = 23) was assessed on the same measures 2 months apart. Results For the MPH group, repeated measures analysis of variance revealed significant improvement in performance on a measure of sustained attention (CPT indices, P < .05); parent, teacher, and self-report ratings of attention (CRS indices, P < .05), and parent ratings of social skills or behavioral problems (SSRS and CBCL indices; P < .05). In contrast, the cancer control group only showed improvement on parent ratings of attention (Conners' Parent Rating Scale indices; P < .05) and social skills (SSRS and CBCL indices; P < .05). There was no significant improvement on the academic measure (WIAT) in either group. Conclusion Attention and behavioral benefits of MPH for childhood cancer survivors are maintained across settings over the course of a year. Although academic gains were not identified, MPH may offer benefits in academic areas not assessed. PMID:20837955

  3. An Adenoviral Vaccine Encoding Full-Length Inactivated Human HER2 Exhibits Potent Immunogenicty and Enhanced Therapeutic Efficacy Without Oncogenicity

    PubMed Central

    Hartman, Zachary; Wei, Junping; Osada, Takuya; Glass, Oliver; Lei, Gangjun; Yang, Xiao-Yi; Peplinski, Sharon; Kim, Dong-Wan; Xia, Wenle; Spector, Neil; Marks, Jeffrey; Barry, William; Hobeika, Amy; Devi, Gayathri; Amalfitano, Andrea; Morse, Michael A.; Lyerly, H. Kim; Clay, Timothy M.

    2010-01-01

    Purpose Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in imunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use. Experimental Design We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM) and full length HER2 inactivated for kinase function (Ad-HER2-ki) and determined their immunogenicity and anti-tumor effect in wild type (WT) and HER2 tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo. Results Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. And, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage independent growth and were not transformed in vivo. Conclusions Vaccination with mutationally inactivated, non-oncogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective anti-tumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials. PMID:20179231

  4. Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma.

    PubMed

    Guo, Weiwei; Yan, Lichong; Yang, Ling; Liu, Xiaoyu; E, Qiukai; Gao, Peiye; Ye, Xiaofei; Liu, Wen; Zuo, Ji

    2014-01-01

    Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.

  5. The efficacy of the enhanced Aussie Optimism Positive Thinking Skills Program in improving social and emotional learning in middle childhood.

    PubMed

    Myles-Pallister, Jacqueline D; Hassan, Sharinaz; Rooney, Rosanna M; Kane, Robert T

    2014-01-01

    The aim of the current study was to investigate the effects of the modified and enhanced Aussie Optimism Positive Thinking Skills Program (AO-PTS) on Year 4 and 5 children's social and emotional learning (SEL) skills. AO-PTS is a universal-school based program that is implemented by class teachers as part of regular school curricula and was developed for the prevention of depression and anxiety. The study comprised a total of 683 Year 4 and 5 students from 10 private primary schools in Western Australia. Students were assessed on two subscales of emotional attribution at school whilst parents reported on their children's externalizing and internalizing problems outside of school and at home. Two analyses were conducted: seven intervention schools were assessed at pre- and post-test (Analysis 1) and pre-post change in three intervention schools were compared to pre-post change in three matched control schools (Analysis 2). Results from Analysis 1 showed that the intervention children had increased in their overall emotional attribution accuracy and decreased in total difficulties and hyperactivity; Results from Analysis 2 revealed no intervention effect on emotional attribution accuracy or internalizing or externalizing problems. These findings suggest that the enhanced AO-PTS's effects on SEL were not evident in the short-term period after intervention. The non-significant findings and future directions for AO-PTS research and program modification were discussed.

  6. High therapeutic efficacy of Cathelicidin-WA against postweaning diarrhea via inhibiting inflammation and enhancing epithelial barrier in the intestine

    PubMed Central

    Yi, Hongbo; Zhang, Lin; Gan, Zhenshun; Xiong, Haitao; Yu, Caihua; Du, Huahua; Wang, Yizhen

    2016-01-01

    Diarrhea is a leading cause of death among young mammals, especially during weaning. Here, we investigated the effects of Cathelicidin-WA (CWA) on diarrhea, intestinal morphology, inflammatory responses, epithelial barrier and microbiota in the intestine of young mammals during weaning. Piglets with clinical diarrhea were selected and treated with saline (control), CWA or enrofloxacin (Enro) for 4 days. Both CWA and Enro effectively attenuated diarrhea. Compared with the control, CWA decreased IL-6, IL-8 and IL-22 levels and reduced neutrophil infiltration into the jejunum. CWA inhibited inflammation by down-regulating the TLR4-, MyD88- and NF-κB-dependent pathways. Additionally, CWA improved intestinal morphology by increasing villus and microvillus heights and enhancing intestinal barrier function by increasing tight junction (TJ) protein expression and augmenting wound-healing ability in intestinal epithelial cells. CWA also improved microbiota composition and increased short-chain fatty acid (SCFA) levels in feces. By contrast, Enro not only disrupted the intestinal barrier but also negatively affected microbiota composition and SCFA levels in the intestine. In conclusion, CWA effectively attenuated inflammation, enhanced intestinal barrier function, and improved microbiota composition in the intestines of weaned piglets. These results suggest that CWA could be an effective and safe therapy for diarrhea or other intestinal diseases in young mammals. PMID:27181680

  7. Triterpene-loaded microemulsion using Coix lacryma-jobi seed extract as oil phase for enhanced antitumor efficacy: preparation and in vivo evaluation.

    PubMed

    Qu, Ding; He, Junjie; Liu, Congyan; Zhou, Jing; Chen, Yan

    2014-01-01

    Ganoderma lucidum triterpene-loaded microemulsions (TMEs) using Coix lacryma-jobi (adlay) seed oil as oil phase were prepared, characterized, and evaluated for enhanced antitumor activity. Ternary phase diagrams for the TMEs were constructed and the optimal preparation was developed. Transmission electron microscopy and dynamic light scattering showed that this formulation had a well defined spherical shape, a homogeneous distribution, a small size, and a narrow polydispersity index. The drug-loading rate was determined to be 9.87% by ultraviolet spectrophotometry, and acceptable stability under various stimulations in vitro was confirmed. Importantly, the TME formulation showed a significantly greater antiproliferative effect towards human lung carcinoma (A549) cells and murine lung tumor (Lewis) cells in comparison with suspension formulations containing triterpene and adlay seed oil as a positive control. The half-maximal inhibitory concentration of the TMEs was about 0.62 mg crude drug per mL, being 2.5-fold improved relative to that of the corresponding suspension formulation, but no significant cytotoxicity was observed for the bare microemulsion in A549 cells and Lewis cells. In vivo, the TME formulation showed markedly enhanced antitumor efficacy in a xenograft model of Lewis lung cancer after intragastric administration. Compared with cyclophosphamide, the TME formulation showed similar antitumor activity but less general toxicity. These results indicate the feasibility of using a microemulsion to increase the solubility of triterpene and adlay. TMEs hold promise as an efficient drug delivery system for the treatment of lung cancer.

  8. Triterpene-loaded microemulsion using Coix lacryma-jobi seed extract as oil phase for enhanced antitumor efficacy: preparation and in vivo evaluation

    PubMed Central

    Qu, Ding; He, Junjie; Liu, Congyan; Zhou, Jing; Chen, Yan

    2014-01-01

    Ganoderma lucidum triterpene-loaded microemulsions (TMEs) using Coix lacryma-jobi (adlay) seed oil as oil phase were prepared, characterized, and evaluated for enhanced antitumor activity. Ternary phase diagrams for the TMEs were constructed and the optimal preparation was developed. Transmission electron microscopy and dynamic light scattering showed that this formulation had a well defined spherical shape, a homogeneous distribution, a small size, and a narrow polydispersity index. The drug-loading rate was determined to be 9.87% by ultraviolet spectrophotometry, and acceptable stability under various stimulations in vitro was confirmed. Importantly, the TME formulation showed a significantly greater antiproliferative effect towards human lung carcinoma (A549) cells and murine lung tumor (Lewis) cells in comparison with suspension formulations containing triterpene and adlay seed oil as a positive control. The half-maximal inhibitory concentration of the TMEs was about 0.62 mg crude drug per mL, being 2.5-fold improved relative to that of the corresponding suspension formulation, but no significant cytotoxicity was observed for the bare microemulsion in A549 cells and Lewis cells. In vivo, the TME formulation showed markedly enhanced antitumor efficacy in a xenograft model of Lewis lung cancer after intragastric administration. Compared with cyclophosphamide, the TME formulation showed similar antitumor activity but less general toxicity. These results indicate the feasibility of using a microemulsion to increase the solubility of triterpene and adlay. TMEs hold promise as an efficient drug delivery system for the treatment of lung cancer. PMID:24379669

  9. Enhanced Efficacy of an AAV Vector Encoding Chimeric, Highly-Secreted Acid α-glucosidase in Glycogen Storage Disease Type II

    PubMed Central

    Sun, Baodong; Zhang, Haoyue; Benjamin, Daniel K.; Brown, Talmage; Bird, Andrew; Young, Sarah P.; McVie-Wylie, Alison; Chen, Y-T; Koeberl, Dwight D.

    2009-01-01

    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 α-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 1×1010 vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3×1010 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. PMID:16987711

  10. One-step mixing with humanized anti-mPEG bispecific antibody enhances tumor accumulation and therapeutic efficacy of mPEGylated nanoparticles.

    PubMed

    Kao, Chien-Han; Wang, Jaw-Yuan; Chuang, Kuo-Hsiang; Chuang, Chih-Hung; Cheng, Ta-Chun; Hsieh, Yuan-Chin; Tseng, Yun-Long; Chen, Bing-Mae; Roffler, Steve R; Cheng, Tian-Lu

    2014-12-01

    Methoxy PEGylated nanoparticles (mPEG-NPs) are increasingly used for cancer imaging and therapy. Here we describe a general and simple approach to confer tumor tropism to any mPEG-NP. We demonstrate this approach with humanized bispecific antibodies (BsAbs) that can bind to both mPEG molecules on mPEG-NPs and to EGFR or HER2 molecules overexpressed on the surface of cancer cells. Simple mixing of BsAbs with mPEG-NPs can mediate preferential binding of diverse mPEG-NPs to cancer cells that overexpress EGFR or HER2 under physiological conditions and significantly increase cancer cell killing by liposomal doxorubicin to EGFR(+) and HER2(+) cancer cells. BsAbs modification also enhanced accumulation of fluorescence-labeled NPs and significantly increased the anticancer activity of drug-loaded NPs to antigen-positive human tumors in a mouse model. Anti-mPEG BsAbs offer a simple one-step method to confer tumor specificity to mPEG-NPs for enhanced tumor accumulation and improved therapeutic efficacy.

  11. Liraglutide Enhances the Efficacy of Human Mesenchymal Stem Cells in Preserving Islet β-cell Function in Severe Non-obese Diabetic Mice

    PubMed Central

    Li, Li-rong; Lu, Jing; Jia, Xiao-lei; Hui, Hui; Zhang, Jie; Liu, Ying; Cui, Wei-juan; Xu, Qian-yue; Zhu, Da-long

    2016-01-01

    Glucagon-like peptide 1 (GLP-1) can promote islet β cell replication and function, and mesenchymal stem cells (MSCs) can inhibit T cell autoimmunity. The aim of this study was to test the dynamic distribution of infused human MSCs and the therapeutic effect of combined MSCs and liraglutide, a long-acting GLP-1 analog, on preserving β cell function in severe nonobese diabetic (NOD) mice. We found that infused MSCs accumulated in the pancreas at 4 wks post infusion, which was not affected by liraglutide treatment. Liraglutide significantly enhanced the function of MSCs to preserve islet β cells by reducing glucose levels 30 min post glucose challenge and increasing the content and secretion of insulin by islet β cells in severely diabetic mice. Infusion with MSCs significantly reduced insulitis scores but increased the frequency of splenic Tregs, accompanied by a reduction in plasma IFN-γ and TNF-α levels and an elevation of plasma IL-10 and transforming growth factor-β1 (TGF-β1) levels in NOD mice. Although liraglutide mitigated MSC-mediated changes in the frequency of Tregs and the level of plasma IL-10, it significantly increased the plasma TGF-β1 levels in severely diabetic mice. Therefore, our findings suggest that liraglutide could enhance the therapeutic efficacy of MSCs in the treatment of severe type 1 diabetes. PMID:27878211

  12. Stepwise targeted drug delivery to liver cancer cells for enhanced therapeutic efficacy by galactose-grafted, ultra-pH-sensitive micelles.

    PubMed

    Yan, Guoqing; Wang, Jun; Hu, Liefeng; Wang, Xin; Yang, Guanqing; Fu, Shengxiang; Cheng, Xu; Zhang, Panpan; Tang, Rupei

    2017-03-15

    To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA-DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart.

  13. Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation.

    PubMed

    Cashman, Kathleen A; Broderick, Kate E; Wilkinson, Eric R; Shaia, Carl I; Bell, Todd M; Shurtleff, Amy C; Spik, Kristin W; Badger, Catherine V; Guttieri, Mary C; Sardesai, Niranjan Y; Schmaljohn, Connie S

    2013-07-18

    Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development.

  14. PLGA-PLL-PEG-Tf-based targeted nanoparticles drug delivery system enhance antitumor efficacy via intrinsic apoptosis pathway

    PubMed Central

    Bao, Wen; Liu, Ran; Wang, Yonglu; Wang, Fei; Xia, Guohua; Zhang, Haijun; Li, Xueming; Yin, Haixiang; Chen, Baoan

    2015-01-01

    Chemotherapy offers a systemic cancer treatment; however, it is limited in clinical administration due to its serious side effects. In cancer medicine, the use of nanoparticles (NPs) drug delivery system (DDS) can sustainedly release anticancer drug at the specific site and reduce the incidence of toxicity in normal tissues. In the present study, we aimed to evaluate the benefit of a novel chemotherapeutic DDS and its underlying mechanisms. Daunorubicin (DNR) was loaded into poly (lactic-co-glycolic acid) (PLGA)-poly-l-lysine (PLL)-polyethylene glycol (PEG)-transferrin (Tf) NPs to construct DNR-PLGA-PLL-PEG-Tf-NPs (DNR-loaded NPs) as a DDS. After incubating with PLGA-PLL-PEG-Tf-NPs, DNR, and DNR-loaded NPs, the leukemia K562 cells were collected and the intracellular concentration of DNR was detected by flow cytometry, respectively. Furthermore, the effect of drugs on the growth of tumors in K562 xenografts was observed and the relevant toxicity of therapeutic drugs on organs was investigated in vivo. Meanwhile, cell apoptosis in the excised xenografts was measured by transferase-mediated dUTP nick-end labeling assay, and the expression of apoptosis-related proteins, including Bcl-2, Bax, Caspase-9, Caspase-3, and cleaved-PARP, was determined by Western blotting analysis. Results showed that DNR-loaded NPs increased intracellular concentration of DNR in K562 cells in vitro and induced a remarkable improvement in anticancer activity in the xenografts in vivo. The expression of Bcl-2 protein was downregulated and that of Bax, Caspase-9, Caspase-3, and cleaved-PARP proteins were obviously upregulated in the DNR-loaded NPs group than that in other ones. Interestingly, pathological assessment showed no apparent damage to the main organs. In summary, the results obtained from this study showed that the novel NPs DDS could improve the efficacy of DNR in the treatment of leukemia and induce apoptosis via intrinsic pathway. Thus, it can be inferred that the new drug

  15. Chitosan coating to enhance the therapeutic efficacy of calcium sulfate-based antibiotic therapy in the treatment of chronic osteomyelitis.

    PubMed

    Beenken, Karen E; Smith, James K; Skinner, Robert A; Mclaren, Sandra G; Bellamy, William; Gruenwald, M Johannes; Spencer, Horace J; Jennings, Jessica A; Haggard, Warren O; Smeltzer, Mark S

    2014-10-01

    We demonstrate that coating calcium sulfate with deacetylated chitosan enhances the elution profile of daptomycin by prolonging the period during which high concentrations of antibiotic are released. Coatings reduced initial bolus release of daptomycin by a factor of 10 to approximately 1000 µg/ml, and levels remained above 100 µg/ml for up to 10 days. Chitosan-coated and uncoated calcium sulfate implants with and without 15% daptomycin were evaluated in an experimental model of staphylococcal osteomyelitis through bacteriology scores, radiology, histopathology, and Gram staining. Significant reduction in bacteriology scores was observed for implants containing daptomycin and coated with chitosan compared with all the other groups. We confirm that the use of chitosan-coated calcium sulfate beads for local antibiotic delivery can be correlated with an improved therapeutic outcome following surgical debridement in the treatment of chronic osteomyelitis.

  16. Targeting Antitumor Immune Response for Enhancing the Efficacy of Photodynamic Therapy of Cancer: Recent Advances and Future Perspectives

    PubMed Central

    2016-01-01

    Photodynamic therapy (PDT) is a minimally invasive therapeutic strategy for cancer treatment, which can destroy local tumor cells and induce systemic antitumor immune response, whereas, focusing on improving direct cytotoxicity to tumor cells treated by PDT, there is growing interest in developing approaches to further explore the immune stimulatory properties of PDT. In this review we summarize the current knowledge of the innate and adaptive immune responses induced by PDT against tumors, providing evidence showing PDT facilitated-antitumor immunity. Various immunotherapeutic approaches on different cells are reviewed for their effectiveness in improving the treatment efficiency in concert with PDT. Future perspectives are discussed for further enhancing PDT efficiency via intracellular targetable drug delivery as well as optimized experimental model development associated with the study of antitumor immune response. PMID:27672421

  17. Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells

    PubMed Central

    Thotala, Dinesh; Karvas, Rowan M.; Engelbach, John A.; Garbow, Joel R.; Hallahan, Andrew N.; DeWees, Todd A.; Laszlo, Andrei; Hallahan, Dennis E.

