Science.gov

Sample records for enhance antiglaucoma efficacy

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

    PubMed Central

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

    2011-01-01

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

  2. Enhancing Teacher Efficacy in Special Education.

    ERIC Educational Resources Information Center

    McDaniel, Elizabeth A.; McCarthy, Holly DiBella

    1989-01-01

    A special education teacher's sense of teaching efficacy and personal teaching efficacy influences teacher motivation and effort, teacher-student interactions, and student achievement. Methods for enhancing teachers' sense of efficacy are suggested. (JDD)

  3. Bimatoprost: a novel antiglaucoma agent.

    PubMed

    Woodward, David F; Phelps, R L; Krauss, A H-P; Weber, A; Short, B; Chen, J; Liang, Y; Wheeler, L A

    2004-01-01

    The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a beta-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2alpha-ethanolamide (prostamide F2alpha), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties. PMID:15179448

  4. 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…

  5. Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork.

    PubMed

    Izzotti, Alberto; La Maestra, Sebastiano; Micale, Rosanna Tindara; Longobardi, Maria Grazia; Saccà, Sergio Claudio

    2015-02-01

    Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized. PMID:25772104

  6. 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.

  7. [In vitro evaluation for corneal damages by anti-glaucoma combination eye drops using human corneal epithelial cell (HCE-T)].

    PubMed

    Nagai, Noriaki; Murao, Takatoshi; Oe, Kyouhei; Ito, Yoshimasa; Okamoto, Norio; Shimomura, Yoshikazu

    2011-01-01

    The combination of anti-glaucoma eye drops is frequently used in clinical treatment, and it is known that the combination can cause corneal damage. Recently, an anti-glaucoma combination eye drops is developed, and the treatment by the combination eye drops is expected to enhance quality of life. However, effects of the combination eye drops on corneal epithelial cell damage have not been clarified. In this study, we investigated the corneal epithelial cell damage of commercially available anti-glaucoma combination eye drops, such as Xalacom® (latanoprost/timolol maleate combination eye drops), Duotrav® (travoprost/timolol maleate combination eye drops) and Cosopt® (dorzolamide hydrochloride/timolol maleate combination eye drops) using the human corneal epithelial cell (HCE-T). The cytotoxicity in Xalacom® was higher than that in Xalatan® (eye drops containing latanoprost) and Timoptol® (eye drops containing timolol maleate), and the benzalkonium chloride (BAC) and timolol maleate were related to cytotoxicity in Xalacom®. The cytotoxicity in Duotrav® and Cosopt® was lower than that in Timoptol®. The Duotrav® is preserved with a non-BAC system (POLYQUAD, polidronium chloride). Therefore, it was suggested that the POLYQUAD related to the low cytotoxicity in Duotrav®. On the other hand, the D-mannitol reduced the cytotoxicity by BAC in this study. This result suggested that the cytotoxicity in Cosopt® was reduced by D-mannitol. The Duotrav® and Cosopt® may be less damaging to the ocular surface of glaucoma patients receiving long-term eye drop therapy in compared with the combination of anti-glaucoma eye drops. PMID:21628988

  8. Bt Toxin Modification for Enhanced Efficacy

    PubMed Central

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

    2014-01-01

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

  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. PMID:26272426

  10. Enhanced Efficacy of Photodynamic Therapy via a Sequential Targeting Protocol

    PubMed Central

    Kessel, David; Reiners, John J.

    2014-01-01

    This study was designed to examine determinants of the discovery that low-dose lysosomal photodamage (lyso-PDT) could potentiate the efficacy of subsequent low-dose mitochondrial photodamage (mito-PDT). The chlorin NPe6 and the benzoporphyrin BPD were used to separately target lysosomes and mitochondria, respectively, in murine hepatoma cells. Lyso-PDT (LD5 conditions) followed by mito-PDT (LD15 conditions) enhanced the loss of the mitochondrial membrane potential, activation of procaspases-3/7 and photokilling. Reversing the sequence was less effective. The optimal sequence did not enhance reactive oxygen species formation above that obtained with low-dose mito-PDT. In contrast, alkalinization of lysosomes with bafilomycin also enhanced low-dose mito-PDT photokilling, but via a different pathway. This involves redistribution of iron from lysosomes to mitochondria leading to enhanced hydroxyl radical formation, effects not observed after the sequential procedure. Moreover, Ru360, an inhibitor of mitochondrial calcium and iron uptake, partially suppressed the ability of Bafilomycin to enhance mito-PDT photokilling without affecting the enhanced efficacy of the sequential protocol. We conclude that sequential PDT protocol promotes PDT efficacy by a process not involving iron translocation, but via promotion of the pro-apoptotic signal that derives from mitochondrial photodamage. PMID:24617972

  11. Enhancing the antibacterial efficacy of isoeugenol by emulsion encapsulation.

    PubMed

    Krogsgård Nielsen, Christina; Kjems, Jørgen; Mygind, Tina; Snabe, Torben; Schwarz, Karin; Serfert, Yvonne; Meyer, Rikke Louise

    2016-07-16

    Food spoilage and foodborne illnesses are two global challenges for food manufacturers. Essential oils are natural antibacterials that could have a potential for use in food preservation. Unfortunately high concentrations are needed to obtain the desired antibacterial effect, and this limits their use in food due to their adverse organoleptic properties. Encapsulation could make essential oils more effective by concentrating them in the aqueous phase of the food matrix where the bacteria are present. Here we tested encapsulation of the essential oil isoeugenol in spray-dried emulsions as a means of making isoeugenol a more effective antibacterial for use in food preservation. We used β-lactoglobulin and n-OSA starch as emulsifiers, and some emulsions were coated with positively charged chitosan to promote the contact with bacteria through electrostatic interactions. The antibacterial efficacy was quantified as the minimal bactericidal concentration in growth media, milk and carrot juice. The emulsion encapsulation system developed in this study provided high loading capacities, and encapsulation enhanced the efficacy of isoeugenol against Gram-positive and -negative bacteria in media and carrot juice but not in milk. Chitosan-coating did not enhance the efficacy further, possibly due to the aggregation of the chitosan-coated emulsions. The encapsulation system is easy to upscale and should be applicable for encapsulation of similar essential oils. Therefore, we believe it has potential to be used for natural food preservation. PMID:27089032

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

    PubMed

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

    2008-01-01

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

  13. 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

  14. Leadership and Leader Developmental Self-Efficacy: Their Role in Enhancing Leader Development Efforts.

    PubMed

    Murphy, Susan Elaine; Johnson, Stefanie K

    2016-01-01

    This chapter describes the role of two types of self-efficacy-leader self-efficacy and leader developmental efficacy-for enhancing leadership development. Practical implications for designing and developing leadership programs that take into account these two types of self-efficacy are discussed. PMID:26895265

  15. 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.