    2015-01-01

    Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3β (GSK3β), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo. VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy. PMID:26413814

  18. Enhanced intracellular delivery and antibacterial efficacy of enrofloxacin-loaded docosanoic acid solid lipid nanoparticles against intracellular Salmonella

    PubMed Central

    Xie, Shuyu; Yang, Fei; Tao, Yanfei; Chen, Dongmei; Qu, Wei; Huang, Lingli; Liu, Zhenli; Pan, Yuanhu; Yuan, Zonghui

    2017-01-01

    Enrofloxacin-loaded docosanoic acid solid lipid nanoparticles (SLNs) with different physicochemical properties were developed to enhance activity against intracellular Salmonella. Their cellular uptake, intracellular elimination and antibacterial activity were studied in RAW 264.7 cells. During the experimental period, SLN-encapsulated enrofloxacin accumulated in the cells approximately 27.06–37.71 times more efficiently than free drugs at the same extracellular concentration. After incubation for 0.5 h, the intracellular enrofloxacin was enhanced from 0.336 to 1.147 μg/mg of protein as the sizes of nanoparticles were increased from 150 to 605 nm, and from 0.960 to 1.147 μg/mg of protein when the charge was improved from −8.1 to −24.9 mv. The cellular uptake was more significantly influenced by the size than it was by the charge, and was not affected by whether the charge was positive or negative. The elimination of optimal SLN-encapsulated enrofloxacin from the cells was significantly slower than that of free enrofloxacin after removing extracellular drug. The inhibition effect against intracellular Salmonella CVCC541 of 0.24 and 0.06 μg/mL encapsulated enrofloxacin was stronger than 0.6 μg/mL free drug after all of the incubation periods and at 48 h, respectively. Docosanoic acid SLNs are thus considered as a promising carrier for intracellular bacterial treatment. PMID:28112240

  19. Omega-3 Polyunsaturated Fatty Acids Enhance Cisplatin Efficacy in Gastric Cancer Cells by Inducing Apoptosis via ADORA1.

    PubMed

    Sheng, Hong; Chen, Xuehua; Liu, Binya; Li, Pu; Cao, Weixin

    2016-01-01

    It has been suggested that administration of the omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can alter the toxicity and/or activity of several anticancer drugs in in vitro and in vivo studies. Here, we investigated the ability of ω-3 PUFAs to potentiate the antineoplastic activity of cisplatin (CDDP) in gastric cancer cells. The increase in CDDP-induced growth inhibition was measured by the IC50 values obtained when the cells were incubated with CDDP alone or with CDDP plus DHA or EPA. DHA and EPA enhanced the growth-inhibition activity of increasing concentrations of CDDP. The interactions between CDDP and DHA or EPA at the cellular level were assessed through the combination index (CI) method of Chou-Talalay. The results demonstrated synergism between CDDP and DHA or EPA in MKN45 cells. Cell cycle analysis showed that the combination treatment increased G0/G1 phase and S phase arrest, and significantly increased the number of apoptotic cells. According to our previous study, ω -3 PUFAs induce apoptosis of gastric cells via ADORA1, a subtype of adenosine receptor functionally related to cell death. The ADORA1 mRNA and protein expression was higher in the combination treatment than in the individual treatments. Notable, when GC cells were pretreated with DPCPX, a selective ADORA1 antagonist, the combination treatment effect on apoptosis was significantly reduced. Our results suggest that ω-3 PUFAs enhance the antineoplastic effects of CDDP in gastric cancer cells, and the synergistic effect between ω-3 PUFAs and CDDP is partly dependent on activating the ADORA1-mediated apoptosis pathway.

  20. Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection.

    PubMed

    MacCallum, D M; Desbois, A P; Coote, P J

    2013-08-01

    The objective of this study was to determine whether combinations of antimicrobial peptides (AMPs) with caspofungin display enhanced antifungal activity versus Candida albicans in vitro and in vivo. Three conventional AMPs that satisfied criteria favouring their potential development as novel antifungals were selected for investigation. Colistin sulphate was also included as a cyclic peptide antibiotic used in the clinic. Minimum inhibitory concentrations (MICs) were determined for each antifungal agent and checkerboard assays were used to determine fractional inhibitory concentration index (FICI) values for dual combinations of AMPs or colistin with caspofungin. Viability assays were performed for the same combinations in order to investigate fungicidal interactions. Synergistic antifungal combinations were then tested for efficacy in vivo and compared to monotherapies in wax moth larva and murine models of systemic C. albicans infection. In combination with caspofungin, each of the AMPs [hMUC7-12, DsS3(1-16), hLF(1-11)] and colistin were synergistic and candidacidal in vitro. The treatment of infected wax moth larvae with combinations of caspofungin with hMUC7-12, DsS3(1-16) or colistin resulted in significant enhancements in survival compared to treatment with monotherapies. Notably, the treatment of C. albicans-infected mice with a combination of caspofungin and DsS3(1-16) resulted in the enhancement of survival compared to groups treated with just the individual agents. This study demonstrates that combination therapies containing caspofungin and AMPs or colistin merit further development as potential novel treatments for C. albicans infections.

  1. Protein-Pacing Caloric-Restriction Enhances Body Composition Similarly in Obese Men and Women during Weight Loss and Sustains Efficacy during Long-Term Weight Maintenance.

    PubMed

    Arciero, Paul J; Edmonds, Rohan; He, Feng; Ward, Emery; Gumpricht, Eric; Mohr, Alex; Ormsbee, Michael J; Astrup, Arne

    2016-07-30

    Short-Term protein-pacing (P; ~6 meals/day, >30% protein/day) and caloric restriction (CR, ~25% energy deficit) improves total (TBF), abdominal (ABF) and visceral (VAT) fat loss, energy expenditure, and biomarkers compared to heart healthy (HH) recommendations (3 meals/day, 15% protein/day) in obese adults. Less is known whether obese men and women respond similarly to P-CR during weight loss (WL) and whether a modified P-CR (mP-CR) is more efficacious than a HH diet during long-term (52 week) weight maintenance (WM). The purposes of this study were to evaluate the efficacy of: (1) P-CR on TBF, ABF, resting metabolic rate (RMR), and biomarkers between obese men and women during WL (weeks 0-12); and (2) mP-CR compared to a HH diet during WM (weeks 13-64). During WL, men (n = 21) and women (n = 19) were assessed for TBF, ABF, VAT, RMR, and biomarkers at weeks 0 (pre) and 12 (post). Men and women had similar reductions (p < 0.01) in weight (10%), TBF (19%), ABF (25%), VAT (33%), glucose (7%-12%), insulin (40%), leptin (>50%) and increase in % lean body mass (9%). RMR (kcals/kg bodyweight) was unchanged and respiratory quotient decreased 9%. Twenty-four subjects (mP-CR, n = 10; HH, n = 14) completed WM. mP-CR regained significantly less body weight (6%), TBF (12%), and ABF (17%) compared to HH (p < 0.05). Our results demonstrate P-CR enhances weight loss, body composition and biomarkers, and maintains these changes for 52-weeks compared to a traditional HH diet.

  2. Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model.

    PubMed

    Hylander, Bonnie L; Sen, Arindam; Beachy, Sarah H; Pitoniak, Rose; Ullas, Soumya; Gibbs, John F; Qiu, Jingxin; Prey, Joshua D; Fetterly, Gerald J; Repasky, Elizabeth A

    2015-11-10

    Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8h post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24h post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72h. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72h although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48h after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has a potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.

  3. Self-compassion enhances the efficacy of explicit cognitive reappraisal as an emotion regulation strategy in individuals with major depressive disorder.

    PubMed

    Diedrich, Alice; Hofmann, Stefan G; Cuijpers, Pim; Berking, Matthias

    2016-07-01

    Cognitive reappraisal has been shown to be an effective strategy to regulate depressed mood in healthy and remitted depressed individuals. However, individuals currently suffering from a clinical depression often experience difficulties in utilizing this strategy. Therefore, the goal of this study was to examine whether the efficacy of explicit cognitive reappraisal in major depressive disorder can be enhanced through the use of self-compassion and emotion-focused acceptance as preparatory strategies. Thereby, explicit cognitive reappraisal refers to purposefully identifying, challenging, and modifying depressiogenic cognitions to reduce depressed mood. To test our hypotheses, we induced depressed mood at four points in time in 54 participants (64.8% female; age M = 35.59, SD = 11.49 years) meeting criteria for major depressive disorder. After each mood induction, participants were instructed to either wait, or employ self-compassion, acceptance, or reappraisal to regulate their depressed mood. Depressed mood was assessed before and after each mood induction and regulation period on a visual analog scale. Results indicated that participants who had utilized self-compassion as a preparatory strategy experienced a significantly greater reduction of depressed mood during reappraisal than did those who had been instructed to wait prior to reappraisal. Participants who had used acceptance as a preparatory strategy did not experience a significantly greater reduction of depressed mood during subsequent reappraisal than those in the waiting condition. These findings provide preliminary evidence that the efficacy of explicit cognitive reappraisal is moderated by the precursory use of other emotion regulation strategies. In particular, they suggest that depressed individuals might benefit from using self-compassion to facilitate the subsequent use of explicit cognitive reappraisal.

  4. Protein-Pacing Caloric-Restriction Enhances Body Composition Similarly in Obese Men and Women during Weight Loss and Sustains Efficacy during Long-Term Weight Maintenance

    PubMed Central

    Arciero, Paul J.; Edmonds, Rohan; He, Feng; Ward, Emery; Gumpricht, Eric; Mohr, Alex; Ormsbee, Michael J.; Astrup, Arne

    2016-01-01

    Short-Term protein-pacing (P; ~6 meals/day, >30% protein/day) and caloric restriction (CR, ~25% energy deficit) improves total (TBF), abdominal (ABF) and visceral (VAT) fat loss, energy expenditure, and biomarkers compared to heart healthy (HH) recommendations (3 meals/day, 15% protein/day) in obese adults. Less is known whether obese men and women respond similarly to P-CR during weight loss (WL) and whether a modified P-CR (mP-CR) is more efficacious than a HH diet during long-term (52 week) weight maintenance (WM). The purposes of this study were to evaluate the efficacy of: (1) P-CR on TBF, ABF, resting metabolic rate (RMR), and biomarkers between obese men and women during WL (weeks 0–12); and (2) mP-CR compared to a HH diet during WM (weeks 13–64). During WL, men (n = 21) and women (n = 19) were assessed for TBF, ABF, VAT, RMR, and biomarkers at weeks 0 (pre) and 12 (post). Men and women had similar reductions (p < 0.01) in weight (10%), TBF (19%), ABF (25%), VAT (33%), glucose (7%–12%), insulin (40%), leptin (>50%) and increase in % lean body mass (9%). RMR (kcals/kg bodyweight) was unchanged and respiratory quotient decreased 9%. Twenty-four subjects (mP-CR, n = 10; HH, n = 14) completed WM. mP-CR regained significantly less body weight (6%), TBF (12%), and ABF (17%) compared to HH (p < 0.05). Our results demonstrate P-CR enhances weight loss, body composition and biomarkers, and maintains these changes for 52-weeks compared to a traditional HH diet. PMID:27483317

  5. Daurinol Enhances the Efficacy of Radiotherapy in Lung Cancer via Suppression of Aurora Kinase A/B Expression.

    PubMed

    Woo, Jong Kyu; Kang, Ju-Hee; Shin, DongYun; Park, Seong-Hyeok; Kang, Kyungsu; Nho, Chu Won; Seong, Je Kyung; Lee, Sang-Jin; Oh, Seung Hyun

    2015-07-01

    The aurora kinases constitute one family of serine/threonine kinases whose activity is essential for mitotic progression. The aurora kinases are frequently upregulated in human cancers and are associated with sensitivity to chemotherapy in certain ones. In the present study, we investigated whether aurora kinases could be a target to overcome radioresistance or enhance the radiosensitivity of lung cancer. For that purpose, we determined the therapeutic potential of daurinol, an investigational topoisomerase inhibitor, alone and in combination with radiation, by observing its effect on aurora kinases. Daurinol decreased cell viability and proliferation in human colon and lung cancer cells. Gene expression in daurinol-treated human colon cancer cells was evaluated using RNA microarray. The mRNA expression of 18 genes involved in the mitotic spindle check point, including aurora kinase A (AURKA) and aurora kinase B (AURKB), was decreased in daurinol-treated human colon cancer cells as compared with vehicle-treated cells. As expected, radiation increased expression levels of AURKA and AURKB. This increase was effectively attenuated by siRNAs against AURKA and AURKB, which suppressed cell growth and increased apoptosis under radiation. Furthermore, the expression of AURKA and AURKB was suppressed by daurinol in the presence or absence of radiation in colon and lung cancer cells. Daurinol alone or in combination with radiation decreased lung cancer growth in xenograft mouse models. Our data clearly confirm the antitumor and radiosensitizing activity of daurinol in human lung cancer cells through the inhibition of AURKA and AURKB.

  6. Disrupting 5-HT2A Receptor/PDZ Protein Interactions Reduces Hyperalgesia and Enhances SSRI Efficacy in Neuropathic Pain

    PubMed Central

    Pichon, Xavier; Wattiez, Anne S; Becamel, Carine; Ehrlich, Ingrid; Bockaert, Joel; Eschalier, Alain; Marin, Philippe; Courteix, Christine

    2010-01-01

    Antidepressants are one of the first-line treatments for neuropathic pain. Despite the influence of serotonin (5-hydroxytryptamine, 5-HT) in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are less effective than tricyclic antidepressants. Here, we show, in diabetic neuropathic rats, an alteration of the antihyperalgesic effect induced by stimulation of 5-HT2A receptors, which are known to mediate SSRI-induced analgesia. 5-HT2A receptor density was not changed in the spinal cord of diabetic rats, whereas postsynaptic density protein-95 (PSD-95), one of the PSD-95/disc large suppressor/zonula occludens-1 (PDZ) domain containing proteins interacting with these receptors, was upregulated. Intrathecal injection of a cell-penetrating peptidyl mimetic of the 5-HT2A receptor C-terminus, which disrupts 5-HT2A receptor–PDZ protein interactions, induced an antihyperalgesic effect in diabetic rats, which results from activation of 5-HT2A receptors by endogenous 5-HT. The peptide also enhanced antihyperalgesia induced by the SSRI fluoxetine. Its effects likely resulted from an increase in receptor responsiveness, because it revealed functional 5-HT2A receptor-operated Ca2+ responses in neurons, an effect mimicked by knockdown of PSD-95. Hence, 5-HT2A receptor/PDZ protein interactions might contribute to the resistance to SSRI-induced analgesia in painful diabetic neuropathy. Disruption of these interactions might be a valuable strategy to design novel treatments for neuropathic pain and to increase the effectiveness of SSRIs. PMID:20531396

  7. Glycyrrhiza uralensis water extract enhances dendritic cell maturation and antitumor efficacy of HPV dendritic cell-based vaccine

    PubMed Central

    Aipire, Adila; Li, Jinyu; Yuan, Pengfei; He, Jiang; Hu, Yelang; Liu, Lu; Feng, Xiaoli; Li, Yijie; Zhang, Fuchun; Yang, Jianhua; Li, Jinyao

    2017-01-01

    Licorice has been used as herbal medicine and natural sweetener. Here, we prepared Glycyrrhiza uralensis water extract (GUWE) and investigated the effect of GUWE on the maturation and function of dendritic cells (DCs) and its adjuvant effect on DC-based vaccine. We observed that GUWE dose-dependently promoted DC maturation and cytokine secretion through TLR4 signaling pathway. The capacity of DC to stimulate allogenic splenocyte proliferation was also enhanced by GUWE treatment. Compared with control group, GUWE treated DCs pulsed with human papillomavirus (HPV)-16 E6/E7 peptides significantly inhibited the tumor growth in both early and late therapeutic groups. In early therapeutic group, the frequencies of induced regulatory T cells (iTregs: CD4+CD25−Fopx3+) and CD4+ and CD8+ T cells were significantly decreased and increased, respectively. HPV-16-specific CD8+ T cell responses were significantly induced and negatively correlated with iTreg frequencies and tumor weight. These results indicated the immunoregulatory activities of licorice. PMID:28272545

  8. Glycyrrhiza uralensis water extract enhances dendritic cell maturation and antitumor efficacy of HPV dendritic cell-based vaccine.

    PubMed

    Aipire, Adila; Li, Jinyu; Yuan, Pengfei; He, Jiang; Hu, Yelang; Liu, Lu; Feng, Xiaoli; Li, Yijie; Zhang, Fuchun; Yang, Jianhua; Li, Jinyao

    2017-03-08

    Licorice has been used as herbal medicine and natural sweetener. Here, we prepared Glycyrrhiza uralensis water extract (GUWE) and investigated the effect of GUWE on the maturation and function of dendritic cells (DCs) and its adjuvant effect on DC-based vaccine. We observed that GUWE dose-dependently promoted DC maturation and cytokine secretion through TLR4 signaling pathway. The capacity of DC to stimulate allogenic splenocyte proliferation was also enhanced by GUWE treatment. Compared with control group, GUWE treated DCs pulsed with human papillomavirus (HPV)-16 E6/E7 peptides significantly inhibited the tumor growth in both early and late therapeutic groups. In early therapeutic group, the frequencies of induced regulatory T cells (iTregs: CD4(+)CD25(-)Fopx3(+)) and CD4(+) and CD8(+) T cells were significantly decreased and increased, respectively. HPV-16-specific CD8(+) T cell responses were significantly induced and negatively correlated with iTreg frequencies and tumor weight. These results indicated the immunoregulatory activities of licorice.

  9. Enzyme-Sensitive and Amphiphilic PEGylated Dendrimer-Paclitaxel Prodrug-Based Nanoparticles for Enhanced Stability and Anticancer Efficacy.

    PubMed

    Li, Ning; Cai, Hao; Jiang, Lei; Hu, Jiani; Bains, Ashika; Hu, Jesse; Gong, Qiyong; Luo, Kui; Gu, Zhongwei

    2017-03-01

    In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge. In addition to high stability during circulation, as demonstrated by protein adsorption assays and drug release studies in the cancer's intracellular environment, the nanoparticles were able to quickly release the drug intact in its original molecular structure, as verified via high-performance liquid chromatography and mass spectrometry analyses. Compared to free PTX, the enzyme-responsive feature of nanoparticles promoted higher cytotoxicity against 4T1 cancer cells and much lower cytotoxicity against normal cells. The nanoparticles accumulated in the tumor and were retained for an extended period of time, as confirmed by fluorescence imaging. Therefore, these nanoparticles exhibited significantly enhanced antitumor efficiency in the 4T1 breast cancer model as indicated by the observed inhibition of angiogenesis and proliferation as well as induction of apoptosis. Moreover, the nanoparticles reduced the occurrence of side effects, particularly dose-limited toxicities, as monitored by body weight and hematological features. Hence, our Janus PEGylated dendrimer-PTX prodrug-based nanoparticles may potentially serve as nanoscale vehicles for breast cancer therapy.