  16. 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. PMID:16294801

  17. How to enhance the efficacy of health network growth.

    PubMed

    Weil, T P

    2000-01-01

    In almost every American metropolitan area, health executives are busily enhancing the efficacy of their health networks by corporately restructuring so that their organization can become a fiscally and politically powerful oligopoly or a regulated monopoly. When the formation of these alliances are initially announced by the local media, they are reported to be vehicles to enhance access, social equity and quality of care, and to reduce costs. Since an increasing number of these health networks are currently experiencing fiscal, cultural and other difficulties, it is critical to study: (a) what factors should be considered when developing an effective and efficient health network?; (b) what are the practical issues in their strategic formation and management so they eventually achieve their full potential?; and (c) why will some divestitures among these health networks occur and how will these corporate 'spin offs' impact on consumers, providers, insurers and governmental agencies? Within the next decade the United States will face some inevitable economic difficulties. At that time, enhancing access and reducing costs will become more critical issues for health networks. These alliances may then need to become more responsive to consumer pressures as the Americans shift their political proclivities from the current quasi-competitive to a more quasi-regulatory position. In this context, the use of global budgetary targets is discussed as a possible option in the United States to constrain costs, an approach used in almost all other western industrialized nations. PMID:10947565

  18. Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery.

    PubMed

    Mo, Ran; Jiang, Tianyue; Gu, Zhen

    2014-06-01

    A liposome-based co-delivery system composed of a fusogenic liposome encapsulating ATP-responsive elements with chemotherapeutics and a liposome containing ATP was developed for ATP-mediated drug release triggered by liposomal fusion. The fusogenic liposome had a protein-DNA complex core containing an ATP-responsive DNA scaffold with doxorubicin (DOX) and could release DOX through a conformational change from the duplex to the aptamer/ATP complex in the presence of ATP. A cell-penetrating peptide-modified fusogenic liposomal membrane was coated on the core, which had an acid-triggered fusogenic potential with the ATP-loaded liposomes or endosomes/lysosomes. Directly delivering extrinsic liposomal ATP promoted the drug release from the fusogenic liposome in the acidic intracellular compartments upon a pH-sensitive membrane fusion and anticancer efficacy was enhanced both in vitro and in vivo. PMID:24764317

  19. Asplatin enhances drug efficacy by altering the cellular response.

    PubMed

    Cheng, Qinqin; Shi, Hongdong; Wang, Hongxia; Wang, Jun; Liu, Yangzhong

    2016-07-13

    Aspirin, a widely used anti-inflammatory drug, has been shown to be effective for the prevention and remission of cancers (Science, 2012, 337(21) 1471-1473). Asplatin, a Pt(iv) prodrug of cisplatin with the ligation of aspirin (c,c,t-[PtCl2(NH3)2(OH)(aspirin)]), demonstrates significantly higher cytotoxicity than cisplatin towards tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. In this work, we have studied the molecular mechanism of asplatin by investigating the cellular response to this compound in order to understand the prominent inhibitory effect on the proliferation of cancer cells. The apoptosis analyses and the related gene expression measurements show that aspirin released from asplatin significantly modulates the cellular response to the platinum agent. Asplatin promotes the apoptosis via the BCL-2 associated mitochondrial pathway. The down-regulation of BCL-2 along with the up-regulation of BAX and BAK enhances the mitochondrial outer membrane permeability, resulting in the cytochrome c release from mitochondria into the cytosol. This event promotes the apoptosis by activation of caspase processing. Consequently, the ligation of aspirin significantly enhances the drug efficacy of the platinum complex in the low micromolar range. The alteration of the cellular response is probably responsible for the circumvention of the cisplatin resistance by asplatin. These results provide an insight into the mechanism of asplatin and provide information for designing new classic platinum drugs. PMID:27125788

  20. Targeted Delivery of Antiglaucoma Drugs to the Supraciliary Space Using Microneedles

    PubMed Central

    Kim, Yoo C.; Edelhauser, Henry F.; Prausnitz, Mark R.

    2014-01-01

    Purpose. In this work, we tested the hypothesis that highly targeted delivery of antiglaucoma drugs to the supraciliary space by using a hollow microneedle allows dramatic dose sparing of the drug compared to topical eye drops. The supraciliary space is the most anterior portion of the suprachoroidal space, located below the sclera and above the choroid and ciliary body. Methods. A single, hollow 33-gauge microneedle, 700 to 800 μm in length, was inserted into the sclera and used to infuse antiglaucoma drugs into the supraciliary space of New Zealand white rabbits (N = 3–6 per group). Sulprostone, a prostaglandin analog, and brimonidine, an α2-adrenergic agonist, were delivered via supraciliary and topical administration at various doses. The drugs were delivered unilaterally, and intraocular pressure (IOP) of both eyes was measured by rebound tonometry for 9 hours after injection to assess the pharmacodynamic responses. To assess safety of the supraciliary injection, IOP change immediately after intravitreal and supraciliary injection were compared. Results. Supraciliary delivery of both sulprostone and brimonidine reduced IOP by as much as 3 mm Hg bilaterally in a dose-related response; comparison with topical administration at the conventional human dose showed approximately 100-fold dose sparing by supraciliary injection for both drugs. A safety study showed that the kinetics of IOP elevation immediately after supraciliary and intravitreal injection of placebo formulations were similar. Conclusions. This study introduced the use of targeted drug delivery to the supraciliary space by using a microneedle and demonstrated dramatic dose sparing of antiglaucoma therapeutic agents compared to topical eye drops. Targeted delivery in this way can increase safety by reducing side effects and could allow a single injection to contain enough drug for long-term sustained delivery. PMID:25212782

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

    PubMed

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

    2007-09-01

    A previously healthy, 1-year 7-month-old boy was brought to the emergency department after having unintentionally ingested topical brimonidine antiglaucoma drops. He was pale and lethargic and had brief periods of apnea and bradycardia. Activated charcoal was administered, and supportive measures were initiated, achieving complete resolution of the symptoms 4 hours after admission. Brimonidine poisoning is very rare, and a high index of suspicion is necessary to identify its signs and symptoms in the pediatric emergency department. To our knowledge, only 1 case of brimonidine poisoning after oral ingestion of this topical drug has been previously reported in the literature. PMID:17876259

  2. Ocular Surface Cytotoxicity and Safety Evaluation of Tafluprost, a Recently Developed Anti-Glaucoma Prostaglandin Analog