  10. Enhanced oral bioavailability and anticancer efficacy of fisetin by encapsulating as inclusion complex with HPβCD in polymeric nanoparticles.

    PubMed

    Kadari, Amrita; Gudem, Sagarika; Kulhari, Hitesh; Bhandi, Murali Mohan; Borkar, Roshan M; Kolapalli, Venkata Ramana Murthy; Sistla, Ramakrishna

    2017-11-01

    Fisetin (FST), a potent anticancer phytoconstituent, exhibits poor aqueous solubility and hence poor bioavailability. The aim of the present study is to improve the oral bioavailability of FST by encapsulating into PLGA NPs (poly-lactide-co-glycolic acid nanoparticles) as a complex of HPβCD (hydroxyl propyl beta cyclodextrin) and to assess its anti-cancer activity against breast cancer cells. FST-HPβCD inclusion complex (FHIC) was prepared and the supramolecular complex formation was characterized by FTIR, DSC, PXRD and (1)H NMR. FHIC encapsulated PLGA nanoparticles (FHIC-PNP) were prepared and were studied for in vitro anticancer activity, cellular uptake, apoptosis and reactive oxygen species generation in MCF-7 human breast cancer cells. Comparative bioavailability of FST was determined after oral administration in C57BL6 mice as pure FST and FHIC-PNP. The results revealed that FHIC-PNP not only enhanced the anti-cancer activity and apoptosis of FST against MCF-7 cells but also improved its oral bioavailability, as demonstrated by increased peak plasma concentration and total drug absorbed.

  11. Efficacy of engineered FVIII-producing skeletal muscle enhanced by growth factor-releasing co-axial electrospun fibers.

    PubMed

    Liao, I-Chien; Leong, Kam W

    2011-02-01

    Co-axial electrospun fibers can offer both topographical and biochemical cues for tissue engineering applications. In this study, we demonstrate the sustained treatment of hemophilia through a non-viral, tissue engineering approach facilitated by growth factor-releasing co-axial electrospun fibers. FVIII-producing skeletal myotubes were first engineered on aligned electrospun fibers in vitro, followed by implantation in hemophilic mice with or without a layer of core-shell electrospun fibers designed to provide sustained delivery of angiogenic or lymphangiogenic growth factors, which serves to stimulate the lymphatic or vascular systems to enhance the FVIII transport from the implant site into systemic circulation. Upon subcutaneous implantation into hemophilic mice, the construct seamlessly integrated with the host tissue within one month, and specifically induced either vascular or lymphatic network infiltration in accordance with the growth factors released from the electrospun fibers. Engineered constructs that induced angiogenesis resulted in sustained elevation of plasma FVIII and significantly reduced blood coagulation time for at least 2-months. Biomaterials-assisted functional tissue engineering was shown in this study to offer protein replacement therapy for a genetic disorder such as hemophilia.

  12. Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review

    PubMed Central

    Bagot, Kara Simone; Kaminer, Yifrah

    2015-01-01

    Background and Aims Increasing prescription stimulant abuse among youth without diagnoses of attention deficit hyperactivity disorder (ADHD) is of concern. The most frequently cited motive for abuse is improved academic achievement via neurocognitive enhancement. Our aim in reviewing the literature was to identify neurocognitive effects of prescription stimulants in non-ADHD youth. Methods A systematic review was conducted for youth aged 12–25 years using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Fourteen papers were included. Results Modafinil appears to improve reaction time (P ≤ 0.04), logical reasoning (P ≤ 0.05) and problem-solving. Methylphenidate appears to improve performance in novel tasks and attention-based tasks (P ≤ 0.05), and reduces planning latency in more complex tasks (P ≤ 0.05). Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall. Across all three types of prescription stimulants, research shows improved attention with lack of consensus on whether these improvements are limited to simple versus complex tasks in varying youth populations. Conclusions The heterogeneity of the non-attention deficit hyperactivity disorder youth population, the variation in cognitive task characteristics and lack of replication of studies makes assessing the potential global neurocognitive benefits of stimulants among non-attention deficit hyper-activity disorder youth difficult; however, some youth may derive benefit in specific cognitive domains. PMID:24749160

  13. Increased Anxiety-Like Behavior and Enhanced Synaptic Efficacy in the Amygdala of GluR5 Knockout Mice

    PubMed Central

    Xu, Hui; Vadakkan, Kunjumon I.; Ren, Ming; Knifed, Eva; Shum, Fanny; Quan, Jessica; Zhang, Xue-Han; Zhuo, Min

    2007-01-01

    GABAergic transmission in the amygdala modulates the expression of anxiety. Understanding the interplay between GABAergic transmission and excitatory circuits in the amygdala is, therefore, critical for understanding the neurobiological basis of anxiety. Here, we used a multi-disciplinary approach to demonstrate that GluR5-containing kainate receptors regulate local inhibitory circuits, modulate the excitatory transmission from the basolateral amygdala to the central amygdala, and control behavioral anxiety. Genetic deletion of GluR5 or local injection of a GluR5 antagonist into the basolateral amygdala increases anxiety-like behavior. Activation of GluR5 selectively depolarized inhibitory neurons, thereby increasing GABA release and contributing to tonic GABA current in the basolateral amygdala. The enhanced GABAergic transmission leads to reduced excitatory inputs in the central amygdala. Our results suggest that GluR5 is a key regulator of inhibitory circuits in the amygdala and highlight the potential use of GluR5-specific drugs in the treatment of pathological anxiety. PMID:17245443

  14. Heat shock protein 90 and calcineurin pathway inhibitors enhance the efficacy of triazoles against Scedosporium prolificans via induction of apoptosis

    PubMed Central

    Shirazi, Fazal; Kontoyiannis, Dimitrios P.

    2014-01-01

    Scedosporium prolificans is a pathogenic mold resistant to current antifungals, and infection results in high mortality. Simultaneous targeting of both ergosterol biosynthesis and heat shock protein 90 (Hsp90) or the calcineurin pathway in S. prolificans may be an important strategy for enhancing the potency of antifungal agents. We hypothesized that the inactive triazoles posaconazole (PCZ) and itraconazole (ICZ) acquire fungicidal activity when combined with the calcineurin inhibitor tacrolimus (TCR) or Hsp90 inhibitor 17-demethoxy-17-(2-propenylamino) geldanamycin (17AAG). PCZ, ICZ, TCR and 17AAG alone were inactive in vitro against S. prolificans spores (MICs > 128 μg/ml). In contrast, MICs for PCZ or ICZ in combination with TCR or 17AAG (0.125-0.50 μg/ml) were much lower compared with drug alone. In addition PCZ and ICZ in combination with TCR or 17AAG became fungicidal. Because apoptosis is regulated by the calcineurin pathway in fungi and is under the control of Hsp90, we hypothesized that this synergistic fungicidal effect is mediated via apoptosis. This observed fungicidal activity was mediated by increased apoptosis of S. prolificans germlings, as evidenced by reactive oxygen species accumulation, decreased mitochondrial membrane potential, phosphatidylserine externalization, and DNA fragmentation. Furthermore, induction of caspase-like activity was correlated with TCR or 17AAG + PCZ/ICZ-induced cell death. In conclusion, we report for the first time that PCZ or ICZ in combination with TCR or 17AAG renders S. prolificans exquisitely sensitive to PCZ or ICZ via apoptosis. This finding may stimulate the development of new therapeutic strategies for patients infected with this recalcitrant fungus. PMID:28357242

  15. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition

    PubMed Central

    Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A.; Feng, Dan; Bielecki, Timothy A.; Band, Vimla; Cohen, Samuel M.; Bronich, Tatiana K.; Band, Hamid

    2016-01-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla®; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance

  16. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    PubMed

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  17. Efficacy of ultrasound mediated microbubbles in diclofenac gel to enhance transdermal permeation in rheumatoid arthritis induced rat.

    PubMed

    Liao, A H; Chuang, H C; Chung, H Y

    2015-08-01

    In previous study in the literature, the effect of ultrasound on the transdermal permeation of the nonsteroidal anti-inflammatory drug, diclofenac has been investigated. Therapeutic ultrasound can increase circulation in the inflamed joint and decrease arthritic pain. Recently, transdermal drug delivery has been demonstrated by ultrasound (US) combining with microbubbles (MBs) contrast agent. In this study, the efficiency of US-MBs mediated diclofenac delivery for adjuvant-induced rheumatoid arthritis (RA) in rats was evaluated. RA was induced by injection of 100 μl Freund's complete adjuvant into the ankle joint in SD male rats (250-300g) and were randomly divided into five groups: (1) control group (C); (2) penetrating diclofenac alone (D); (3) US alone (U); (4) US combined with penetrating diclofenac (DU); (5) US combined with MBs and penetrating diclofenac (DUB). The evaluations of ankle width were performed for 10 days by high frequency (40MHz) US B-mode and color Doppler mode imaging before and after treatment. Longitudinal US images of arthritis induced show synovitis and neovascularity. After treatment, only a little neovascularity has been observed. The recovery rate at 10th day in the group DUB (97.7±2.7 %) was significantly higher than in the group C (1.0±2.7 %), group D (37.5±4.6 %), group U (75.5±4.2 %) and group DU (87.3±5.2 %) (p <; 0.05). Our results investigated that the treatments of US and MBs can increase skin permeability to enhance diclofenac sodium delivery and inhibit inflammation of the tissues surrounded the arthritic ankle. In color Doppler imaging, after the combination treatment, the synovial neoangiogenesis in the arthritic area was reduced quickly.

  18. Size Selective Green Synthesis of Silver and Gold Nanoparticles: Enhanced Antibacterial Efficacy of Resveratrol Capped Silver Sol.

    PubMed

    Shukla, Shashi P; Roy, Mainak; Mukherjee, Poulomi; Das, Laboni; Neogy, Suman; Srivastava, Dinesh; Adhikari, Soumyakanti

    2016-03-01

    In view of potential biomedical application of the noble metal nanoparticles, we report a size controlled yet simple and green synthesis of resveratrol stabilized silver and gold nanoparticles having low polydispersity of size. Here, resveratrol plays two simultaneous roles, reducing the metal ions and providing efficient capping of the small nanoparticles. This gives rise to specific size of silver and gold nanoparticles at specific ratios of metal to resveratrol. The particles have been characterized by XRD and transmission electron microscopy. The nanoparticle sols are stable for months. The UV Visible absorption spectra of the silver sol show the plasmon peak of spherical nanoparticles, presence of which is further reflected in the TEM images. Size of the silver particles obtained is in between 11 to 21 nm depending on the ratio of resveratrol to metal ion used. Resveratrol capped silver nanoparticles exhibit high antibacterial activity against Gram negative wild type E coli BW (25113). The minimum inhibitory concentration (MIC) of nano-silver against the bacterium has been estimated to be 6.48 μg/ml, which is significantly lower than that reported in some earlier as well as recent publications. Reaction of gold ions with resveratrol, on the other hand, produces gold nanoparticles of sizes varying from 7 to 29 nm at different ratios of resveratrol to the metal ions. Particles with higher size and aspect ratio are formed at lower concentration of the capping agent whereas particles with very small size and pseudo-spherical morphology are formed at higher capping concentration. Difference in the formation kinetics of silver and gold nanoparticles has been attributed to the different growth mechanisms in the two cases. Possible modes of anchorage of resveratrol to silver nanoparticles have been investigated using surface enhanced resonance Raman spectroscopy (SERS) which shows that the silver nanoparticles are capped by resveratrol molecule primarily through O

  19. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

    SciTech Connect

    Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; Swartz, Melody A.; Hubbell, Jeffrey A.

    2015-05-16

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6chi Ly6gmonocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6clo Ly6g+ granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6chi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8+ T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.

  20. Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1.

    PubMed

    Díaz-Lezama, Nundehui; Wu, Zhijian; Adán-Castro, Elva; Arnold, Edith; Vázquez-Membrillo, Miguel; Arredondo-Zamarripa, David; Ledesma-Colunga, Maria G; Moreno-Carranza, Bibiana; Martinez de la Escalera, Gonzalo; Colosi, Peter; Clapp, Carmen

    2016-03-01

    Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated

  1. Efficacy of various protein-based coating on enhancing the shelf life of fresh eggs during storage.

    PubMed

    Caner, Cengiz; Yüceer, Muhammed

    2015-07-01

    highlights the promising use of various coatings to both enhance the functional properties and to reduce the breakage of eggs.

  2. Chemical additive to enhance antimicrobial efficacy of chlorine and control cross-contamination during immersion chill of broiler carcasses.

    PubMed

    Schambach, B T; Berrang, M E; Harrison, M A; Meinersmann, R J

    2014-09-01

    Immersion chilling of broiler carcasses can be a site for cross-contamination between the occasional highly contaminated carcass and those that are co-chilled. Chlorine is often used as an antimicrobial but can be overcome by organic material. A proprietary chlorine stabilizer (T-128) based on phosphoric acid-propylene glycol was tested as a chill tank additive in experiments simulating commercial broiler chilling. In bench-scale experiments, 0.5% T-128 was compared with plain water (control), 50 ppm of chlorine, and the combination of 0.5% T-128 with 50 ppm of chlorine to control transfer of Salmonella and Campylobacter from inoculated wing drummettes to co-chilled uninoculated drummettes. Both chlorine and T-128 lessened cross-contamination with Salmonella (P < 0.05); T-128 and T-128 with chlorine were significantly more effective (P < 0.05) than the control or plain chlorine for control of Campylobacter. T-128 treatments were noted to have a pH of less than 4.0; an additional experiment demonstrated that the antimicrobial effect of T-128 was not due merely to a lower pH. In commercial broiler chilling, a pH close to 6.0 is preferred to maximize chlorine effectiveness, while maintaining water-holding capacity of the meat. In a set of pilot-scale experiments with T-128, a near-ideal pH of 6.3 was achieved by using tap water instead of the distilled water used in bench-scale experiments. Pilot-scale chill tanks were used to compare the combination of 0.5% T-128 and 50 ppm of chlorine with 50 ppm of plain chlorine for control of cross-contamination between whole carcasses inoculated with Salmonella and Campylobacter and co-chilled uninoculated carcasses. The T-128 treatment resulted in significantly less crosscontamination by either direct contact or water transfer with both organisms compared with plain chlorine treatment. T-128 may have use in commercial broiler processing to enhance the effectiveness of chlorine in processing water.

  3. A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents

    PubMed Central

    Tatarkiewicz, K; Hargrove, D M; Jodka, C M; Gedulin, B R; Smith, P A; Hoyt, J A; Lwin, A; Collins, L; Mamedova, L; Levy, O E; D’Souza, L; Janssen, S; Srivastava, V; Ghosh, S S; Parkes, D G

    2014-01-01

    Aim Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. Methods AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala2]GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu14] exenatide. Human GIP or [d-Ala2]GIP(1–42) were used for comparison. Results AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala2]GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala2]GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. Conclusions These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes. PMID:23859463

  4. PLGA-encapsulated tea polyphenols enhance the chemotherapeutic efficacy of cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma

    PubMed Central

    Singh, Madhulika; Bhatnagar, Priyanka; Mishra, Sanjay; Kumar, Pradeep; Shukla, Yogeshwer; Gupta, Kailash Chand

    2015-01-01

    The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-κB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich’s ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG. PMID:26586942

  5. Lithium Modulates Autophagy in Esophageal and Colorectal Cancer Cells and Enhances the Efficacy of Therapeutic Agents In Vitro and In Vivo

    PubMed Central

    O’Donovan, Tracey R.; Rajendran, Simon; O’Reilly, Seamus; McKenna, Sharon L.

    2015-01-01

    Many epithelial cancers, particularly gastrointestinal tract cancers, remain poor prognosis diseases, due to resistance to cytotoxic therapy and local or metastatic recurrence. We have previously shown that apoptosis incompetent esophageal cancer cells induce autophagy in response to chemotherapeutic agents and this can facilitate their recovery. However, known pharmacological inhibitors of autophagy could not enhance cytotoxicity. In this study, we have examined two well known, clinically approved autophagy inducers, rapamycin and lithium, for their effects on chemosensitivity in apoptosis incompetent cancer cells. Both lithium and rapamycin were shown to induce autophagosomes in esophageal and colorectal cancer cells by western blot analysis of LC3 isoforms, morphology and FACS quantitation of Cyto-ID or mCherry-GFP-LC3. Analysis of autophagic flux indicates inefficient autophagosome processing in lithium treated cells, whereas rapamycin treated cells showed efficient flux. Viability and recovery was assessed by clonogenic assays. When combined with the chemotherapeutic agent 5-fluorouracil, rapamycin was protective. In contrast, lithium showed strong enhancement of non-apoptotic cell death. The combination of lithium with 5-fluorouracil or oxaliplatin was then tested in the syngenic mouse (balb/c) colorectal cancer model—CT26. When either chemotherapeutic agent was combined with lithium a significant reduction in tumor volume was achieved. In addition, survival was dramatically increased in the combination group (p < 0.0001), with > 50% of animals achieving long term cure without re-occurrence (> 1 year tumor free). Thus, combination treatment with lithium can substantially improve the efficacy of chemotherapeutic agents in apoptosis deficient cancer cells. Induction of compromised autophagy may contribute to this cytotoxicity. PMID:26248051

  6. Intracellular Delivery of a Protein Antigen with an Endosomal-Releasing Polymer Enhances CD8 T-Cell Production and Prophylactic Vaccine Efficacy

    PubMed Central

    Foster, Suzanne; Duvall, Craig L.; Crownover, Emily F.; Hoffman, Allan S.; Stayton, Patrick S.

    2010-01-01

    Protein-based vaccines have significant potential as infectious disease and anticancer therapeutics, but clinical impact has been limited in some applications by their ability to generate a coordinated cellular immune response. Here, a pH-responsive carrier incorporating poly(propylacrylic acid) (PPAA was evaluated to test whether improved cytosolic delivery of a protein antigen could enhance CD8+ cytotoxic lymphocyte generation and prophylactic tumor vaccine responses. PPAA was directly conjugated to the model ovalbumin antigen via reducible disulfide linkages and was also tested in a particulate formulation after condensation with the cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA). Intracellular trafficking studies revealed that both PPAA-containing formulations were stably internalized compared to control conjugates and evaded exocytotic pathways, leading to increased intracellular accumulation and potential access to the cytosolic MHC-1 antigen presentation pathway. In an EG.7-OVA mouse tumor protection model, both PPAA-containing carriers robustly inhibited tumor growth and led to an approximately 3.5 fold increase in the longevity of tumor free survival relative to controls. Mechanistically this response was attributed to the 8-fold increase in production of ovalbumin-specific CD8+ T-lymphocytes and an 11-fold increase in production of anti-ovalbumin IgG. Significantly, this is one of the first demonstrated examples of in vivo immunotherapeutic efficacy using soluble protein-polymer conjugates. These results suggest that carriers enhancing cytosolic delivery of protein antigens could lead to more robust CD8+ T-cell response and demonstrate the potential of pH-responsive PPAA-based carriers for therapeutic vaccine applications. PMID:21043513

  7. Integration of Artificial Photosynthesis System for Enhanced Electronic Energy-Transfer Efficacy: A Case Study for Solar-Energy Driven Bioconversion of Carbon Dioxide to Methanol.

    PubMed

    Ji, Xiaoyuan; Su, Zhiguo; Wang, Ping; Ma, Guanghui; Zhang, Songping

    2016-09-01

    Biocatalyzed artificial photosynthesis systems provide a promising strategy to store solar energy in a great variety of chemicals. However, the lack of direct interface between the light-capturing components and the oxidoreductase generally hinders the trafficking of the chemicals and photo-excited electrons into the active center of the redox biocatalysts. To address this problem, a completely integrated artificial photosynthesis system for enhanced electronic energy-transfer efficacy is reported by combining co-axial electrospinning/electrospray and layer-by-layer (LbL) self-assembly. The biocatalysis part including multiple oxidoreductases and coenzymes NAD(H) was in situ encapsulated inside the lumen polyelectrolyte-doped hollow nanofibers or microcapsules fabricated via co-axial electrospinning/electrospray; while the precise and spatial arrangement of the photocatalysis part, including electron mediator and photosensitizer for photo-regeneration of the coenzyme, was achieved by ion-exchange interaction-driven LbL self-assembly. The feasibility and advantages of this integrated artificial photosynthesis system is fully demonstrated by the catalyzed cascade reduction of CO2 to methanol by three dehydrogenases (formate, formaldehyde, and alcohol dehydrogenases), incorporating the photo-regeneration of NADH under visible-light irradiation. Compared to solution-based systems, the methanol yield increases from 35.6% to 90.6% using the integrated artificial photosynthesis. This work provides a novel platform for the efficient and sustained production of a broad range of chemicals and fuels from sunlight.

  8. Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Liu, Guosong; Weinger, Jason G.; Lu, Zhong-Lin; Xue, Feng; Sadeghpour, Safa

    2015-01-01

    Background: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents. Objective: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50–70) with cognitive impairment. Subjects were treated with MMFS-01 (n = 23) or placebo (n = 21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains. Results: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p = 0.003; Cohen’s d = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined. Conclusions: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults. PMID:26519439

  9. Pectin Enhances Bio-Control Efficacy by Inducing Colonization and Secretion of Secondary Metabolites by Bacillus amyloliquefaciens SQY 162 in the Rhizosphere of Tobacco

    PubMed Central

    Guo, Rong; Pan, Bin; Shi, Wen; Yuan, Saifei; Guan, Huilin; Gong, Ming; Shen, Biao; Shen, Qirong

    2015-01-01

    Bacillus amyloliquefaciens is a plant-beneficial Gram-positive bacterium involved in suppressing soil-borne pathogens through the secretion of secondary metabolites and high rhizosphere competence. Biofilm formation is regarded as a prerequisite for high rhizosphere competence. In this work, we show that plant extracts affect the chemotaxis and biofilm formation of B. amyloliquefaciens SQY 162 (SQY 162). All carbohydrates tested induced the chemotaxis and biofilm formation of the SQY 162 strain; however, the bacterial growth rate was not influenced by the addition of carbohydrates. A strong chemotactic response and biofilm formation of SQY 162 were both induced by pectin through stimulation of surfactin synthesis and transcriptional expression of biofilm formation related matrix genes. These results suggested that pectin might serve as an environmental factor in the stimulation of the biofilm formation of SQY 162. Furthermore, in pot experiments the surfactin production and the population of SQY 162 in the rhizosphere significantly increased with the addition of sucrose or pectin, whereas the abundance of the bacterial pathogen Ralstonia decreased. With increased production of secondary metabolites in the rhizosphere of tobacco by SQY 162 and improved colonization density of SQY 162 in the pectin treatment, the disease incidences of bacterial wilt were efficiently suppressed. The present study revealed that certain plant extracts might serve as energy sources or environmental cues for SQY 162 to enhance the population density on tobacco root and bio-control efficacy of tobacco bacterial wilt. PMID:25996156

  10. Comparative efficacy of a yeast product and bacitracin methylene disalicylate in enhancing early growth and intestinal maturation in broiler chicks from breeder hens of different ages.

    PubMed

    Fasina, Y O; Thanissery, R R

    2011-05-01

    The intestine of the newly hatched chick is immature at hatch. Yeast contains nucleotides and β-glucans that enhance intestinal development and chick growth. Accordingly, a 14-d experiment was conducted to evaluate the efficacy of a novel yeast product and bacitracin methylene disalicylate in enhancing early growth and intestinal maturation in chicks obtained from young (26-27 wk old) and old (58 to 59 wk old) breeder hens. Chicks (384) were randomly assigned to 8 dietary treatments. Treatment 1 (YH) consisted of chicks, from young hens, fed corn-soybean meal (SBM) diet alone. Treatment 2 (YHB) consisted of chicks, from young hens, fed corn-SBM basal into which BMD was added at 0.055 g/kg. Treatment 3 (YHE) consisted of chicks, from young hens, fed corn-SBM basal into which yeast extract (YE) was added at 0.075% level. Treatment 4 (YHED) consisted of chicks, from young hens, fed corn-SBM basal into which YE was added at 0.15% level. Treatments 5 (OH), 6 (OHB), 7 (OHE), and 8 (OHED) consisted of chicks from old hens fed diets similar to those given to YH in treatments 1, 2, 3, and 4, respectively. Growth performance (body weight gain and feed conversion ratio) was evaluated on d 7 and 14. Intestinal tissue samples were also analyzed for alkaline phosphatase (ALP) activity as an indicator of intestinal maturation on d 4 and 13 of experiment. Results showed that by d 14 of experiment, only BMD treatments (YHB and OHB) improved body weight gain (P < 0.05). However, the body weight gains of chicks in the yeast-supplemented treatments (YHE, YHED, OHE, and OHED) were statistically similar (P > 0.05) to those of the BMD treatments. Ileal ALP activity was consistently enhanced by BMD and yeast product supplemented at 0.075% of the diet. It was concluded that antibiotic BMD and our novel yeast product supplemented at 0.075% of the diet improved early chick growth and maturation of the ileal segment of the small intestine.

  11. Efficacy of Enhanced External Counterpulsation in Patients With Chronic Refractory Angina on Canadian Cardiovascular Society (CCS) Angina Class: An Updated Meta-Analysis.

    PubMed

    Zhang, Chunmei; Liu, Xiangjuan; Wang, Xiaomeng; Wang, Qi; Zhang, Yun; Ge, Zhiming

    2015-11-01

    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 I 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, I = 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, I = 32.7%, P = 0.1668). After 3 large studies were excluded, the pooled proportion was 82% (95%CI 0.79-0.86, I = 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 who were unresponsive to medical management and

  12. Enhancing Preservice Teachers' Sense of Efficacy and Attitudes toward School Diversity through Preparation: A Case of One U.S. Inclusive Teacher Education Program

    ERIC Educational Resources Information Center

    Gao, Wei; Mager, Gerald

    2011-01-01

    Conducted in one inclusive teacher education program in the United States, this study explored the trajectory of and the relationships between preservice teachers' sense of efficacy and attitudes toward school diversity through the course of preparation. Findings revealed that, in general, changes of preservice teachers' perceived efficacy,…

  13. Targeted Smart pH and Thermoresponsive N,O-Carboxymethyl Chitosan Conjugated Nanogels for Enhanced Therapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Verma, Neeraj K; Purohit, Mahaveer P; Equbal, Danish; Dhiman, Nitesh; Singh, Amrita; Kar, Aditya K; Shankar, Jai; Tehlan, Sarita; Patnaik, Satyakam

    2016-11-16

    In cancer treatment, developing ideal anticancer drug delivery systems to target tumor microenvironment by circumventing various physiological barriers still remains a daunting challenge. Here, in our work, a series of pH- and temperature-responsive nanogels based on poly(N-isopropylacrylamide-co-1-propene-2-3-dicarboxylate-co-2-acrylamido-2-methyl-1-propanesulfonate [poly(NIPAAm-IA-AMPS)] cross-linked by ethylene glycol dimethacrylate (EGDMA) were synthesized by random copolymerization. The molar ratio between monomer-comonomers-cross-linker was varied to fine-tune the optimum responsiveness of the nanogels. These optimized nanogels were further coupled to N,O-carboxymethyl chitosan (NOCC) stoichiometrically using EDC-NHS coupling chemistry to enhance the swelling behavior at lower pH. Interestingly, these NOCC-g-nanogels, when dispersed in aqueous media under sonication, attain nanosize and retain their high water-retention capacity with conspicuous pH and temperature responsiveness (viz. nanogel shrinkage in size beyond 35 °C and swelled at acidic pH) in vitro, as reflected by dynamic light scattering data. Doxorubicin (DOX), a potent anticancer drug, was loaded into these nanogels using the physical entrapment method. These drug-loaded nanogels exhibited a slow and sustained DOX release profile at physiological temperature and cytosolic pH. Furthermore, confocal and TEM results demonstrate that these nanogels were swiftly internalized by MCF-7 cells, and cell viability data showed preferential heightened cytotoxicity toward cancer cells (MCF-7 and MDA-MB231) compared to the MCF10A cells (human breast epithelial cell). Furthermore, intracellular DNA damage and cell cycle arrest assays suggest a mitochondrial mediated apoptosis in MCF-7 cells. This study substantiates our NOCC-g-nanogel platform as an excellent modality for passive diffusive loading and targeted release of entrapped drug(s) at physiological conditions in a controlled way for the improved

  14. Effect of In-Plume Aerosol Processing on the Efficacy of Marine Cloud Albedo Enhancement from Controlled Sea-Spray Injections

    NASA Astrophysics Data System (ADS)

    Stevens, R. G.; Spracklen, D.; Korhonen, H.; Pierce, J. R.

    2010-12-01

    The intentional enhancement of cloud albedo via controlled sea-spray injection from ships has been suggested as a possible means to control anthropogenic global warming (1); however, there remains significant uncertainty in the efficacy of this method due to uncertainties in aerosol and cloud microphysics. Recent analysis showed that more sea-spray may be necessary than previously assumed to reach a desired cooling due to nonlinearities in the aerosol/cloud microphysics (2). A major assumption used in (2) is that all sea-spray was emitted uniformly into some oceanic grid boxes, and thus did not account for sub-grid aerosol microphysics within the sea-spray plumes. However, as a consequnce of the fast sea-spray injection rates which are proposed, in the order of 1x10^17 1/s (1), particle concentrations in these plumes may be quite high and particle coagulation may significantly reduce the number of emitted particles and increase their average size. Therefore, it is possible that the emissions necessary to reach a desired cooling may be even larger than currently assumed. We explore the processing of the freshly emitted sea-spray plumes in the Large-Eddy Simulation (LES)/Cloud Resolving Model (CRM) the System for Atmospheric Modelling (SAM, 3) with the online aerosol microphysics module TOMAS (4). We determine how the final number and size of particles (once well mixed with background air) depends on the emission rate and size distribution of the sea-spray plume and on the pre-existing aerosol concentrations and local atmospheric conditions. Finally, we make suggestions for effective size-resolved emissions for use in climate models. (1) Salter, S. et al., Phil. Trans. R. Soc. A., 2008. (2) Korhonen, H. et al., Atmos. Chem. Phys., 10, 4133-4143, 2010. (3) Khairoutdinov, M., and Randall, D.,. J. Atmos. Sci., 60, 607-625, 2003. (4) Pierce, J. and Adams, P., Atmos. Chem. Phys., 9, 1339-1356, 2009.

  15. Effect of In-Plume Aerosol Processing on the Efficacy of Marine Cloud Albedo Enhancement from Controlled Sea-Spray Injections

    NASA Astrophysics Data System (ADS)

    Stuart, G. S.; Stevens, R. G.; Spracklen, D. V.; Korhonen, H.; Pierce, J. R.

    2012-12-01

    The intentional enhancement of cloud albedo via controlled sea-spray injection from ships has been proposed as a possible method to control anthropogenic global warming (1); however, there remains significant uncertainty in the efficacy of this method due to uncertainties in aerosol and cloud microphysics. A major assumption used in multiple recent studies (2,3) is that all sea-spray was emitted uniformly into some oceanic grid boxes, and thus did not account for sub-grid aerosol microphysics within the sea-spray plumes. However, as a consequence of the fast sea-spray injection rates which are proposed, in the order of 10^17 1/s (1), particle concentrations in these plumes may be quite high and particle coagulation may significantly reduce the number of emitted particles and increase their average size. Therefore, it is possible that the emissions necessary to reach a desired cooling may be even larger than currently assumed. We explore the evolution of these sea-salt plumes using a multi-shelled Gaussian plume model with size-resolved aerosol coagulation. We determine how the final number and size of particles depends on the emission rate and size distribution of the emitted sea-spray plume and local atmospheric conditions, including wind speed and boundary-layer stability. Under the injection rates reported in (1) and typical marine conditions, we find that the number of aerosol particles is reduced by about 40%. This fraction decreases for decreasing emission rates or increasing wind speeds due to lower particle concentrations in the plume. Finally, we make suggestions for effective size-resolved emissions for use in climate models. (1) Salter, S. et al., Phil. Trans. R. Soc. A., 2008. (2) Korhonen, H. et al., Atmos. Chem. Phys., 10, 4133-4143, 2010. (3) Partanen, A.-I. et al., J. Geophys. Res., 117, D02203, 2012.

  16. A pilot plant scale evaluation of a new process aid for enhancing chlorine efficacy against pathogen survival and cross-contamination during produce wash.

    PubMed

    Luo, Yaguang; Nou, Xiangwu; Millner, Patricia; Zhou, Bin; Shen, Cangliang; Yang, Yang; Wu, Yunpeng; Wang, Qin; Feng, Hao; Shelton, Dan

    2012-08-17

    Developing food safety intervention technology that can be readily adopted by the industry often requires test conditions that match as closely as possible to those of commercial food processing operations; yet biosafety risks inherent in pathogen studies constrain most experiments to laboratory settings. In this study, we report the first semi-commercial pilot-scale evaluation of a new process aid, T128, for its impact on enhancing the antimicrobial efficacy of chlorinated wash water against pathogen survival and cross-contamination. A non-pathogenic, BSL-1, strain of Escherichia coli O157:H7 was inoculated onto freshly harvested baby spinach leaves and washed with large amounts of freshly cut un-inoculated iceberg lettuce shreds in wash water with free chlorine periodically replenished, in the presence or absence of T128. Changes in water quality and pathogen survival and cross-contamination were monitored at every 2 min intervals for up to 36 min for each treatment during the wash operation. Results indicated that the use of T128 did not significantly (P>0.05) influence the rate of wash water deterioration, nor the pathogen populations remaining on the inoculated spinach leaves. However, in the absence of T128 (control), survival of E. coli O157:H7 in wash water and cross-contamination of un-inoculated lettuce frequently occurred when free chlorine in solution dropped below 1mg/l during the wash process. In contrast, the use of T128 significantly reduced the occurrence of E. coli O157:H7 surviving in wash water and of cross-contamination to un-inoculated shredded iceberg lettuce under the same operational conditions, suggesting that the application of T128 in a chlorine-based fresh produce sanitization system could increase the safety margin of process control on fresh-cut operations.

  17. Chief Joseph Kokanee Enhancement Project; Strobe Light Deterrent Efficacy Test and Fish Behavior Determination at the Grand Coulee Dam Third Powerplant Forebay, 2002-2003 Annual Report.

    SciTech Connect

    Johnson, R.; McKinstry, C.; Simmons, C.

    2003-01-01

    Since 1995, the Confederated Tribes of the Colville Reservation (Colville Confederated Tribes) have managed the Chief Joseph Kokanee Enhancement Project as part of the Northwest Power Planning Council (NWPPC) Fish and Wildlife Program. Project objectives have focused on understanding natural production of kokanee (a land-locked sockeye salmon) and other fish stocks in the area above Grand Coulee and Chief Joseph Dams on the Columbia River. A 42-month investigation concluded that entrainment at Grand Coulee Dam ranged from 211,685 to 576,676 fish annually. Further analysis revealed that 85% of the total entrainment occurred at the dam's third powerplant. These numbers represent a significant loss to the tribal fisheries upstream of the dam. In response to a suggestion by the NWPPC Independent Scientific Review Panel, the scope of work for the Chief Joseph Kokanee Enhancement Project was expanded to include a multiyear pilot test of a strobe light system to help mitigate fish entrainment. This report details the work conducted during the second year of the study by researchers of the Colville Confederated Tribes in collaboration with the Pacific Northwest National Laboratory. The 2002 study period extended from May 18 through July 30. The objective of the study was to determine the efficacy of a prototype strobe light system to elicit a negative phototactic response in kokanee and rainbow trout. The prototype system consisted of six strobe lights affixed to an aluminum frame suspended vertically underwater from a barge secured in the center of the entrance to the third powerplant forebay. The lights, controlled by a computer, were aimed to illuminate a specific region directly upstream of the barge. Three light level treatments were used: 6 of 6 lights on, 3 of 6 lights on, and all lights off. These three treatment conditions were applied for an entire 24-hr day and were randomly assigned within a 3-day block throughout the study period. A seven-transducer splitbeam

  18. Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction.