    PubMed Central

    Niwano, Yoshimi; Iwasawa, Atsuo; Ayaki, Masahiko

    2014-01-01

    In vitro cytotoxicity of tafluprost, which is the most recently developed anti-glaucoma prostaglandin (PG) analog, in ocular surface cells is addressed in comparison with other PG analogs. Irrespective of cell lines and models, the cytotoxicity of anti-glaucoma PG eyedrops was primarily related to the concentration of benzalkonium chloride (BAK) contained in the eyedrops as a preservative. Accordingly, preservative-free tafluprost was apparently less cytotoxic than BAK-preserved PG analogs. Furthermore, our study for cytotoxicity assays on ocular cells, conducted by comprehensive investigations covering a variety of concentrations and treatment times, which is termed the cell viability score (CVS) system, demonstrated that 0.001% BAK-preserved tafluprost was not cytotoxic, and suggested that tafluprost may even reduce the cytotoxic effect of BAK. It has been reported that adverse reactions associated with tafluprost in healthy human volunteers and patients with glaucoma include conjunctival hyperemia, eyelid pigmentation, eyelash bristles, and deepening of upper eyelid sulcus. Nonetheless, most clinical studies have demonstrated that not only preservative-free tafluprost but also BAK-preserved tafluprost is well tolerated and safe in patients with glaucoma and ocular hypertension. PMID:24558301

  3. 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

  4. Antiglaucoma pharmacotherapy

    PubMed Central

    Tătaru, CP; Purcărea, VL

    2012-01-01

    This review presents the pharmacotherapeutic approaches available in the treatment of glaucomatous optic neuropathy. Although its etiology is multi-factorial, currently, the main therapy is to decrease intraocular pressure. New therapies are being developed; the current trend is a retinal ganglion cell neuroprotection. Neuroprotection is achieved by combining antihypertensive agents with drugs that directly protect the optic nerve by promoting cell survival and inhibition of neuronal signals that initiate apoptosis. The treatment should also preserve the ocular hemodynamics, ensure proper patient compliance and be free of side effects. PMID:23049625

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

    NASA Astrophysics Data System (ADS)

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

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

  6. 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…

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

    PubMed Central

    Scozzafava, Andrea; Jitianu, Andrei

    1997-01-01

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

  8. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity

    PubMed Central

    Lee, S-Y; Wong, T T; Chua, J; Boo, C; Soh, Y F; Tong, L

    2013-01-01

    Purpose To evaluate the tear film osmolarity (TFO) and ocular surface clinical signs and symptoms in chronically medicated glaucoma patients and post-trabeculectomy patients. Methods This is a single-center, prospective case-controlled study. One-hundred and thirty eyes of 130 participants aged ≥45 years were included (49 normal controls, 50 glaucoma patients on chronic preserved anti-glaucoma medication ≥6 months, and 31 post-trabeculectomy patients not on medication ≥6 months). TFO, tear break-up time (TBUT), Schirmer's test I and dry eye symptoms were evaluated. Data from both groups of glaucoma patients were compared with age and sex-matched controls. Logistic regression was performed to calculate the odds ratios. Results Mean TFO in the three groups were 301.4±7.7, 307.0±9.3, and 307.4±11.6 mOsm/l, respectively. Compared with normal controls, chronically medicated glaucoma patients and post-trabeculectomy patients were more likely to have a raised TFO, with odds ratios (95% CI) of 4.43 (1.74–11.32) and 2.76 (1.02–7.94), respectively. Both groups of glaucoma patients were also more likely to experience dry eye symptoms, with ORs of 4.72 (1.92–11.59) and 4.24 (1.54–11.72). There was no significant difference in TFO and symptoms between both groups of glaucoma patients, and in TBUT and Schirmer's test across all three groups. Conclusions Patients on chronic topical anti-glaucoma medication and post-trabeculectomy patients were more likely to have raised TFO and dry eye symptoms, suggesting significant ocular surface disease. Glaucoma practitioners should be aware that dry eye symptoms and raised TFO may occur in the absence of TBUT and Schirmer's test abnormality. PMID:23846375

  9. Arteether nanoemulsion for enhanced efficacy against Plasmodium yoelii nigeriensis malaria: an approach by enhanced bioavailability.

    PubMed

    Dwivedi, Pankaj; Khatik, Renuka; Chaturvedi, Priyanka; Khandelwal, Kiran; Taneja, Isha; Raju, Kanumuri Siva Rama; Dwivedi, Hemlata; Singh, Sunil Kumar; Gupta, Pramod Kumar; Shukla, Prashant; Tripathi, Priyanka; Singh, Sarika; Tripathi, Renu; Wahajuddin; Paliwal, Sarvesh Kumar; Dwivedi, Anil Kumar; Mishra, Prabhat Ranjan

    2015-02-01

    The present work is focused on the preparation of nanoemulsions (NEs) loaded with arteether (ART) for its enhanced efficacy against malaria parasites. ART-NEs have been prepared using high pressure homogenization (HPH) technique with the aim of improving its solubility and thus its bioavailability. ART-NEs were optimized in terms of pressure and number of cycles. Globule size and size distributions were chosen as quality parameters. The maximum drug loading was achieved up to 93 ± 7.4% with globule size 156 ± 10.2 nm and zeta potential of -23.3 ± 3.4 mV. The developed ART-NEs were found to be stable in terms of globule size and size distribution at different pH. The in vitro release profile of the ART-NEs showed 62% drug release within 12h. The percentage cell viability of blank NEs were within acceptable limits. A sensitive assay method for the determination of ART in rat plasma by liquid chromatography-mass spectrometry (LC-MS) was employed after oral administration of ART-NEs. The pharmacokinetic study showed significantly enhanced bioavailability of ART in ART-NE-V. The area under curve (AUC) of ART-NE-V was AUC0-t 1988.411 ± 119.66 h ng/ml which was significantly higher (p<0.05) than ART in ground nut oil (GNO) AUC0-t 671.852 ± 187.05 h ng/ml. The Cmax of ART-NE-V (1506 ± 161.22 ng/ml) was also significantly higher (p<0.05) than ART in GNO (175.2 ± 16.54 ng/ml) and ART given intramuscularly (IM) (278.05 ± 38.59 ng/ml). The ART-NE-V was having significantly high antimalarial efficacy and survival rate of mice giving 80% cure rate at 12.5 mg/kg for 5 days in comparison to 30% cure rate of ART in GNO at the same daily dose and it was also comparable to the 100% cure rate at 12.5 mg/kg for 5 days for ART given intramuscularly. In conclusion ART-NE can be a promising oral delivery system for ART. PMID:25616971

  10. 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.

  11. 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.