    PubMed

    Al-Sadoon, Mohamed K; Rabah, Danny M; Badr, Gamal

    2013-01-01

    Multiple myeloma (MM) is a clonal disease of plasma cells that reside in the bone marrow (BM). MM is an incurable disease; thus, screening for novel anti-myeloma drugs remains critically important. We recently described a silica nanoparticle-based snake venom delivery model that targets cancer cells, but not normal cells. Using this model, we demonstrated a strong enhancement of the antitumor activity of snake venom extracted from Walterinnesia aegyptia (WEV) in two breast carcinoma cell lines when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we aimed to delineate the in vivo therapeutic efficacy of WEV+NP in an MM-bearing experimental nude mouse model. We found that treatment with WEV+NP or WEV alone significantly inhibited tumor growth compared to treatment with NP or vehicle. WEV+NP- and WEV-treated cancer cells exhibited marked elevations in oxidative stress and robust reductions in the levels of interleukin-6 (IL-6) and B cell-activating factor (BAFF). WEV+NP also decreased the surface expression of the chemokine receptors CXCR3, CXCR4 and CXCR6 to a greater extent than WEV alone, and WEV+NP subsequently reduced migration in response to the cognate ligands CXCL10, CXCL12 and CXCL16. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (EGF-1)- and IL-6-mediated MM cell proliferation, altered the cell cycle and enhanced the induction of apoptosis of MM cells. In addition, the results of treatment with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the expression of cyclin D1, Bcl-2 and the phosphorylation of AKT; increased the expression of cyclin B1; altered the mitochondrial membrane potential; increased the activity of caspase-3, -8 and -9; and sensitized MM cells to growth arrest and apoptosis. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom to fight cancer cells.

  19. Chief Joseph Kokanee Enhancement Project : Strobe Light Deterrent Efficacy Test and Fish Behavior Determination at Grond Coulee Dam Third Powerplant Forebay.

    SciTech Connect

    Simmons, M.A.; McKinstry, C.A.; Simmons, C.S.

    2002-01-01

    Since 1995, the Colville Confederated Tribes have managed the Chief Joseph Kokanee Enhancement Project as part of the Northwest Power Planning Council's (NWPPC) Fish and Wildlife Program. Project objectives have focused on understanding natural production of kokanee (a land-locked sockeye salmon) and other fish stocks in the area above Grand Coulee and Chief Joseph Dams on the Columbia River. A 42-month investigation concluded that entrainment at Grand Coulee Dam ranged from 211,685 to 576,676 fish annually. Further analysis revealed that 85% of the total entrainment occurred at the dam's third powerplant. These numbers represent a significant loss to the tribal fisheries upstream of the dam. In response to a suggestion by the NWPPC's Independent Scientific Review Panel, the scope of work for the Chief Joseph Kokanee Enhancement Project was expanded to include a multiyear pilot test of a strobe light system to help mitigate fish entrainment. This report details the work conducted during the first year of the study by researchers of the Colville Confederated Tribes in collaboration with the Pacific Northwest National Laboratory (PNNL). The objective of the study was to determine the efficacy of a prototype strobe light system to elicit a negative phototactic response in kokanee and rainbow trout. Analysis of the effect of strobe lights on the distribution (numbers) and behavior of kokanee and rainbow trout was based on 51, 683 fish targets detected during the study period (June 30 through August 1, 2001). Study findings include the following: (1) Analysis of the count data indicated that significantly more fish were present when the lights were on compared to off. This was true for both the 24-hr tests as well as the 1-hr tests. Powerplant discharge, distance from lights, and date were significant factors in the analysis. (2) Behavioral results indicated that fish within 14 m of the lights were trying to avoid the lights by swimming across the lighted region or

  20. Chief Joseph Kokanee Enhancement Project; Strobe Light Deterrent Efficacy Test and Fish Behavior Determination at the Grand Coulee Dam Third Powerplant Forebay, 2003-2004 Annual Report.

    SciTech Connect

    Simmons, M.; McKinstry, C.; Cook, C.

    2004-01-01

    Since 1995, the Confederated Tribes of the Colville Reservation (Colville Confederated Tribes) have managed the Chief Joseph Kokanee Enhancement Project as part of the Northwest Power Planning Council (NWPPC) Fish and Wildlife Program. Project objectives have focused on understanding natural production of kokanee (a land-locked sockeye salmon) and other fish stocks in the area above Grand Coulee and Chief Joseph Dams on the Columbia River. A 42-month investigation from 1996 to 1999 determined that from 211,685 to 576,676 fish were entrained annually at Grand Coulee Dam. Analysis of the entrainment data found that 85% of the total entrainment occurred at the dam's third powerplant. These numbers represent a significant loss to the tribal fisheries upstream of the dam. In response to a suggestion by the NWPPC Independent Scientific Review Panel, the scope of work for the Chief Joseph Kokanee Enhancement Project was expanded to include a multiyear pilot test of a strobe light system to help mitigate fish entrainment. This report details the work conducted during the third year of the strobe light study by researchers of the Colville Confederated Tribes in collaboration with the Pacific Northwest National Laboratory. The objective of the study is to determine the efficacy of a prototype strobe light system to elicit a negative phototactic response in kokanee and rainbow trout under field conditions. The prototype system consists of six strobe lights affixed to an aluminum frame suspended 15 m vertically underwater from a barge secured in the center of the entrance to the third powerplant forebay. The lights, controlled by a computer, illuminate a region directly upstream of the barge. The 2003 study period extended from June 16 through August 1. Three light treatments were used: all six lights on for 24 hours, all lights off for 24 hours, and three of six lights cycled on and off every hour for 24 hours. These three treatment conditions were assigned randomly within a

  1. The Development and Evaluation of an Achievement Test for Measuring the Efficacy of Task-Based Writing Activities to Enhance Iranian EFL Learners' Reading Comprehension

    ERIC Educational Resources Information Center

    Nejad, Ferdows Mohsen; Khosravian, Fereshteh

    2014-01-01

    The present study examined the reliability of an achievement test to measure the efficacy of task-based writing activities to improve Iranian EFL learners' reading comprehension at the intermediate level in a private language institute in Ilam, Iran, namely Alefba language institute. To achieve the goal, the techniques for evaluating reliability…

  2. Pre-Service Teachers' Knowledge of Phonemic Awareness: Relationship to Perceived Knowledge, Self-Efficacy Beliefs, and Exposure to a Multimedia-Enhanced Lecture

    ERIC Educational Resources Information Center

    Martinussen, Rhonda; Ferrari, Julia; Aitken, Madison; Willows, Dale

    2015-01-01

    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…

  3. Using Vicarious Experience and Verbal Persuasion to Enhance Self-Efficacy in Pre-Service Teachers: "Priming the Pump" for Consultation.

    ERIC Educational Resources Information Center

    Hagen, Kenneth M.; Gutkin, Terry B.; Wilson, Caryll Palmer; Oats, Robert G.

    1998-01-01

    Investigates whether self-efficacy perceptions pertaining to working with difficult-to-teach children could be increased for preservice teachers using vicarious experience and verbal persuasion. Experimental group viewed a videotape demonstrating behavior management procedures while the control group viewed a placebo video. Experimental group…

  4. Enhancing Physical Education and Sport Science Students' Self-Efficacy and Attitudes regarding Information and Communication Technologies through a Computer Literacy Course

    ERIC Educational Resources Information Center

    Papastergiou, Marina

    2010-01-01

    Information and Communication Technologies (ICT) have become an integral component of Physical Education (PE) and Sport Science (SS) curricula and professions. It is thus imperative that PE and SS students develop ICT skills, self-efficacy in ICT and positive attitudes towards ICT. This study was aimed at designing a computer literacy course…

  5. Lipid nanocarriers of a lipid-conjugated estrogenic derivative inhibit tumor growth and enhance cisplatin activity against triple-negative breast cancer: pharmacokinetic and efficacy evaluation.

    PubMed

    Andey, Terrick; Sudhakar, Godeshala; Marepally, Srujan; Patel, Apurva; Banerjee, Rajkumar; Singh, Mandip

    2015-04-06

    Breast cancer is the leading cause of malignancies among women globally. The triple negative breast cancer (TNBC) subtype is the most difficult to treat and accounts for 15% of all cases. Targeted therapies have been developed for TNBC but come short of clinical translation due to acquired tumor resistance. An effective therapy against TNBC must combine properties of target specificity, efficient tumor killing, and translational relevance. The objective of this study was to formulate a nontoxic, cationic, lipid-conjugated estrogenic derivative (ESC8), with demonstrated anticancer activity, for oral delivery in mice bearing triple negative breast cancer (TNBC) as xenograft tumors. The in vitro cell viability, Caco-2 permeability, and cell cycle dynamics of ESC8-treated TNBC cells were investigated. ESC8 was formulated as liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) and characterized for size, zeta potential, entrapment efficiency, size stability, and tumor biodistribution. Pharmacokinetic modeling of plasma concentration-time course data was carried out following intravenous and oral administration in Sprague-Dawley rats. In vivo efficacy investigation of ESC8-SLNC was carried out in Nu/Nu mice bearing MDA-MB-231 TNBC as xenograft tumors, and the molecular dynamics modulating tumor growth inhibition was analyzed by Western blot. In vitro ESC8 inhibited TNBC and non-TNBC cell viability with IC50 ranging from 1.81 to 3.33 μM. ESC8 was superior to tamoxifen and Cisplatin in inhibiting MDA-MB-231 cell viability; and at 2.0 μM ESC8 enhanced Cisplatin cytotoxicity 16-fold. Intravenous ESC8 (2.0 mg/kg) was eliminated at a rate of 0.048 ± 0.01 h(-1) with a half-life of 14.63 ± 2.95 h in rats. ESC8 was orally bioavailable (47.03%) as solid lipid nanoparticles (ESC8-SLN). ESC8-SLN (10 mg/kg/day, ×14 days, p.o.) inhibited breast tumor growth by 74% (P < 0.0001 vs control) in mice bearing MDA-MB-231 cells as xenografts; and when

  6. Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer

    PubMed Central

    Ren, Tao; Shan, Jinlu; Li, Mengxia; Qing, Yi; Qian, Chengyuan; Wang, Guangjie; Li, Qing; Lu, Guoshou; Li, Chongyi; Peng, Yu; Luo, Hao; Zhang, Shiheng; Yang, Yuxing; Cheng, Yi; Wang, Dong; Zhou, Shu-Feng

    2015-01-01

    AT-101 is a BH3 mimetic and pan-Bcl-2 inhibitor that has shown potent anticancer activity in non-small-cell lung cancer (NSCLC) in murine models, but failed to show clinical efficacy when used in combination with docetaxel in NSCLC patients. Our recent study has demonstrated that AT-101 enhanced the antitumor effect of cisplatin (CDDP) in a murine model of NSCLC via inhibition of the interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway. This study explored the underlying mechanisms for the enhanced anticancer activity of CDDP by AT-101. Our results show that, when compared with monotherapy, AT-101 significantly enhanced the inhibitory effects of CDDP on proliferation and migration of A549 cells and on tube formation and migration in human umbilical vein endothelial cells. AT-101 promoted the proapoptotic activity of CDDP in A549 cells. AT-101 also enhanced the inhibitory effect of CDDP on DNA repair and redox activities of apurinic/apyrimidinic endonuclease 1 (APE1) in A549 cells. In tumor tissues from nude mice treated with AT-101 plus CDDP or monotherapy, the combination therapy resulted in greater inhibition of angiogenesis and tumor cell proliferation than the monotherapy. These results suggest that AT-101 can enhance the antitumor activity of CDDP in NSCLC via inhibition of APE1 DNA repair and redox activities and by angiogenesis and induction of apoptosis, but other mechanisms cannot be excluded. We are now conducting a Phase II trial to examine the clinical efficacy and safety profile of combined use of AT-101 plus CDDP in advanced NSCLC patients. PMID:26089640

  7. Theoretical substantiation of biological efficacy enhancement for β-delayed particle decay {sup 9}C beam: A Monte Carlo study in combination with analysis with the local effect model approach

    SciTech Connect

    Tian, Liheng; Yan, Yuanlin; Ma, Yuanyuan; Huang, Qiyan; Li, Qiang Liu, Xinguo; Dai, Zhongying; Fu, Tingyan; He, Pengbo

    2016-03-15

    Purpose: To improve the efficacy of heavy ion therapy, β-delayed particle decay {sup 9}C beam as a double irradiation source for cancer therapy has been proposed. The authors’ previous experiment showed that relative biological effectiveness (RBE) values at the depths around the Bragg peak of a {sup 9}C beam were enhanced and compared to its stable counterpart {sup 12}C beam. The purpose of this study was to explore the nature of the biological efficacy enhancement theoretically. Methods: A Monte Carlo simulation study was conducted in this study. First a simplified cell model was established so as to form a tumor tissue. Subsequently, the tumor tissue was imported into the Monte Carlo simulation software package GATE and then the tumor cells were virtually irradiated with comparable {sup 9}C and {sup 12}C beams, respectively, in the simulations. The transportation and particle deposition data of the {sup 9}C and {sup 12}C beams, derived from the GATE simulations, were analyzed with the authors’ local effect model implementation so as to deduce cell survival fractions. Results: The particles emitted from the decay process of deposited {sup 9}C particles around a cell nucleus increased the dose delivered to the nucleus and elicited clustered damages around the secondary particles’ trajectories. Therefore, compared to the {sup 12}C beam, the RBE value of the {sup 9}C beam increased at the depths around their Bragg peaks. Conclusions: Collectively, the increased local doses and clustered damages due to the decayed particles emitted from deposited {sup 9}C particles led to the RBE enhancement in contrast with the {sup 12}C beam. Thus, the enhanced RBE effect of a {sup 9}C beam for a simplified tumor model was shown theoretically in this study.

  8. Going Below Minimums: The Efficacy of Display Enhanced/Synthetic Vision Fusion for Go-Around Decisions during Non-Normal Operations

    NASA Technical Reports Server (NTRS)

    Prinzel, Lawrence J., III; Kramer, Lynda J.; Bailey, Randall E.

    2007-01-01

    The use of enhanced vision systems in civil aircraft is projected to increase rapidly as the Federal Aviation Administration recently changed the aircraft operating rules under Part 91, revising the flight visibility requirements for conducting approach and landing operations. Operators conducting straight-in instrument approach procedures may now operate below the published approach minimums when using an approved enhanced flight vision system that shows the required visual references on the pilot's Head-Up Display. An experiment was conducted to evaluate the complementary use of synthetic vision systems and enhanced vision system technologies, focusing on new techniques for integration and/or fusion of synthetic and enhanced vision technologies and crew resource management while operating under these newly adopted rules. Experimental results specific to flight crew response to non-normal events using the fused synthetic/enhanced vision system are presented.

  9. Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects.

    PubMed

    Largent-Milnes, T M; Brookshire, S W; Skinner, D P; Hanlon, K E; Giuvelis, D; Yamamoto, T; Davis, P; Campos, C R; Nair, P; Deekonda, S; Bilsky, E J; Porreca, F; Hruby, V J; Vanderah, T W

    2013-10-01

    The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

  10. Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

    PubMed Central

    Largent-Milnes, T. M.; Brookshire, S. W.; Skinner, D. P.; Hanlon, K. E.; Giuvelis, D.; Yamamoto, T.; Davis, P.; Campos, C. R.; Nair, P.; Deekonda, S.; Bilsky, E. J.; Porreca, F.; Hruby, V. J.

    2013-01-01

    The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain. PMID:23860305

  11. Comparative in vitro and in vivo studies on long-wavelength photosensitizers derived from bacteriopurpurinimide and Bacteriochlorin p6: fused imide ring enhances the in vivo PDT efficacy.

    PubMed

    Chen, Yihui; Potter, William R; Missert, Joseph R; Morgan, Janet; Pandey, Ravindra K

    2007-01-01

    In situ conversion of bacteriochlorophyll-a, present in Rhodobacter sphaeroides (Rb. sphaeroides) gave bacteriopurpurin-18 in modest yield, which in a sequence of reactions was converted into two series of bacteriochlorins: bacteriopurpurinimide and bacteriopurpurin p6 with and without a fused imide ring system, respectively. To determine the effect of overall lipophilicity in photosensitizing efficacy, these bacteriochlorins were independently reacted with HBr gas and subsequently treated with various alkyl alcohols to afford the corresponding alkyl ether derivatives as diastereomeric mixtures (the R- and S-isomers were obtained in almost equal ratios). Between the two series of bacteriochlorins, the bacteriopurpurinimides containing a fused imide ring system were found to be more effective in vivo (C3H mice bearing RIF tumors). To investigate the effect of the presence of the chiral center at position 3 of the most effective purpurinimide 9 [3(1'-heptyloxy)ethyl-3-deacetyl-bacteriopurpurin-18-N-hexylimide propyl ester], the acetyl group was replaced with a hydroxymethyl substituent and converted into 3(1'-decyloxy)methyl-3-deacetyl-purpurin-18-N-hexylimide methyl ester 26 with a similar lipophilicity. Interestingly, compared to 26, the bacteriopurpurinimide 9 was found to be more effective, suggesting that the chiral center at position 3 certainly plays an important role in photosensitizing activity. Among a series of alkyl ether analogues, between the PDT efficacy and the lipophilicity (log P and log D) calculated by computational methods (PALLAS program), a parabolic relationship was observed to some extent. However, it was limited to a particular series, e.g., compounds with similar log P values between bacteriopurpurinimides and bacteriochlorin e6 did not produce similar in vivo efficacy. As expected, within a series, a linear relationship was observed between the log P values and the HPLC retention times of the photosensitizers. Some of the mitochondrial

  12. Inhibition of the Protein Tyrosine Phosphatase, SHP-1, in Dendritic Cells to Enhance their Efficacy as Cell-Based Prostate Cancer Vaccines

    DTIC Science & Technology

    2008-05-01

    hypothesis that the Src homology region 2 domain-containing phosphatase-1 (SHP-1), is a global inhibitor of DC activation and that by blocking SHP-1 in... inhibitor of DC function and that its inhibition in DCs enhances the strength of immune responses. Finally, using 2 ectopic mouse tumor models (B16 melanoma...enhance function and to overcome the limitations of the "first-generation vaccines". Our specific approach is to inhibit inhibitors of DC function

  13. Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis

    PubMed Central

    Kanakaraj, Palanisamy; Puffer, Bridget A.; Yao, Xiao-Tao; Kankanala, Spandana; Boyd, Ernest; Shah, Rutul R.; Wang, Geping; Patel, Dimki; Krishnamurthy, Rajesh; Kaithamana, Shashi; Smith, Rodger G.; LaFleur, David W.; Barbas III, Carlos F.; Hilbert, David M.; Kiener, Peter A.; Roschke, Viktor V.