  12. Verapamil Enhances the Antitumoral Efficacy of Oncolytic Adenoviruses

    PubMed Central

    Gros, Alena; Puig, Cristina; Guedan, Sonia; Rojas, Juan José; Alemany, Ramon; Cascallo, Manel

    2010-01-01

    The therapeutic potential of oncolytic adenoviruses is limited by the rate of adenovirus release. Based on the observation that several viruses induce cell death and progeny release by disrupting intracellular calcium homeostasis, we hypothesized that the alteration in intracellular calcium concentration induced by verapamil could improve the rate of virus release and spread, eventually enhancing the antitumoral activity of oncolytic adenoviruses. Our results indicate that verapamil substantially enhanced the release of adenovirus from a variety of cell types resulting in an improved cell-to-cell spread and cytotoxicity. Furthermore, the combination of the systemic administration of an oncolytic adenovirus (ICOVIR-5) with verapamil in vivo greatly improved its antitumoral activity in two different tumor xenograft models without affecting the selectivity of this virus. Overall, our findings indicate that verapamil provides a new, safe, and versatile way to improve the antitumoral potency of oncolytic adenoviruses in the clinical setting. PMID:20179683

  13. Enhancement of DNA vaccine efficacy by intracellular targeting strategies.

    PubMed

    Freitas, Elisabete Borges; Henriques, Ana Margarida; Fevereiro, Miguel; Prazeres, Duarte Miguel; Monteiro, Gabriel Amaro

    2014-01-01

    Immune response against an encoded antigenic protein can be elicited by including targeting sequences to DNA vaccines that promote protein sorting to processing pathways, related with antigen presentation by major histocompatibility complexes (MHC). Candidate DNA vaccines coding for neuraminidase 3 of the avian influenza virus were designed to encode different sequences that direct the protein to specific cellular compartments such as endoplasmic reticulum (i.e., adenovirus E1A), lysosomes (i.e., LAMP), and the combination of protein targeting to the endoplasmic reticulum and lysosome (i.e., E1A-LAMP). The DNA vaccine prototypes were engineered by biomolecular techniques and subsequently produced in E. coli cells. The biological activity of the vaccines was tested firstly in vitro, in Chinese hamster ovary cells, through flow cytometry and real-time polymerase chain reaction analysis. Then, an essential in vivo study was performed in chickens, in order to evaluate the efficacy of DNA prototype vaccines, by measuring the antibody production by enzyme-linked immunosorbent assay. PMID:24715281

  14. 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.

  15. 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.

  16. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

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

  19. "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)

  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. 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 ...

  2. 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…

  3. 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…

  4. Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma.

    PubMed

    Rasmussen, Rikke D; Gajjar, Madhavsai K; Jensen, Kamilla E; Hamerlik, Petra

    2016-05-01

    Recent clinical trials have demonstrated that targeting chromatin remodeling factors is as a promising strategy for the treatment of glioblastoma (GBM). We and others have shown constitutive activation of DNA damage response (DDR) pathways in gliomas and suggested that targeting the DDR may improve the currently grim prognosis for patients. Based on our previous findings that inhibition of poly(ADP-ribose) polymerase (PARP) increases radio-sensitivity of the notoriously radio-resistant GBM cells, we hypothesized that epigenetic down-regulation of the DDR responses and induction of oxidative stress via HDAC inhibition would contribute to more efficient targeting of this deadly disease. Our data show that SAHA, an HDAC class I + II inhibitor, in combination with olaparib (PARP inhibitor): i) enhanced inhibition of GBM cell survival, ii) induced apoptosis, and iii) impaired cell cycle progression. These results provide a pre-clinical rationale for combined administration of SAHA and olaparib, which are already individually in clinical trials. PMID:26794465

  5. CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy

    PubMed Central

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

    2016-01-01

    ABSTRACT We have armed a tumor-selective oncolytic vaccinia virus (vvDD) with the chemokine (CK) CXCL11, in order to enhance its ability to attract CXCR3+ antitumor CTLs and possibly NK cells to the tumor microenvironment (TME) and improve its therapeutic efficacy. As expected, vvDD-CXCL11 attracted high numbers of tumor-specific T cells to the TME in a murine AB12 mesothelioma model. Intratumoral virus-directed CXCL11 expression enhanced local numbers of CD8+ CTLs and levels of granzyme B, while reducing expression of several suppressive molecules, TGF-β, COX2, and CCL22 in the TME. Unexpectedly, we observed that vvDD-CXCL11, but not parental vvDD, induced a systemic increase in tumor-specific IFNγ-producing CD8+ T cells in the spleen and other lymph organs, indicating the induction of systemic antitumor immunity. This effect was associated with enhanced therapeutic efficacy and a survival benefit in tumor-bearing mice treated with vvDD-CXCL11, mediated by CD8+ T cells and IFNγ, but not CD4+ T cells. These results demonstrate that intratumoral expression of CXCL11, in addition to promoting local trafficking of T cells and to a lesser extent NK cells, has a novel function as a factor eliciting systemic immunity to cancer-associated antigens. Our data provide a rationale for expressing CXCL11 to enhance the therapeutic efficacy of oncolytic viruses (OVs) and cancer vaccines. PMID:27141352

  6. 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.

  7. 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.

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

    PubMed

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

    2014-07-01

    A novel approach of enhancing the Tamoxifen uptake via Intestinal Lymphatic System is executed by developing long chain lipid and oil based nanostructured lipid carrier system (Tmx-NLC). The aim was to achieve improved systemic bioavailability of Tamoxifen, prevent systemic and hepatotoxicity and enhance antitumor efficacy. Following the proof of concept achieved in cell culture experiments and in vivo pharmacokinetic and biodistribution study, the current work focuses on investigation of antitumor efficacy and treatment associated toxicity in murine mammary tumor mice model. The efficacy study demonstrated greater tumor suppression and 100% survival with 1.5 and 3 mg/kg Tmx-NLC compared to 3 mg/kg Tamoxifen suspension and Mamofen(®) (Khandelwal Pharmaceuticals, Mumbai, India). Tmx-NLC treatment for a month demonstrated improved systemic toxicity profile and no evidences of hepatotoxicity. Thus, developed Tmx-NLC could prove to be a promising delivery strategy to confer superior therapeutic efficacy and ability to address the biopharmaceutical and toxicity associated issues of drug. PMID:24704438

  9. 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

  10. Color rendering ability and luminous efficacy enhancements in white light-emitting diodes

    NASA Astrophysics Data System (ADS)

    Mirhosseini, Roya; Schubert, Martin; Chhajed, Sameer; Cho, Jaehee; Kim, Jong Kyu; Schubert, E. Fred

    2009-08-01

    There exists a fundamental trade-off relation between color rendering index (CRI) and luminous efficacy; in other words, improvements in one are generally detrimental to the other. We analyze and demonstrate through simulation that phosphor-converted white LEDs with dual-blue emitting active regions, as opposed to single-blue emitting active regions, significantly enhance color rendering ability while maximizing the output luminous flux. The improvements are achieved over a broad range of correlated color temperatures.

  11. 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

  12. 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. PMID:20136435

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

    PubMed Central

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

    2013-01-01

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

  14. Enhancing doxorubicin efficacy through inhibition of aspartate transaminase in triple-negative breast cancer cells.

    PubMed

    Yang, Yong

    2016-05-13

    Triple-negative breast cancer (TNBC) cell lines are identified to overexpress aspartate transaminase (GOT1), which can potentially control the intracellular levels of reactive oxygen species (ROS) through NADPH synthesis and enhances tumor growth. In this study, the impact of GOT1 on the efficacy of doxorubicin was investigated. Following doxorubicin administration, TNBC cells acquire metabolic alteration, causing increased glutamine flux for the synthesis of aspartate which can be converted into OAA by GOT1. Subsequently, this OAA is converted into malate and then pyruvate, maintaining the NADP(+)/NADPH ratio which neutralize doxorubicin-induced oxidative stress. Repression of GOT1 using the shRNAs for GOT1 resulted in doxorubicin-induced formation of ROS, thereby increasing doxorubicin sensitivity. The enhanced efficacy of doxorubicin by simultaneous repression of GOT1 was also indicated in an in vivo tumor model of TNBC. These results demonstrate that targeting GOT1 in TNBCs may provide a novel therapeutic approach for improving the efficacy of chemotherapy in patients with these refractory tumors. PMID:27086848

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

    PubMed

    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

  16. 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

  17. 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

  18. 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. PMID:22154081

  19. 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

  20. 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

  1. HIV enhancing activity of semen impairs the antiviral efficacy of microbicides

    PubMed Central

    Zirafi, Onofrio; Kim, Kyeong-Ae; Roan, Nadia R.; Kluge, Silvia F.; Müller, Janis A.; Jiang, Shibo; Mayer, Benjamin; Greene, Warner C.; Kirchhoff, Frank; Münch, Jan

    2015-01-01

    Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. Here, we report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was Maraviroc. This HIV entry inhibitor targets the host cell CCR5 coreceptor and was highly active against both untreated and semen-exposed HIV. These data help explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission. PMID:25391483

  2. 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

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

    PubMed

    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

  4. Enhancement of bioavailability and anthelmintic efficacy of albendazole by solid dispersion and cyclodextrin complexation techniques.

    PubMed

    Kalaiselvan, R; Mohanta, G P; Madhusudan, S; Manna, P K; Manavalan, R

    2007-08-01

    The objective of this study was to improve the oral bioavailability and therapeutic efficacy of albendazole (ABZ) employing solid dispersion and cyclodextrin complexation techniques. Solid dispersion (dispersion) was prepared using ABZ and polyvinylpyrrolidone (PVP) polymer (1:1 weight ratio). Ternary inclusion complex (ternary complex) was prepared using ABZ, hydroxypropyl beta-cyclodextrin (HPbetaCD) and L-tartaric acid (1:1:1 molar ratio). In rabbits with high gastric acidity (gastric pH approximately 1), ternary complex and solid dispersion showed a bioavailability enhancement of 3.2 and 2.4 fold respectively, compared to a commercial suspension (p < 0.05). The rise in gastric pH (pH > 5) caused a 62% reduction in AUC (area under the plasma level curve) for the commercial suspension, whereas the reduction in case of PVP dispersion and ternary complex was only 43% and 37% respectively. The rapid absorption of the drug from solid dispersion and ternary complex was reflected in improved anthelmintic efficacy against the systemic phases of Trichinella spiralis. The ternary complex was significantly more efficient than solid dispersion and exhibited the highest larvicidal activity (90%) at a dose of 50 mg x kg(-1) (p < 0.05). These results suggest that the bioavailability and therapeutic efficacy of the ternary complex might be high even if there is a great variation in the gastric pH. PMID:17867556

  5. 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.

  6. Attention Enhances Synaptic Efficacy and Signal-to-Noise in Neural Circuits

    PubMed Central

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

    2013-01-01

    Summary Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behavior 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 (1) increasing the efficacy of presynaptic input in driving postsynaptic responses, (2) increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and (3) decreasing redundant signals between postsynaptic neurons receiving common input. These 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 milieu. PMID:23803766

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

    PubMed Central

    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. PMID:22072873

  8. Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy.

    PubMed

    Zhang, Lu; Lu, Jiafei; Jin, Yangmin; Qiu, Liyan

    2014-10-01

    In order to enhance the antitumor effects of doxorubicin (DOX), a novel micellar vector with high DOX loading and tumor targeting function based on folate-conjugated amphiphilic copolymer folate-poly(ethylene glycol)-poly(d,l-lactide)-β-cyclodextrin (FA-PEL-CD) was constructed. Cytotoxicity and cellular uptake experiments were performed in HeLa, KB, and A549 cell lines expressing different amounts of folate receptors in order to evaluate the targeting effect of the folate modification. The antitumor experiments performed in a KB cell-xenografted nude mouse model showed that the treatment with 10mg/kg DOX loaded FA-PEL-CD micelles achieved approximately 86% of tumor growth inhibition compared to the control. Ex vivo fluorescence imaging experiments and histological examination confirmed that folate modification can enhance the antitumorigenesis efficacy and reduce the cardiotoxicity of DOX. These results suggest that FA-PEL-CD copolymer-based micelles are promising nanocarriers for targeted doxorubicin delivery, with improved antitumor efficacy and reduced toxicity in normal tissues. PMID:25058857

  9. EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells

    PubMed Central

    Katona, Bryson W; Liu, Yuanyuan; Ma, Anqi; Jin, Jian; Hua, Xianxin

    2014-01-01

    Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co-inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells. PMID:25535899

  10. Guanabenz (Wytensin™) selectively enhances uptake and efficacy of hydrophobically modified siRNAs

    PubMed Central

    Osborn, Maire F.; Alterman, Julia F.; Nikan, Mehran; Cao, Hong; Didiot, Marie C.; Hassler, Matthew R.; Coles, Andrew H.; Khvorova, Anastasia

    2015-01-01

    One of the major obstacles to the pharmaceutical success of oligonucleotide therapeutics (ONTs) is efficient delivery from the point of injection to the intracellular setting where functional gene silencing occurs. In particular, a significant fraction of internalized ONTs are nonproductively sequestered in endo-lysosomal compartments. Here, we describe a two-step, robust assay for high-throughput de novo detection of small bioactive molecules that enhance cellular uptake, endosomal escape, and efficacy of ONTs. Using this assay, we screened the LOPAC (Sigma–Aldrich) Library of Pharmacologically Active Compounds and discovered that Guanabenz acetate (Wytensin™), an FDA-approved drug formerly used as an antihypertensive agent, is capable of markedly increasing the cellular internalization and target mRNA silencing of hydrophobically modified siRNAs (hsiRNAs), yielding a ∼100-fold decrease in hsiRNA IC50 (from 132 nM to 2.4 nM). This is one of the first descriptions of a high-throughput small-molecule screen to identify novel chemistries that specifically enhance siRNA intracellular efficacy, and can be applied toward expansion of the chemical diversity of ONTs. PMID:26400165