    2012-01-01

    Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone. PMID:22864384

  14. Metronomic paclitaxel-loaded mPEG-PLA nanoparticles show enhanced anti-tumor efficacy compared to maximum tolerated dose administration

    NASA Astrophysics Data System (ADS)

    Fei, Tan; Yang, Lian-juan; Mo, Xiao-hui; Wang, Xiu-li; Jun, Gu

    2014-11-01

    Low-dose metronomic (LDM) chemotherapy with cytotoxic agents, aimed at disrupting tumor endothelial cells, is an alternative method to maximum tolerated dose chemotherapy targeting proliferating tumor cells in clinical practice. However, even in the LDM schedule, cytotoxic agents still exhibit serious side effects due to non-distribution and high accumulated doses in the body. Nanocarriers can maximize the efficacy of the encapsulated drug by adjusting the pharmacokinetics and bio-distribution pattern, and minimize excessive toxic side effects. In the present study, we prepared polyethylene glycol (PEG)-coated stealth nanoparticles containing paclitaxel (PTX-NP) in order to evaluate their accumulation in tumor and their anti-tumor activity following LDM administration. PTX-NPs were prepared by a modified emulsification/solvent diffusion method with methoxy PEG-poly(lactide). The in vitro viability, migration, and tube formation of primary human umbilical vein endothelial cells, in addition to thrombospondin-1 positive expression and microvessel density in vivo, confirmed the anti-angiogenic activity of PTX-NP. The cellular uptake and retention study, in addition to pharmacokinetics in Sprague-Dawley rats demonstrated sustained circulation of PTX-NP. The in vivo tumor accumulation of PTX-NP was monitored using the Xenogen IVIS 200 non-invasive optical imaging system. The anti-tumor activity of LDM PTX-NP was studied in B16 melanoma cancer-bearing mice in vivo. In conclusion, PTX-NP improved tumor accumulation and anti-tumor efficacy following LDM administration.

  15. Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells.

    PubMed

    Qiu, Ming; Peng, Qinghai; Jiang, Ivy; Carroll, Christopher; Han, Guangzhou; Rymer, Isha; Lippincott, John; Zachwieja, Joseph; Gajiwala, Ketan; Kraynov, Eugenia; Thibault, Stephane; Stone, Donna; Gao, Yijie; Sofia, Susan; Gallo, Jorge; Li, Gang; Yang, Jennifer; Li, Kang; Wei, Ping

    2013-01-28

    Recent evidence suggests that Notch signaling may play a role in regulation of cancer stem cell (CSC) self-renewal and differentiation hence presenting a promising target for development of novel therapies for aggressive cancers such as triple negative breast cancer (TNBC). We generated Notch1 monoclonal antibodies (mAbs) that specifically bind to the negative regulatory region of human Notch1. Notch1 inhibition in TNBC Sum149 and patient derived xenograft (PDX) 144580 models led to significant TGI particularly in combination with docetaxel. More interestingly, Notch1 mAbs caused a reduction in mammosphere formation and CD44+/CD24-/lo cell population. It also resulted in decreased tumor incidence upon re-implantation and delay in tumor recurrence. Our data demonstrated a potent antitumor efficacy of Notch1 mAbs, with a remarkable activity against CSCs. These findings suggest that anti-Notch1 mAbs may provide novel therapies to improve the efficacy of conventional therapies by directly targeting the CSC niche. They may also delay tumor recurrence and hence have a major impact on cancer patient survival.

  16. Non-RVD mutations that enhance the dynamics of the TAL repeat array along the superhelical axis improve TALEN genome editing efficacy

    PubMed Central

    Tochio, Naoya; Umehara, Kohei; Uewaki, Jun-ichi; Flechsig, Holger; Kondo, Masaharu; Dewa, Takehisa; Sakuma, Tetsushi; Yamamoto, Takashi; Saitoh, Takashi; Togashi, Yuichi; Tate, Shin-ichi

    2016-01-01

    Transcription activator-like effector (TALE) nuclease (TALEN) is widely used as a tool in genome editing. The DNA binding part of TALEN consists of a tandem array of TAL-repeats that form a right-handed superhelix. Each TAL-repeat recognises a specific base by the repeat variable diresidue (RVD) at positions 12 and 13. TALEN comprising the TAL-repeats with periodic mutations to residues at positions 4 and 32 (non-RVD sites) in each repeat (VT-TALE) exhibits increased efficacy in genome editing compared with a counterpart without the mutations (CT-TALE). The molecular basis for the elevated efficacy is unknown. In this report, comparison of the physicochemical properties between CT- and VT-TALEs revealed that VT-TALE has a larger amplitude motion along the superhelical axis (superhelical motion) compared with CT-TALE. The greater superhelical motion in VT-TALE enabled more TAL-repeats to engage in the target sequence recognition compared with CT-TALE. The extended sequence recognition by the TAL-repeats improves site specificity with limiting the spatial distribution of FokI domains to facilitate their dimerization at the desired site. Molecular dynamics simulations revealed that the non-RVD mutations alter inter-repeat hydrogen bonding to amplify the superhelical motion of VT-TALE. The TALEN activity is associated with the inter-repeat hydrogen bonding among the TAL repeats. PMID:27883072

  17. Anti-PD-1 inhibits Foxp3(+) Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model.

    PubMed

    Dyck, Lydia; Wilk, Mieszko M; Raverdeau, Mathilde; Misiak, Alicja; Boon, Louis; Mills, Kingston H G

    2016-12-01

    The co-inhibitory molecule PD-1 suppresses T cell responses and has been targeted in the treatment of cancer. Here, we examined the role of PD-1 in regulating the balance between regulatory and effector T cells and whether blocking PD-1 could enhance tumour vaccine-induced protective immunity. A significantly higher proportion of tumour-resident T cells expressed PD-1 and Foxp3 compared with T cells in the tumour circulation or draining lymph nodes, and this correlated with a lower frequency of IFN-γ- and TNF-secreting CD8 T cells. Blocking PD-1 with a specific antibody reduced Foxp3(+) regulatory T (Treg) cell induction and enhanced proliferation, cytokine production, and tumour killing by CD8 T cells. Treatment of CT26 tumour-bearing mice with anti-PD-1 in combination with a vaccine, comprising heat-shocked irradiated tumour cells and a TLR 7/8 agonist, significantly reduced tumour growth and enhanced survival. Furthermore, surviving mice resisted tumour re-challenge. The rejection of tumours in mice treated with the anti-PD-1 vaccine combination was associated with a reduction in tumour-infiltrating Treg cells and enhancement of IFN-γ-secreting CD8 T cells. Our findings demonstrate that high PD-1 expression correlates with increased tumour-infiltrating Treg cells and reduced effector T cells and that when combined with a potent antigen-adjuvant combination, blocking PD-1 effectively enhances anti-tumour immunity.

  18. Fermenting red ginseng enhances its safety and efficacy as a novel skin care anti-aging ingredient: in vitro and animal study.

    PubMed

    Lee, Hyun-Sun; Kim, Mi-Ryung; Park, Yooheon; Park, Hyo Jung; Chang, Un Jae; Kim, Sun Young; Suh, Hyung Joo

    2012-11-01

    The objective of this study was to evaluate the anti-aging potential and skin safety of red ginseng (RG) and fermented red ginseng (FRG) using Lactobacillus brevis for use as cosmetic ingredients. Concentrations of uronic acid, polyphenols, and flavonoids, and antioxidant activities were greater in FRG compared to RG. The contents of total ginsenosides were not significantly different. However, the ginsenoside metabolite content was higher in FRG (14,914.3 μg/mL) compared to RG (5697.9 μg/mL). The tyrosinase inhibitory activity (IC(50)) of FRG was 27.63 μg/mL, and more potent compared with RG (34.14 μg/mL), (P<.05). The elastase inhibitory activity (IC(50)) of FRG was 117.07 μg/mL also higher compared with RG (157.90 μg/mL). In a primary skin irritation test, 10% RG and 10% FRG were classified as practically nonirritating materials. In a skin sensitization test, the RG group showed a sensitization rate of 100% and its mean evaluation score of irritation was 1.4, whereas the FRG group showed 20% and 0.2%, respectively. By fermentation of RG, FRG has increased contents of ginsenoside metabolites, such as Rg3, Rg5, Rk1, compound K, Rh1, F2, Rg2, and flavonoids content. Therefore, FRG offers increased anti-wrinkle efficacy, whitening efficacy, and reduced toxicological potency compared to RG.

  19. Fermenting Red Ginseng Enhances Its Safety and Efficacy as a Novel Skin Care Anti-Aging Ingredient: In Vitro and Animal Study

    PubMed Central

    Lee, Hyun-Sun; Kim, Mi-Ryung; Park, Yooheon; Park, Hyo Jung; Chang, Un Jae; Kim, Sun Young

    2012-01-01

    Abstract The objective of this study was to evaluate the anti-aging potential and skin safety of red ginseng (RG) and fermented red ginseng (FRG) using Lactobacillus brevis for use as cosmetic ingredients. Concentrations of uronic acid, polyphenols, and flavonoids, and antioxidant activities were greater in FRG compared to RG. The contents of total ginsenosides were not significantly different. However, the ginsenoside metabolite content was higher in FRG (14,914.3 μg/mL) compared to RG (5697.9 μg/mL). The tyrosinase inhibitory activity (IC50) of FRG was 27.63 μg/mL, and more potent compared with RG (34.14 μg/mL), (P<.05). The elastase inhibitory activity (IC50) of FRG was 117.07 μg/mL also higher compared with RG (157.90 μg/mL). In a primary skin irritation test, 10% RG and 10% FRG were classified as practically nonirritating materials. In a skin sensitization test, the RG group showed a sensitization rate of 100% and its mean evaluation score of irritation was 1.4, whereas the FRG group showed 20% and 0.2%, respectively. By fermentation of RG, FRG has increased contents of ginsenoside metabolites, such as Rg3, Rg5, Rk1, compound K, Rh1, F2, Rg2, and flavonoids content. Therefore, FRG offers increased anti-wrinkle efficacy, whitening efficacy, and reduced toxicological potency compared to RG. PMID:23126662

  20. Methylseleninic Acid Enhances Taxane Drug Efficacy against Human Prostate Cancer and Down-Regulates ntiapoptotic roteins Bcl-XL and Survivin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE: Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (taxol) through enhancing multiple caspases. This study aimed to: 1) determine the general applicability of the sensitization effect ...

  1. A Pilot Study of the Feasibility and Efficacy of the Strategies to Enhance Positive Parenting (STEPP) Program for Single Mothers of Children with ADHD

    ERIC Educational Resources Information Center

    Chacko, Anil; Wymbs, Brian T.; Flammer-Rivera, Lizette M.; Pelham, William E.; Walker, Kathryn S.; Arnold, Fran W.; Visweswaraiah, Hema; Swanger-Gagne, Michelle; Girio, Erin L.; Pirvics, Lauma L.; Herbst, Laura

    2008-01-01

    Objective: The Strategies to Enhance Positive Parenting (STEPP) program was developed to address putative factors related to poor engagement in and outcomes following traditional behavioral parent training (BPT) for single mothers of children diagnosed with ADHD. Method: Twelve single mothers of children with ADHD were enrolled in an initial…

  2. Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.

    PubMed

    Dahlén, Eva; Barchan, Karin; Herrlander, Daniel; Höjman, Patrik; Karlsson, Marie; Ljung, Lill; Andersson, Mats; Bäckman, Eva; Hager, Ann-Christin Malmborg; Walse, Björn; Joosten, Leo; van den Berg, Wim

    2008-04-01

    Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic

  3. A randomized controlled trial to evaluate the relative efficacy of enhanced versus standard voluntary counseling and testing on promoting condom use among men who have sex with men in China.

    PubMed

    Hao, Chun; Huan, Xiping; Yan, Hongjing; Yang, Haitao; Guan, Wenhui; Xu, Xiaoqin; Zhang, Min; Wang, Na; Tang, Weiming; Gu, Jing; Lau, Joseph T F

    2012-07-01

    The randomized controlled trial investigated the relative efficacy of an enhanced (EVCT) versus standard (SVCT) voluntary counseling and testing in reducing unprotected anal intercourse (UAI) among men who have sex with men (MSM) in China. 295 participants who recruited by respondent driven sampling methods were randomly allocated to the two arms. In addition to the SVCT, the EVCT group watched a theory-based video narrated by a HIV positive MSM, received enhanced counseling and a reminder gift. As compared to the SVCT group, the EVCT group reported lower prevalence of UAI with any male sex partners (48.4% versus 66.7%, RR = 0.7, ARR = -18.3%, p = 0.010) and with regular male sex partners (52.2% versus 68.9%, RR = 0.8, ARR = -16.7%, p = 0.043) at Month 6, whilst baseline between-group differences were statistically non-significant. Between-group differences in HIV/syphilis incidence were statistically non-significant. Translational research should be conducted to integrate non-intensive enhancements such as the EVCT into regular testing services.

  4. Efficacy of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) in adults with community-acquired pneumonia caused by Streptococcus pneumoniae, including penicillin-resistant strains.

    PubMed

    File, Thomas M; Garau, Javier; Jacobs, Michael R; Wynne, Brian; Twynholm, Monique; Berkowitz, Elchonon

    2005-02-01

    Community-acquired pneumonia (CAP) is a common respiratory illness, frequently caused by Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to common antimicrobials has increased over recent years. A new pharmacokinetically enhanced formulation of amoxicillin/clavulanate (2000/125 mg) has been developed, designed to combat infections caused by S. pneumoniae, including penicillin-resistant (PRSP, penicillin minimum inhibitory concentrations (MICs) >or=2mg/l) isolates, and those with elevated amoxicillin/clavulanic acid MICs, while maintaining coverage of beta-lactamase-producing pathogens. A pooled efficacy analysis of four randomized (1:1) and one non-comparative clinical trials of amoxicillin/clavulanate, 2000/125 mg, given twice daily, was conducted in adult patients with CAP. Comparator agents were conventional amoxicillin/clavulanate formulations. At follow-up (days 16-39), efficacy (eradication of the initial pathogen or clinical cure in patients for whom no repeat culture was performed) in patients with S. pneumoniae infection was 92.3% (274/297) for amoxicillin/clavulanate, 2000/125 mg and 85.2% (46/54) for comparators (P=0.11). Twenty-four of 25 PRSP-infected patients receiving amoxicillin/clavulanate, 2000/125 mg were treated successfully. Both amoxicillin/clavulanate, 2000/125 mg and comparators were well tolerated, with few patients withdrawing from the studies.

  5. Inhibition of the Protein Tyrosine Phosphatase, SHP-1, in Dendritic Cells to Enhance their Efficacy as Cell-Based Prostate Cancer Vaccines

    DTIC Science & Technology

    2009-05-01

    inhibitor of DC activation and that by blocking SHP-1in DC would induce stronger anti-tumor immunity. Our results demonstrate that inhibition of SHP...observations suggest that SHP-1 is a pleiotropic inhibitor ofDC function and that its inhibition in DCs enhances the strength of immune responses...approach is to inhibit inhibitors of DC function that normally serve to regulate the initiation of immune responses. We hypothesized that the Src

  6. Nano-Encapsulation of Arsenic Trioxide Enhances Efficacy against Murine Lymphoma Model while Minimizing Its Impact on Ovarian Reserve In Vitro and In Vivo

    PubMed Central

    Raja, Meera R.; Jozefik, Jennifer K.; Spaho, Lidia; Chen, Haimei; Bally, Marcel B.; Mazar, Andrew P.; Avram, Michael J.; Winter, Jane N.; Gordon, Leo I.; Shea, Lonnie D.; O’Halloran, Thomas V.; Woodruff, Teresa K.

    2013-01-01

    Advances in cancer therapy have increased the rate of survival of young cancer patients; however, female lymphoma patients frequently face a temporary or permanent loss of fertility when treated with traditional cytotoxic agents. The potential loss of fertility is an important concern that can influence treatment decisions for many premenopausal cancer patients. The negative effect of chemotherapeutic agents and treatment protocols to patients’ fertility–referred to as fertotoxicity–are thus an increasingly important cancer survivorship issue. We have developed a novel nanoscale formulation of arsenic trioxide, a potent drug for treatment of hematological malignancies, and demonstrate that it has significantly better activity in a murine lymphoma model than the free drug. In parallel, we have developed a novel in vitro assay of ovarian follicle function that predicts in vivo ovarian toxicity of therapeutic agents. Our results reveal that the nanotherapeutic agent is not only more active against lymphoma, but is fertoprotective, i.e., it is much less deleterious to ovarian function than the parent drug. Thus, our in vitro assay allows rapid evaluation of both established and experimental anticancer drugs on ovarian reserve and can inform the selection of efficacious and fertility-sparing treatment regimens for reproductive-age women diagnosed with cancer. PMID:23526987

  7. A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody-ribonuclease fusion protein targeting the EGF receptor.

    PubMed

    Kiesgen, Stefan; Liebers, Nora; Cremer, Martin; Arnold, Ulrich; Weber, Tobias; Keller, Armin; Herold-Mende, Christel; Dyckhoff, Gerhard; Jäger, Dirk; Kontermann, Roland E; Arndt, Michaela A E; Krauss, Jürgen

    2014-10-01

    Due to its frequent overexpression in a variety of solid tumors the epidermal growth factor receptor (EGFR) is a well-established target for therapeutic interventions in epithelial cancers. In order to target EGFR in head and neck cancer, we have generated a ribonuclease (RNase) fusion protein comprising a humanized anti-EGFR antibody single-chain Fv fragment (scFv) and Ranpirnase, an RNase from Rana pipiens. Fusion of Ranpirnase to the N-terminus of the scFv via a flexible glycine-serine linker (G4S)3 resulted in very poor cytotoxicity of the fusion protein. As endosomal accumulation and lysosomal degradation have been reported to diminish the antitumor efficacy of ribonuclease or toxin-based immunoagents, we explored a fusion peptide from dengue virus that has been reported to be involved in the endosomal escape of the virus. This peptide was introduced as a linker between Ranpirnase and the scFv moiety. The modified immunoRNase exhibited exceptionally high cytotoxicity toward EGFR-expressing head and neck cell lines without affecting specificity. These results indicate that endosomal entrapment needs to be considered for Ranpirnase-based immunoagents and might be overcome by the use of tailored transduction domains from viral proteins.