  11. Mechanism of electrical enhancement of efficacy of antibiotics in killing biofilm bacteria.

    PubMed Central

    Costerton, J W; Ellis, B; Lam, K; Johnson, F; Khoury, A E

    1994-01-01

    The bioelectric effect, in which electric fields are used to enhance the efficacy of biocides and antibiotics in killing biofilm bacteria, has been shown to reduce the very high concentrations of these antibacterial agents needed to kill biofilm bacteria to levels very close to those needed to kill planktonic (floating) bacteria of the same species. In this report, we show that biofilm bacteria are readily killed by an antibiotic on all areas of the active electrodes and on the surfaces of conductive elements that lie within the electric field but do not themselves function as electrodes. Considerations of electrode geometry indicate that very low (< 100 microA/cm2) current densities may be effective in this electrical enhancement of antibiotic efficacy against biofilm bacteria, and flow experiments indicate that this bioelectric effect does not appear to depend entirely on the possible local electrochemical generation of antibacterial molecules or ions. These data are expected to facilitate the use of the bioelectric effect in the prevention and treatment of device-related bacterial infections that are caused by bacteria that grow in biofilms and thereby frustrate antibiotic chemotherapy. Images PMID:7695266

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

    PubMed

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

    2016-05-01

    Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC. PMID:26628295

  13. 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

  14. Anterior and posterior segment changes in rat eyes with chronic steroid administration and their responsiveness to antiglaucoma drugs.

    PubMed

    Razali, Norhafiza; Agarwal, Renu; Agarwal, Puneet; Kapitonova, Marina Y; Kannan Kutty, Methil; Smirnov, Alexey; Salmah Bakar, Nor; Ismail, Nafeeza M

    2015-02-15

    Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects. PMID:25481859

  15. Impact on intraocular pressure after 20-mg decanted triamcinolone acetonide (Kenalog) injection when utilizing prophylactic antiglaucoma therapy

    PubMed Central

    Ezon, Isaac C; Nezgoda, Joseph T; Cheng, Lingyun; Freeman, William R

    2014-01-01

    Purpose To analyze intraocular pressure (IOP) response after 20-mg decanted intravitreal triamcinolone acetonide (IVTA) followed by early prophylactic IOP-lowering therapy. Methods We retrospectively reviewed IOP results of 120 high-dose decanted IVTA injections from 58 non-glaucomatous patients with macular edema, with antiglaucoma therapy prescribed from week 1 regardless of baseline IOP. Results In cases of consistent compliance with IOP-lowering drugs (79.2%), IOP increased by 2 mmHg at 4 months (p=0.300) and returned to baseline at 6 months. In cases of non-compliance (20.8%), IOP increased by 7 mmHg at 1 month (p<0.001) and returned to baseline after starting treatment. Multivariate regression analysis showed that non-vitrectomized eyes and non-compliance with IOP-lowering drugs were independent predictors for IOP rise over 21 mmHg (p=0.0098 and p=0.0019, respectively). Non-vitrectomized eyes had a 46% greater chance to experience IOP rise compared to vitrectomized. Poor compliance with IOP-lowering drugs lead to a 45% greater likelihood of experiencing IOP rise compared to compliant patients. Multiple injections were not associated with increased risk for IOP rise over 21 mmHg (p=0.273). Out of 120 cases, 2 eyes (1.7%) developed uncontrolled IOP and required glaucoma surgery by 4 months, with good final IOP outcome. Conclusion 20-mg decanted IVTA can be safely used to treat macular edema in nonglaucomatous patients; IOP elevation can be adequately controlled with prophylactic antiglaucoma drugs. Non-compliance with prophylactic therapy creates an early spike in IOP, and vitreous status can significantly impact IOP rise. Compliance with IOP-lowering drugs should be stressed to patients receiving high-dose IVTA especially if non-vitrectomized. PMID:25077534

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

    NASA Astrophysics Data System (ADS)

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

    2008-11-01

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

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

    PubMed Central

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

    2015-01-01

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

  18. A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension.

    PubMed

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

    2014-02-01

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

  19. 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. PMID:26571136

  20. 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. PMID:26763728

  1. 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.

  2. 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

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

    PubMed

    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

  4. 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

  5. Efficacy of contrast enhanced grey scale ultrasound in characterisation of hepatic focal lesions: A pilot study

    PubMed Central

    Joshi, P.; George, R.A.; Tyagi, A.K.; Sinha, Anamika

    2014-01-01

    Background Contrast enhanced ultrasound (CEUS) has recently gained widespread acceptance as an adjunct to conventional grey scale ultrasound. The present pilot study was undertaken to evaluate the efficacy of this technique in characterisation of hepatic focal lesions. Methods Adult patients who had at least one focal liver lesion underwent ultrasound evaluation in regular and contrast mode before and after intravenous administration of sulphur hexafluoride. The diagnoses were confirmed by comparison with a reference standard (multidetector CT), response to treatment or pathological correlation. Results The rate of correct diagnosis for unenhanced ultrasound was 54%, CEUS was 72% and multidetector CT (MDCT) was 92%. A comparison of unenhanced ultrasound versus CEUS using the McNemar test yielded a p value of 0.0704 (>0.05). However, comparison of CEUS versus MDCT using the McNemar test yielded a p value of 0.0265 (<0.05). Additionally, comparison of unenhanced ultrasound versus MDCT using the McNemar test yielded a p value of <0.0001. Conclusion CEUS increases diagnostic efficacy over unenhanced ultrasound but does not have any significant advantages over MDCT. Currently it may be used as a problem solving tool in atypical haemangiomas, echogenic focal liver lesions, contrast sensitivity and to avoid multiple studies utilising ionising radiation. PMID:25378775

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

    PubMed

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

    2014-05-01

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

  7. 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

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

    PubMed

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

    2006-08-15

    We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines. PMID:16888001

  9. Novel extraction of German cockroach (Dictyoptera: Blattellidae) fecal pellets enhances efficacy of spray formulation insecticides.