  8. Enhanced immunogenicity of multiple-epitopes of foot-and-mouth disease virus fused with porcine interferon alpha in mice and protective efficacy in guinea pigs and swine.

    PubMed

    Du, Yijun; Li, Yufeng; He, Hairong; Qi, Jing; Jiang, Wenming; Wang, Xinglong; Tang, Bo; Cao, Jun; Wang, Xianwei; Jiang, Ping

    2008-04-01

    Foot-and-mouth disease (FMD) is a highly contagious and economically devastating vesicular disease of cloven-hoofed animals. In this study, three amino acid residues 21-60, 141-160 and 200-213 from VP1 protein of FMDV were selected as multiple-epitopes (VPe), and a recombinant adenovirus expressing the multiple-epitopes fused with porcine interferon alpha (rAd-pIFN alpha-VPe) was constructed. Six groups of female BALB/c mice (18 mice per group) were inoculated subcutaneously (s.c.) twice at 2-week intervals with the recombinant adenoviruses and the immune responses were examined. Following this the protective efficacy of rAd-pIFN alpha-VPe was examined in guinea pigs and swine. The results showed that both FMDV-specific humoral and cell-mediated immune responses could be induced by rAd-VPe and increased when rAd-pIFN alpha is included in this regime in mice model. Moreover, the levels of the immune responses in the group inoculated with rAd-pIFN alpha-VPe were significantly higher than the group inoculated with rAd-VPe plus rAd-pIFN alpha. All guinea pigs and swine vaccinated with rAd-pIFN alpha-VPe were completely protected from viral challenge. It demonstrated that recombinant adenovirus rAd-pIFN alpha-VPe might be an attractive candidate vaccine for preventing FMDV infection.

  9. Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer

    PubMed Central

    Shiota, Masaki; Bishop, Jennifer L.; Takeuchi, Ario; Nip, Ka Mun; Cordonnier, Thomas; Beraldi, Eliana; Kuruma, Hidetoshi; Gleave, Martin E.; Zoubeidi, Amina

    2015-01-01

    Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC. PMID:25871401

  10. Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer

    PubMed Central

    Yang, Chih-Yung; Liu, Hong-Wen; Tsai, Ya-Ching; Tseng, Ju-Yu; Liang, Shu-Ching; Chen, Chin-Yau; Lian, Wei-Nan; Wei, Ming-Cheng; Lu, Maggie; Lu, Ruey-Hwa; Lin, Chi-Hung; Jiang, Jeng-Kai

    2015-01-01

    Our previous studies showed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Rα. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Rα-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Rα-overexpressing CT26 cells. AP1-conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy. PMID:26436767

  11. Enhancement of the efficacy of a combination of Mesocyclops aspericornis and Bacillus thuringiensis var. israelensis by community-based products in controlling Aedes aegypti larvae in Thailand.

    PubMed

    Kosiyachinda, Pahol; Bhumiratana, Amaret; Kittayapong, Pattamaporn

    2003-08-01

    Prolonged efficacy of a combination of bacteria (Bacillus thuringiensis var. israelensis [Bti] and copepods (Mesocyclops aspericornis) in controlling immature forms of Aedes aegypti in peridomestic water containers was achieved by adding various products from local villages as supplementary food for copepods. In all experiments, 100 first-instar larvae were added into the breeding containers every day for eight weeks. Combinations of biological control agents and each local supplementary food were applied once at the beginning of the experiment. At the end of the experiment, the average number of mosquito larvae in containers with a combination of copepods and Bti with one gram of rice grain had decreased to only 0.5% of that with no control agent. In comparison, the average numbers of mosquito larvae in containers with Bti only, or copepods only, were approximately 10% and 33% of those in containers with no control agents, respectively. In addition, the number of copepods in containers with mosquito larvae and supplementary food was at least three times higher than those with mosquito larvae alone.

  12. Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non-Small-Cell Lung Cancer

    SciTech Connect

    Shibuya, Keiko; Komaki, Ritsuko; Shintani, Tomoaki; Itasaka, Satoshi; Ryan, Anderson; Juergensmeier, Juliane M.; Milas, Luka; Ang, Kian; Herbst, Roy S.; O'Reilly, Michael S.

    2007-12-01

    Purpose: Conventional therapies for patients with lung cancer have reached a therapeutic plateau. We therefore evaluated the feasibility of combined vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and epidermal growth factor (EGF) receptor (EGFR) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer. Methods and Materials: Effects of irradiation and/or ZD6474, a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays. The feasibility of combining ZD6474 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma. Lung tumor burden and spread within the thorax were assessed, and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters, including CD31, VEGF, VEGFR2, EGF, EGFR, matrix metalloproteinase-2 and -9, and basic fibroblast growth factor. Results: ZD6474 enhanced the radioresponse of NCI-H441 human lung adenocarcinoma cells by a factor of 1.37 and markedly inhibited sublethal damage repair. In vivo, the combined blockade of VEGFR2 and EGFR by ZD6474 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy. Conclusions: When radiation therapy is combined with VEGFR2 and EGFR blockade, significant enhancement of antiangiogenic, antivascular, and antitumor effects are seen in an orthotopic model of lung cancer. These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer.

  13. A comparative study on the enhancement efficacy of specific and non-specific iron chelators for protoporphyrin IX production and photosensitization in HaCat cells.

    PubMed

    Xia, Yumin; Huang, Yingying; Lin, Longde; Liu, Xiaoming; Jiang, Shan; Xiong, Layuan

    2009-12-01

    The iron chelators can be utilized in target cells to improve 5-aminolaevulinic acid (ALA)-based photodynamic therapy (PDT). The purpose of this study is to compare the effect of two kinds of iron chelators, desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA) on the enhancement of ALA-PDT. HaCat cells were cultured in medium containing 2.0 mmol/L of ALA and 0.5 mmol/L of DFO or EDTA. After 3-h incubation in the dark, the concentration of cellular protoporphyrin IX (PpIX) was detected by high performance liquid chromatography (HPLC), and the fluorescence of PpIX was observed at 630 nm emission under confocal laser scanning microscope. For PDT, HaCat cells were irradiated using 632.8 nm laser, and the fractions of apoptotic and necrotic cells were flow cytometrically assayed. Related differences in morphology and ultrastructure of Ha-Cat cells were observed using optical microscope or transmission electron microscope. Compared to incubation with ALA alone, the addition of DFO or EDTA increased the concentration of cellular PpIX and the fluorescent density of PpIX, and also increased cell death ratio after PDT. PDT using ALA plus DFO produced the highest cellular PpIX level, greatest cell death ratio and most severe structural damage to the cells. It was concluded that both DFO and EDTA could enhance ALA-based PpIX production and PDT. Compared to the non-specific iron chelator of EDTA, the specific chelator, DFO, showed more potential for the enhancement.

  14. Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells

    PubMed Central

    Wei, Fang; Wang, Huiping; Chen, Xiafang; Li, Chuanyuan; Huang, Qian

    2014-01-01

    Oncolytic viruses have recently received widespread attention for their potential in innovative cancer therapy. Many telomerase promoter-regulated oncolytic adenoviral vectors retain E1A and E1B. However, the functions of E1A and E1B proteins in the oncolytic role of replication-competent adenovirus (RCAd) and RCAd enhanced transduction of replication defective adenoviruses (RDAd) have not been addressed well. In this study, we constructed viruses expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa. We then tested their roles in oncolysis and replication of RCAd as well as their roles in RCAd enhanced transfection rate and transgene expression of RDAd in various cancer cells in vitro and in xenografted human NCI-H460 tumors in nude mice. We demonstrated that RCAds expressing E1A alone and plus E1B-19 kDa exhibited an obvious ability in replication and oncolytic effects as well as enhanced RDAd replication and transgene expression, with the former showed more effective oncolysis, while the latter exhibited superior viral replication and transgene promotion activity. However, RCAd expressing both E1A and E1B-19 kDa/55 kDa was clearly worst in all these abilities. The effects of E1A and E1B observed through using RCAd were further validated by using plasmids expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa proteins. Our study provided evidence that E1A was essential for inducing replication and oncolytic effects of RCAd as well as RCAd enhanced RDAd transduction, and expression of E1B-19 kDa other than E1B-55 kDa could promote these effects. E1B-55 kDa is not necessary for the oncolytic effects of adenoviruses and somehow inhibits RCAd-mediated RDAd replication and transgene expression. PMID:25019940

  15. Combination photodynamic therapy using 5-fluorouracil and aminolevulinate enhances tumor-selective production of protoporphyrin IX and improves treatment efficacy of squamous skin cancers and precancers

    NASA Astrophysics Data System (ADS)

    Maytin, Edward V.; Anand, Sanjay

    2016-03-01

    In combination photodynamic therapy (cPDT), a small-molecule drug is used to modulate the physiological state of tumor cells prior to giving aminolevulinate (ALA; a precursor for protoporphyrin IX, PpIX). In our laboratory we have identified three agents (methotrexate, 5-fluorouracil, and vitamin D) that can enhance therapeutic effectiveness of ALAbased photodynamic therapy for cutaneous squamous cell carcinoma (SCC). However, only one (5-fluorouracil; 5-FU) is FDA-approved for skin cancer management. Here, we describe animal and human studies on 5-FU mechanisms of action, in terms of how 5-FU pretreatment leads to enhanced PpIX accumulation and improves selectivity of ALA-PDT treatment. In A431 subcutaneous tumors in mice, 5-FU changed expression of heme enzyme (upregulating coproporphyrinogen oxidase, and down-regulating ferrochelatase), inhibited tumor cell proliferation (Ki-67), enhanced differentiation (E-cadherin), and led to strong, tumor-selective increases in apoptosis. Interestingly, enhancement of apoptosis by 5-FU correlated strongly with an increased accumulation of p53 in tumor cells that persisted for 24 h post- PDT. In a clinical trial using a split-body, bilaterally controlled study design, human subjects with actinic keratoses (AK; preneoplastic precursors of SCC) were pretreated on one side of the face, scalp, or forearms with 5-FU cream for 6 days, while the control side received no 5-FU. On the seventh day, the levels of PpIX in 4 test lesions were measured by noninvasive fluorescence dosimetry, and then all lesions were treated with PDT using methyl-aminolevulinate (MAL) and red light (635 nm). Relative amounts of PpIX were found to be increased ~2-fold in 5-FU pretreated lesions relative to controls. At 3 months after PDT, the overall clinical response to PDT (reduction in lesion counts) was 2- to 3-fold better for the 5-FU pretreated lesions, a clinically important result. In summary, 5-FU is a useful adjuvant to aminolevulinate-based PDT

  16. Efficacy of FurosapTM, a novel Trigonella foenum-graecum seed extract, in Enhancing Testosterone Level and Improving Sperm Profile in Male Volunteers

    PubMed Central

    Maheshwari, Anuj; Verma, Narsingh; Swaroop, Anand; Bagchi, Manashi; Preuss, Harry G.; Tiwari, Kiran; Bagchi, Debasis

    2017-01-01

    Background: Dietary fiber rich fenugreek (Trigonella foenum-graecum) seeds have exhibited cardioprotective, hypolipidemic and other health benefits. Furosap (FS), an innovative, patented, 20% protodioscin-enriched extract was developed in our laboratory from fenugreek seeds. This study examined the free and total testosterone levels, sperm profile and morphology, sexual health, mood and mental alertness, and broad spectrum safety parameters of FS in 50 male volunteers following supplementation over a period of 12 weeks. Methods: Institutional Review Board (IRB) and other regulatory approvals were obtained for our study. This one-arm, open-labelled, multi-center study was conducted in 50 male volunteers (age: 35 to 65 years) over a period of 12 weeks to determine the efficacy of FS (500 mg/day/subject) on free and total testosterone levels, sperm profile, sperm morphology, libido and sexual health, mood and mental alertness, and broad spectrum safety parameters. Results: Free testosterone levels were improved up to 46% in 90% of the study population. 85.4% of the study population showed improvements in sperm counts. Sperm morphology improved in 14.6% of volunteers. Majority of the subjects enrolled in the study demonstrated improvements in mental alertness and mood. Furthermore, cardiovascular health and libido were significantly improved. Extensive safety parameters were evaluated which included blood chemistry data. No significant changes were observed in serum lipid function, cholesterol, triglyceride, HDL and LDL levels, hemogram (CBC), hepatotoxicity and nephrotoxicity. Conclusion: Overall, the results demonstrate that FS, enriched in 20% protodioscin, is safe and effective in attenuating testosterone levels, healthy sperm profile, mental alertness, cardiovascular health and overall performance in human subjects. PMID:28138310

  17. Enhanced in Vivo Efficacy of a Type I Interferon Superagonist with Extended Plasma Half-life in a Mouse Model of Multiple Sclerosis*

    PubMed Central

    Harari, Daniel; Kuhn, Nadine; Abramovich, Renne; Sasson, Keren; Zozulya, Alla L.; Smith, Paul; Schlapschy, Martin; Aharoni, Rina; Köster, Mario; Eilam, Raya; Skerra, Arne; Schreiber, Gideon

    2014-01-01

    IFNβ is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNβ. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via “PASylation.” PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35–55-induced experimental autoimmune encephalomyelitis compared with IFNβ, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b+/CD45hi myeloid lineage cells detectable in the CNS, as well as a decrease in IBA+ cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4+ cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease. PMID:25193661

  18. Ferrocene and (arene)ruthenium(II) complexes of the natural anticancer naphthoquinone plumbagin with enhanced efficacy against resistant cancer cells and a genuine mode of action.

    PubMed

    Spoerlein-Guettler, Cornelia; Mahal, Katharina; Schobert, Rainer; Biersack, Bernhard

    2014-09-01

    A series of ferrocene and (arene)ruthenium(II) complexes attached to the naturally occurring anticancer naphthoquinones plumbagin and juglone was tested for efficacy against various cancer cell lines and for alterations in the mode of action. The plumbagin ferrocene and (p-cymene)Ru(II) conjugates 1c and 2a overcame the multi-drug drug resistance of KB-V1/Vbl cervix carcinoma cells and showed IC50 (72 h) values around 1 μM in growth inhibition assays using 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT). They were further investigated for their influence on the cell cycle of KB-V1/Vbl and HCT-116 colon carcinoma cells, on the generation of reactive oxygen species (ROS) by the latter cell line, for their substrate character for the P-glycoprotein drug eflux pump via the calcein-AM efflux assays, and for DNA affinity by the electrophoretic mobility shift assay (EMSA). The derivatives 1c and 2a increased the number of dead cancer cells (sub-G0/G1 fraction) in a dose- and time-dependent manner. ROS levels were significantly increased upon treatment with 1c and 2a. These compounds also showed a greater affinity to linear DNA than plumbagin. While plumbagin did not affect calcein-AM transport by P-glycoprotein the derivatives 1c and 2a exhibited a 50% or 80% inhibition of the P-glycoprotein-mediated calcein-AM efflux relative to the clinically established sensitizer verapamil.

  19. Efficacy of nonselective optogenetic control of the medial septum over hippocampal oscillations: the influence of speed and implications for cognitive enhancement.

    PubMed

    Blumberg, Benjamin J; Flynn, Sean P; Barriere, Sylvain J; Mouchati, Philippe R; Scott, Rod C; Holmes, Gregory L; Barry, Jeremy M

    2016-12-01

    Optogenetics holds great promise for both the dissection of neural circuits and the evaluation of theories centered on the temporal organizing properties of oscillations that underpin cognition. To date, no studies have examined the efficacy of optogenetic stimulation for altering hippocampal oscillations in freely moving wild-type rats, or how these alterations would affect performance on behavioral tasks. Here, we used an AAV virus to express ChR2 in the medial septum (MS) of wild-type rats, and optically stimulated septal neurons at 6 Hz and 30 Hz. We measured the corresponding effects of these stimulations on the oscillations of the MS and hippocampal subfields CA1 and CA3 in three different contexts: (1) With minimal movement while the rats sat in a confined chamber; (2) Explored a novel open field; and (3) Learned and performed a T-maze behavioral task. While control yellow light stimulation did not affect oscillations, 6-Hz blue light septal stimulations altered hippocampal theta oscillations in a manner that depended on the animal's mobility and speed. While the 30 Hz blue light septal stimulations only altered theta frequency in CA1 while the rat had limited mobility, it robustly increased the amplitude of hippocampal signals at 30 Hz in both regions in all three recording contexts. We found that animals were more likely to make a correct choice during Day 1 of T-maze training during both MS stimulation protocols than during control stimulation, and that improved performance was independent of theta frequency alterations.

  20. Co-delivery of IL17RB siRNA and doxorubicin by chitosan-based nanoparticles for enhanced anticancer efficacy in breast cancer cells.

    PubMed

    Alinejad, Vahideh; Hossein Somi, Mohammad; Baradaran, Behzad; Akbarzadeh, Parvin; Atyabi, Fatemeh; Kazerooni, Hanif; Samadi Kafil, Hosein; Aghebati Maleki, Leili; Siah Mansouri, Homayoon; Yousefi, Mehdi

    2016-10-01

    Overexpression of IL17RB is associated with poor prognosis and short survival of the breast cancer patients.IL17RB/IL17B signaling triggers a substantial increase in the cell growth, proliferation and migration through the activation of NF-κB as well as the up-regulation of the Bcl-2. In this study we designed carboxymethyl dextran (CMD) Chitosan nanoparticles (ChNPs) to encapsulated IL17RB siRNA and doxorubicin (DOX) as an anticancer drug. Then we investigated the efficiency of the simultaneous delivery of drug/siRNA on viability and gene expression of MDA-MB361 cell lines. Furthermore the efficacy of dual agent nanoparticles to induce apoptosis and inhibit migration of breast cancer cells was assessed by Annexin-V and wound healing assays respectively. Our results showed that DOX-siRNA-CMD-ChNPs had about 114nm size; with polydispersity index and zeta potential about 0.3 and 10.1mV respectively. Fourier transform infrared spectroscopy (FTIR) confirmed the formation of DOX-siRNA-CMD-ChNPs complex. In addition IL17RB siRNA had significant effect on DOX-induced cytotoxicity in MDA-MB361 cells. Furthermore treatment with dual agent nanoparticles resulted in a significant silencing of NF-κB and Bcl-2 relative gene expression, apoptosis induction and migration inhibition in MDA-MB361 cells. In conclusion, co-delivery of IL17RB siRNA and DOX can be considered as an effective system for the treatment of breast cancer.