    PubMed

    Miller, D M; Koehler, P G

    2000-02-01

    Methanol extracts of German cockroach, Blattella germanica (L.), fecal pellets have limited use as pheromone attractants in the urban environment because of their unpleasant color and odor. To eliminate these characteristics, a novel aqueous extract of German cockroach feces was formulated. Fetal material was extracted with methylene chloride and mixed with water. The aqueous phase of the extract was colorless and relatively odorless compared with methanol fecal extracts. Aqueous extract was bioassayed and compared with methanol extracts for aggregation activity. The efficacy of chlorpyrifos and boric acid formulations was tested with and without the addition of fecal extracts. In tests with chlorpyrifos, the addition of the aqueous extract produced significantly greater mortality in young nymphs than either chlorpyrifos alone or chlorpyrifos + methanol extract. There were no differences in mortality between the 2 extract + boric acid treatments during the test period, and both enhanced mortality. PMID:14658519

  10. Mechanisms Mediating Enhanced Neutralization Efficacy of Staphylococcal Enterotoxin B by Combinations of Monoclonal Antibodies*

    PubMed Central

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

    2015-01-01

    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. PMID:25572397

  11. 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.

  12. 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

  13. 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. PMID:25572397

  14. 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

  15. The efficacy of contrast-enhanced harmonic endoscopic ultrasonography in diagnosing gallbladder cancer

    PubMed Central

    Sugimoto, Mitsuru; Takagi, Tadayuki; Konno, Naoki; Suzuki, Rei; Asama, Hiroyuki; Hikichi, Takuto; Watanabe, Ko; Waragai, Yuichi; Kikuchi, Hitomi; Takasumi, Mika; Ohira, Hiromasa

    2016-01-01

    The aim of this study was to review the efficacy of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in diagnosing gallbladder (GB)-protruded lesions. Thirty-eight patients underwent CH-EUS for the diagnosis of GB-protruded lesions. Twenty-four patients whose major axes of their largest lesions were longer than 10 mm were recruited. The ability of CH-EUS to diagnose malignant or benign lesions was reviewed. We treated lesions with brindled enhanced patterns as malignant and those with uniformly enhanced or unenhanced patterns as benign. Furthermore, three gastroenterologists who were not familiar with pancreaticobiliary EUS compared the diagnostic abilities of CH-EUS and conventional EUS using photographs. The sensitivity, specificity, and malignant accuracy of CH-EUS were 100, 94.4, and 95.8%, respectively. The number of lesions that presented with enhanced patterns was significantly different between the malignant lesions and the benign lesions (P < 0.001). In the comparison of diagnostic abilities between CH-EUS and conventional EUS by the three gastroenterologists, CH-EUS was significantly superior to conventional EUS in terms of sensitivity, specificity, and accuracy (76.1 vs. 42.9%, P = 0.029; 66.7 vs. 39.2%, P = 0.005; and 69.4 vs. 40.3%, P < 0.001; respectively). In conclusion, CH-EUS was useful for diagnosing malignant and benign GB-protruded lesions. PMID:27162097

  16. 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. PMID:16300862

  17. Engineering of hollow mesoporous silica nanoparticles for remarkably enhanced tumor active targeting efficacy.

    PubMed

    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

  18. 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

  19. Mitochondria and nuclei dual-targeted heterogeneous hydroxyapatite nanoparticles for enhancing therapeutic efficacy of doxorubicin.

    PubMed

    Xiong, Hui; Du, Shi; Ni, Jiang; Zhou, Jianping; Yao, Jing

    2016-07-01

    Dual-targeted nanoparticles have been increasingly used to realize greater anti-proliferation effect by attacking double key sites of tumor cells. In order to retain nuclei inhibition effect and enhance DOX-induced apoptosis by mitochondrial pathway simultaneously, hyaluronic acid (HA) modified hydroxyapatite (HAP) nanoparticles (HAP-HA), the functional calcium-based tumor targeting nanoparticles, have been developed. In this nanosystem, HA acts as an active tumor-targeting ligand to bind the CD44 receptors which are overexpressed on the surface of tumor cells while HAP can load and deliver DOX to both nuclei and mitochondria of tumor cells. In this study, DOX-loaded HAP-HA nanoparticles (DOX/HAP-HA) exhibited satisfactory drug loading efficiency which was up to 214.55 ± 51.05 μg mg(-1) and showed a uniform nano-scaled particle size. The mitochondrial and nuclei targetability of DOX/HAP-HA was confirmed by confocal laser scanning microscopy analyses. Besides, western blot assay demonstrated that DOX/HAP-HA could markedly enhance mitochondrial cytochrome C leakage and thereby activate apoptotic cascade associated with it. In addition, in vivo anti-tumor efficacy and toxicity evaluation of DOX/HAP-HA indicated that DOX/HAP-HA was more effective and less harmful compared to other groups. DOX/HAP-HA might be a new promising targeted delivery system for effective cancer therapy. PMID:27105438

  20. Poly-L-lysine-coated nanoparticles: a potent delivery system to enhance DNA vaccine efficacy.

    PubMed

    Minigo, Gabriela; Scholzen, Anja; Tang, Choon K; Hanley, Jennifer C; Kalkanidis, Martha; Pietersz, Geoffrey A; Apostolopoulos, Vasso; Plebanski, Magdalena

    2007-01-26

    DNA formulations provide the basis for safe and cost efficient vaccines. However, naked plasmid DNA is only poorly immunogenic and new effective delivery strategies are needed to enhance the potency of DNA vaccines. In this study, we present a novel approach for the delivery of DNA vaccines using inert poly-L-lysine (PLL) coated polystyrene particles, which greatly enhance DNA immunogenicity. Intradermal injection of plasmid DNA encoding for chicken egg ovalbumin (OVA) complexed with PLL-coated polystyrene nanoparticles induced high levels of CD8 T cells as well as OVA-specific antibodies in C57BL/6 mice and furthermore inhibited tumour growth after challenge with the OVA expressing EG7 tumour cell line. Importantly, vaccine efficacy depended critically on the size of the particles used as well as on the presence of the PLL linker. Our data show that PLL-coated polystyrene nanoparticles of 0.05 microm but not 0.02 microm or 1.0 microm in diameter are highly effective for the delivery of DNA vaccines. PMID:17052812

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

    PubMed

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

    2016-04-01

    Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound and a sonosensitizer agent. We examined whether 5-aminolevulinic acid (5-ALA)-based SDT at 1 or 3 MHz could enhance the cytotoxicity of bleomycin (BLM) toward mouse mammary tumor cells both in vitro and in vivo. At 1 MHz, cell viability in the 5-ALA-based SDT group at 1, 2, and 3 W/cm(2) was 34.30%, 50.90%, and 60.16%, respectively. Cell viability in the 5-ALA-based SDT+BLM group at 1, 2, and 3 W/cm(2) was 0.09%, 0.32%, and 0.17%, respectively. In contrast, at 3 MHz, 5-ALA-based SDT+BLM did not show pronounced cytotoxicity. In the in vivo study, 5-ALA-based SDT+BLM was significantly more cytotoxic than 5-ALA-based SDT at 1 MHz and 3 MHz. These findings suggest that the mechanism of tumor shrinkage induced by 5-ALA-based SDT+BLM might involve not only direct cell killing, but also vascular shutdown. Thus, we show here that 5-ALA-based SDT enhances the efficacy of BLM both in vitro and in vivo. PMID:26799128

  3. Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases.