  1. Antibiotic-free nanotherapeutics: ultra-small, mucus-penetrating solid lipid nanoparticles enhance the pulmonary delivery and anti-virulence efficacy of novel quorum sensing inhibitors.

    PubMed

    Nafee, Noha; Husari, Ayman; Maurer, Christine K; Lu, Cenbin; de Rossi, Chiara; Steinbach, Anke; Hartmann, Rolf W; Lehr, Claus-Michael; Schneider, Marc

    2014-10-28

    Cystic fibrosis (CF) is a genetic disease mainly manifested in the respiratory tract. Pseudomonas aeruginosa (P. aeruginosa) is the most common pathogen identified in cultures of the CF airways, however, its eradication with antibiotics remains challenging as it grows in biofilms that counterwork human immune response and dramatically decrease susceptibility to antibiotics. P. aeruginosa regulates pathogenicity via a cell-to-cell communication system known as quorum sensing (QS) involving the virulence factor (pyocyanin), thus representing an attractive target for coping with bacterial pathogenicity. The first in vivo potent QS inhibitor (QSI) was recently developed. Nevertheless, its lipophilic nature might hamper its penetration of non-cellular barriers such as mucus and bacterial biofilms, which limits its biomedical application. Successful anti-infective inhalation therapy necessitates proper design of a biodegradable nanocarrier allowing: 1) high loading and prolonged release, 2) mucus penetration, 3) effective pulmonary delivery, and 4) maintenance of the anti-virulence activity of the QSI. In this context, various pharmaceutical lipids were used to prepare ultra-small solid lipid nanoparticles (us-SLNs) by hot melt homogenization. Plain and QSI-loaded SLNs were characterized in terms of colloidal properties, drug loading, in vitro release and acute toxicity on Calu-3 cells. Mucus penetration was studied using a newly-developed confocal microscopy technique based on 3D-time-lapse imaging. For pulmonary application, nebulization efficiency of SLNs and lung deposition using next generation impactor (NGI) were performed. The anti-virulence efficacy was investigated by pyocyanin formation in P. aeruginosa cultures. Ultra-small SLNs (<100nm diameter) provided high encapsulation efficiency (68-95%) according to SLN composition, high burst in phosphate buffer saline compared to prolonged release of the payload over >8h in simulated lung fluid with minor burst. All

  2. Enhancing Anti-Tumor Efficacy of Doxorubicin by Non-Covalent Conjugation to Gold Nanoparticles – In Vitro Studies on Feline Fibrosarcoma Cell Lines

    PubMed Central

    Wójcik, Michał; Lewandowski, Wiktor; Król, Magdalena; Pawłowski, Karol; Mieczkowski, Józef; Lechowski, Roman; Zabielska, Katarzyna

    2015-01-01

    Background Feline injection-site sarcomas are malignant skin tumors of mesenchymal origin, the treatment of which is a challenge for veterinary practitioners. Methods of treatment include radical surgery, radiotherapy and chemotherapy. The most commonly used cytostatic drugs are cyclophosphamide, doxorubicin and vincristine. However, the use of cytostatics as adjunctive treatment is limited due to their adverse side-effects, low biodistribution after intravenous administration and multidrug resistance. Colloid gold nanoparticles are promising drug delivery systems to overcome multidrug resistance, which is a main cause of ineffective chemotherapy treatment. The use of colloid gold nanoparticles as building blocks for drug delivery systems is preferred due to ease of surface functionalization with various molecules, chemical stability and their low toxicity. Methods Stability and structure of the glutathione-stabilized gold nanoparticles non-covalently modified with doxorubicin (Au-GSH-Dox) was confirmed using XPS, TEM, FT-IR, SAXRD and SAXS analyses. MTT assay, Annexin V and Propidium Iodide Apoptosis assay and Rhodamine 123 and Verapamil assay were performed on 4 feline fibrosarcoma cell lines (FFS1WAW, FFS1, FFS3, FFS5). Statistical analyses were performed using Graph Pad Prism 5.0 (USA). Results A novel approach, glutathione-stabilized gold nanoparticles (4.3 +/- 1.1 nm in diameter) non-covalently modified with doxorubicin (Au-GSH-Dox) was designed and synthesized. A higher cytotoxic effect (p<0.01) of Au-GSH-Dox than that of free doxorubicin has been observed in 3 (FFS1, FFS3, FFS1WAW) out of 4 feline fibrosarcoma cell lines. The effect has been correlated to the activity of glycoprotein P (main efflux pump responsible for multidrug resistance). Conclusions The results indicate that Au-GSH-Dox may be a potent new therapeutic agent to increase the efficacy of the drug by overcoming the resistance to doxorubicin in feline fibrosarcoma cell lines. Moreover, as

  3. N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

    PubMed Central

    Gregory, K.J.; Herman, E.J.; Ramsey, A.J.; Hammond, A.S.; Byun, N.E.; Stauffer, S.R.; Manka, J.T.; Jadhav, S.; Bridges, T.M.; Weaver, C.D.; Niswender, C.M.; Steckler, T.; Drinkenburg, W.H.; Ahnaou, A.; Lavreysen, H.; Macdonald, G.J.; Bartolomé, J.M.; Mackie, C.; Hrupka, B.J.; Caron, M.G.; Daigle, T.L.; Lindsley, C.W.; Conn, P.J.

    2013-01-01

    Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca2+ mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel

  4. Photodynamic therapy with recombinant adenovirus AdmIL-12 enhances anti-tumour therapy efficacy in human papillomavirus 16 (E6/E7) infected tumour model

    PubMed Central

    Park, Eun Kyung; Bae, Su-Mi; Kwak, Sun-Young; Lee, Sung Jong; Kim, Yong-Wook; Han, Chan-Hee; Cho, Hyun-Jung; Kim, Kyung Tae; Kim, Young-Jae; Kim, Hyun-Jung; Ahn, Woong Shick

    2008-01-01

    Immunotherapy with photodynamic therapy (PDT) offers great promise as a new alternative for cancer treatment; however, its use remains experimental. Here we investigated the utility of adenoviral delivery of interleukin-12 (AdmIL-12) as an adjuvant for PDT in mouse tumour challenge model. PDT was performed by irradiating Radachlorin in C57BL/6 mice transplanted with TC-1 cells. PDT plus AdmIL-12 treatment for tumour suppression as well as specific immune responses were evaluated with the following tests: in vitro and in vivo tumour growth inhibition, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) assay, and cytotoxic T lymphocyte (CTL) assay. Direct intratumoral injection of AdmIL-12 resulted in a significant suppression of tumour growth compared to the control group. Treatment of PDT along with AdmIL-12 further enhanced antitumour effects significantly higher than either AdmIL-12 or PDT alone. This combined treatment resulted in complete regression of 9-mm sized tumour in every animal. We also evaluated immune responses induced by these treatments. Combined treatment significantly increased the production level of IFN-γ and TNF-α compared with that by AdmIL-12 or PDT alone. PDT plus AdmIL-12 enhanced antitumour immunity through increased expansion of the CTL subset mediated by CD8+ T cells. Taken together, these results indicate that the high anti-cancer activity of PDT with AdmIL-12 is a powerful tool against cancer therapy and is a promising subject for further investigation. PMID:18397271

  5. A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells.

    PubMed

    Cheadle, E J; Lipowska-Bhalla, G; Dovedi, S J; Fagnano, E; Klein, C; Honeychurch, J; Illidge, T M

    2017-01-03

    Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses. Here we demonstrate, in syngeneic human CD20 (hCD20)-expressing models of lymphoma, that systemic administration of a TLR7 agonist (R848) increases responses when administered in combination with obinutuzumab and protects against disease recurrence. Depletion studies demonstrate that primary antitumor activity is dependent on both NK cells and CD4(+) T cells but not on CD8(+) T cells. However, both CD4(+) and CD8(+) T cells appear necessary for the generation of protective immunological memory. Importantly, increased tumor-free survival post obinutuzumab and R848 combination therapy was seen in hCD20 transgenic mice, which express hCD20 on normal B cells. These findings provide a rationale for clinical testing of obinutuzumab in combination with systemically administered TLR7 agonists to further improve outcome.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.352.

  6. Enhancing Self-Efficacy for Help-Seeking Among Transition-Aged Youth in Postsecondary Settings With Mental Health and/or Substance Use Concerns, Using Crowd-Sourced Online and Mobile Technologies: The Thought Spot Protocol

    PubMed Central

    Abi-Jaoude, Alexxa; Johnson, Andrew; Ferguson, Genevieve; Sanches, Marcos; Levinson, Andrea; Robb, Janine; Heffernan, Olivia; Herzog, Tyson; Chaim, Gloria; Cleverley, Kristin; Eysenbach, Gunther; Henderson, Joanna; S Hoch, Jeffrey; Hollenberg, Elisa; Jiang, Huan; Isaranuwatchai, Wanrudee; Law, Marcus; Sharpe, Sarah; Tripp, Tim; Voineskos, Aristotle

    2016-01-01

    Background Seventy percent of lifetime cases of mental illness emerge prior to age 24. While early detection and intervention can address approximately 70% of child and youth cases of mental health concerns, the majority of youth with mental health concerns do not receive the services they need. Objective The objective of this paper is to describe the protocol for optimizing and evaluating Thought Spot, a Web- and mobile-based platform cocreated with end users that is designed to improve the ability of students to access mental health and substance use services. Methods This project will be conducted in 2 distinct phases, which will aim to (1) optimize the existing Thought Spot electronic health/mobile health intervention through youth engagement, and (2) evaluate the impact of Thought Spot on self-efficacy for mental health help-seeking and health literacy among university and college students. Phase 1 will utilize participatory action research and participatory design research to cocreate and coproduce solutions with members of our target audience. Phase 2 will consist of a randomized controlled trial to test the hypothesis that the Thought Spot intervention will show improvements in intentions for, and self-efficacy in, help-seeking for mental health concerns. Results We anticipate that enhancements will include (1) user analytics and feedback mechanisms, (2) peer mentorship and/or coaching functionality, (3) crowd-sourcing and data hygiene, and (4) integration of evidence-based consumer health and research information. Conclusions This protocol outlines the important next steps in understanding the impact of the Thought Spot platform on the behavior of postsecondary, transition-aged youth students when they seek information and services related to mental health and substance use. PMID:27815232

  7. The Efficacy of Internet-Based Mindfulness Training and Cognitive-Behavioral Training With Telephone Support in the Enhancement of Mental Health Among College Students and Young Working Adults: Randomized Controlled Trial

    PubMed Central

    Chio, Floria HN; Chan, Amy TY; Lui, Wacy WS; Wu, Ellery KY

    2017-01-01

    Background College students and working adults are particularly vulnerable to stress and other mental health problems, and mental health promotion and prevention are needed to promote their mental health. In recent decades, mindfulness-based training has demonstrated to be efficacious in treating physical and psychological conditions. Objective The aim of our study was to examine the efficacy of an Internet-based mindfulness training program (iMIND) in comparison with the well-established Internet-based cognitive-behavioral training program (iCBT) in promoting mental health among college students and young working adults. Methods This study was a 2-arm, unblinded, randomized controlled trial comparing iMIND with iCBT. Participants were recruited online and offline via mass emails, advertisements in newspapers and magazines, announcement and leaflets in primary care clinics, and social networking sites. Eligible participants were randomized into either the iMIND (n=604) or the iCBT (n=651) condition. Participants received 8 Web-based sessions with information and exercises related to mindfulness or cognitive-behavioral principles. Telephone or email support was provided by trained first tier supporters who were supervised by the study’s research team. Primary outcomes included mental and physical health-related measures, which were self-assessed online at preprogram, postprogram, and 3-month follow-up. Results Among the 1255 study participants, 213 and 127 completed the post- and 3-month follow-up assessment, respectively. Missing data were treated using restricted maximum likelihood estimation. Both iMIND (n=604) and iCBT (n=651) were efficacious in improving mental health, psychological distress, life satisfaction, sleep disturbance, and energy level. Conclusions Both Internet-based mental health programs showed potential in improving the mental health from pre- to postassessment, and such improvement was sustained at the 3-month follow-up. The high attrition

  8. [Composition of NOM in raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project and comparison of efficacy of enhanced coagulation].

    PubMed

    Cheng, Tuo; Xu, Bin; Zhu, He-Zhen; Xia, Sheng-Ji; Chu, Wen-Hai; Hu, Guang-Xin

    2015-03-01

    The best enhanced coagulation conditions for the raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project and the molecular weights as well as hydrophobicity composition of Natural organic matter (NOM) in the water were investigated in this study. The results showed that the NOM in the raw water of Danjiangkou Reservoir of South-to-North Water Diversion Project was mainly composed of the fraction with a molecular weight of < 1 000 and transphilic components. Dissolved organic carbon (DOC, 39.98%) and UV254 (39.10%) were the major components. And the fraction with a molecular weight of < 1 000 had the highest contents of THMFP and N-DBPFP. In the raw water of Danjiangkou Reservoir, the sum of transphilic and hydrophobic fractions was up to 80%, and the hydrophobic fraction was the minimum contributor of the NOM, but the THMFP of the hydrophobic fraction had the highest percentage. And when the raw water of Danjiangkou Reservoir was treated using polymeric ferric sulfate (PFS, 4 mg x L(-1)) and poly-acrylamide (PAM, 0.4 mg x L(-1)) , the optimal removal rates of turbidity, DOC, UV254 and THMFP were 76.33%, 25.57%, 37.78% and 23.16%, respectively. The results of this paper can provide theoretical and technological basis for upgrading of the process and operation optimization of original drinking water treatment plants in the intake area of South-to-North Water Diversion Project.

  9. Combinatorial Approach of Antigen Delivery Using M Cell-Homing Peptide and Mucoadhesive Vehicle to Enhance the Efficacy of Oral Vaccine.

    PubMed

    Singh, Bijay; Maharjan, Sushila; Jiang, Tao; Kang, Sang-Kee; Choi, Yun-Jaie; Cho, Chong-Su

    2015-11-02

    Orally ingested pathogens or antigens are taken up by microfold cells (M cells) in Peyer's patches of intestine to initiate protective immunity against infections. However, the uptake of orally delivered protein antigens through M cells is very low due to lack of specificity of proteins toward M cells and degradation of proteins in the harsh environment of gastrointestinal (GI) tract. To overcome these limitations, here we developed a pH-sensitive and mucoadhesive vehicle of thiolated eudragit (TE) microparticles to transport an M cell-targeting peptide-fused model protein antigen. Particularly, TE prolonged the particles transit time through the GI tract and predominantly released the proteins in ileum where M cells are abundant. Thus, oral delivery of TE microparticulate antigens exhibited high transcytosis of antigens through M cells resulting in strong protective sIgA as well as systemic IgG antibody responses. Importantly, the delivery system not only induced CD4(+) T cell immune responses but also generated strong CD8(+) T cell responses with enhanced production of IFN-γ in spleen. Given that M cells are considered a promising target for oral vaccination, this study could provide a new combinatorial method for the development of M-cell-targeted mucosal vaccines.

  10. Anti-BlyS antibody reduces the immune reaction against enzyme and enhances the efficacy of enzyme replacement therapy in Fabry disease model mice.

    PubMed

    Sato, Yohei; Ida, Hiroyuki; Ohashi, Toya

    2017-02-02

    Formation of antibodies against a therapeutic enzyme is an important complication during enzyme replacement therapy (ERT) for lysosomal storage diseases. Fabry disease (FD) is caused by a deficiency of alpha-galactosidase (GLA), which results in the accumulation of globotriaosylceramide (GL-3). We have shown immune tolerance induction (ITI) during ERT in FD model mice by using an anti-B lymphocyte stimulator (anti-BlyS) antibody (belimumab). A single dose of the anti-BlyS antibody temporarily lowered the percentage of B cells and IgG antibody titer against recombinant human GLA. Administration of a low maintenance dose of the anti-BlyS antibody suppressed the B cell population and immunotolerance was induced in 20% of mice, but antibody formation could not be prevented. We then increased the maintenance dose of the anti-BlyS antibody and immunotolerance was induced in 50% of mice. Therapeutic enzyme distribution and clearance of GL-3 were also enhanced by a high maintenance dose of the anti-BlyS antibody.

  11. Enhanced protective efficacy against tuberculosis provided by a recombinant urease deficient BCG expressing heat shock protein 70-major membrane protein-II having PEST sequence.

    PubMed

    Tsukamoto, Yumiko; Maeda, Yumi; Tamura, Toshiki; Mukai, Tetsu; Mitarai, Satoshi; Yamamoto, Saburo; Makino, Masahiko

    2016-12-07

    Enhancement of the T cell-stimulating ability of Mycobacterium bovis BCG (BCG) is necessary to develop an effective tuberculosis vaccine. For this purpose, we introduced the PEST-HSP70-major membrane protein-II (MMPII)-PEST fusion gene into ureC-gene depleted recombinant (r) BCG to produce BCG-PEST. The PEST sequence is involved in the proteasomal processing of antigens. BCG-PEST secreted the PEST-HSP70-MMPII-PEST fusion protein and more efficiently activated human monocyte-derived dendritic cells (DCs) in terms of phenotypic changes and cytokine productions than an empty-vector-introduced BCG or HSP70-MMPII gene-introduced ureC gene-depleted BCG (BCG-DHTM). Autologous human naïve CD8(+) T cells and naïve CD4(+) T cells were effectively activated by BCG-PEST and produced IFN-γ in an antigen-specific manner through DCs. These T cell activations were closely associated with phagosomal maturation and intraproteasomal protein degradation in antigen-presenting cells. Furthermore, BCG-PEST produced long-las