    PubMed

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

    2016-01-15

    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 paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel 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 paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel 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

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

    PubMed

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

    2014-09-01

    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

  5. Motivation Enhancement Therapy with pregnant substance-abusing women: does baseline motivation moderate efficacy?

    PubMed

    Ondersma, Steven J; Winhusen, Theresa; Erickson, Sarah J; Stine, Susan M; Wang, Yun

    2009-04-01

    Some evidence suggests that motivational approaches are less efficacious--or even counter-productive--with persons who are relatively motivated at baseline. The present study was conducted to examine whether disordinal moderation by baseline motivation could partially explain negative findings in a previous study [Winhusen, T., Kropp, F., Babcock, D., Hague, D., Erickson, S.J., Renz, C., Rau, L., Lewis, D., Leimberger, J., Somoza, E., 2008. Motivational enhancement therapy to improve treatment utilization and outcome in pregnant substance users. J. Subst. Abuse Treat. 35, 161-173]. Analyses also focused on the relative utility of the University of Rhode Island Change Assessment (URICA) scale, vs. a single goal question as potential moderators of Motivation Enhancement Therapy (MET). Participants were 200 pregnant women presenting for substance abuse treatment at one of four sites. Women were randomly assigned to either a three-session MET condition or treatment as usual (TAU). Generalized Estimating Equations (GEE) revealed no significant moderation effects on drug use at post-treatment. At follow-up, contrary to expectations, participants who had not set a clear quit goal at baseline were less likely to be drug-free if randomized to MET (OR=0.48); participants who did set a clear quit goal were more likely to be drug-free if randomized to MET (OR=2.53). No moderating effects were identified via the URICA. Disordinal moderation of MET efficacy by baseline motivation may have contributed somewhat to the negative results of the [Winhusen, T., Kropp, F., Babcock, D., Hague, D., Erickson, S.J., Renz, C., Rau, L., Lewis, D., Leimberger, J., Somoza, E., 2008. Motivational enhancement therapy to improve treatment utilization and outcome in pregnant substance users. J. Subst. Abuse Treat. 35, 161-173] study, but in the opposite direction expected. A simple question regarding intent to quit may be useful in identifying persons who may differentially respond to motivational

  6. 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.

  7. 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. PMID:27236589

  8. Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503.

    PubMed

    Rice, Lori; Pampo, Christine; Lepler, Sharon; Rojiani, Amyn M; Siemann, Dietmar W

    2011-01-01

    Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and >95% tumor necrosis 24h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency. PMID:20974154

  9. Efficacy and Pharmacological Mechanism of Pronase-Enhanced Low-Dose Antibiotics for Helicobacter pylori Eradication

    PubMed Central

    Liu, Kai Y.; Du, Fang C.; Fu, Qiang; Zhang, Wei J.; Sun, Hong W.; Zhang, Yi; Gan, Le L.; Yue, Zhi Y.

    2014-01-01

    This study examined the efficacy and pharmacological mechanism of pronase-assisted low-dose antibiotics for eradication of Helicobacter pylori. Mongolian gerbils infected with H. pylori received 7-day treatment (omeprazole, different concentrations of pronase, amoxicillin, and clarithromycin), and the efficacy was assessed using the eradication rate and the colonization of H. pylori. In Mongolian gerbils orally administered pronase, the thickness of the gastric mucous layer (GML) was examined using immunohistochemical and alcian blue staining, and the concentrations of amoxicillin in gastric tissue and serum were detected using high-performance liquid chromatography (HPLC). The eradication rates were 80.0% (12/15) in the high-pronase quadruple group (HPQG) and 86.7% (13/15) in the high-antibiotic group (HAG) (P = 1.000). The antibiotic dose in the HPQG was only 1/20 that in the HAG. Thirty minutes after oral treatment with pronase, the sticky protein of the GML was hydrolyzed, and the GML became thinner. Higher amoxicillin concentrations in both the gastric tissue and serum were observed in the pronase group than in the Am10 group. The concentration of amoxicillin in the Am10-plus-Pr108 group in gastric tissue was 3.8 times higher than in the Am10 group in 5 min. Together, these data suggest that pronase significantly reduced the dose of antibiotics used in H. pylori eradication. The pharmacological mechanism is likely pronase removal of the mucus layer, promoting chemical factor (i.e., gastric acid and pepsinogen) distribution and increasing the antibiotic concentrations in the deep GML, which acted on H. pylori collectively. Thus, pronase may enhance the level of antibiotics for eradication of H. pylori in the clinic. PMID:24687504

  10. Systems Pharmacological Analysis of Paclitaxel-Mediated Tumor Priming That Enhances Nanocarrier Deposition and Efficacy

    PubMed Central

    Straubinger, Robert M.; Mager, Donald E.

    2013-01-01

    Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol®) PK was described by a carrier-mediated dispositional model and SSL-DXR PK was described by a two-compartment model with first-order drug release. A hybrid-physiologic, well-stirred model with partition coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, time-dependent transduction functions. The tumor growth model used net first-order growth and death rate constants, and two transit compartments that captured the temporal displacement of tumor exposure versus effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PAC-induced apoptosis effects on Kp_DXR enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased Kp_DXR 3-fold. The intratumor concentrations producing maximal and half-maximal effects were 18 and 7.2 μg/ml for PAC, and 17.6 and 14.3 μg/ml for SSL-DXR. The duration of drug-induced apoptosis was 27.4 h for PAC and 15.8 h for SSL-DXR. Simulations suggested that PAC administered 24 h before peak priming could increase efficacy 2.5-fold over experimentally reported results. The quantitative approach developed in this article is applicable for evaluating tumor-priming strategies using diverse agents. PMID:23115220

  11. Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.

    PubMed

    Matsumoto, Yoko; Miyamoto, Yuichiro; Cabral, Horacio; Matsumoto, Yu; Nagasaka, Kazunori; Nakagawa, Shunsuke; Yano, Tetsu; Maeda, Daichi; Oda, Katsutoshi; Kawana, Kei; Nishiyama, Nobuhiro; Kataoka, Kazunori; Fujii, Tomoyuki

    2016-06-01

    Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV-negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors. PMID:26987571

  12. 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…

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

    ERIC Educational Resources Information Center

    Sandholtz, Judith Haymore; Ringstaff, Cathy

    2014-01-01

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

  14. 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...

  15. Enhancing the Transition to Kindergarten: A Randomized Trial to Test the Efficacy of the "Stars" Summer Kindergarten Orientation Program

    ERIC Educational Resources Information Center

    Berlin, Lisa J.; Dunning, Rebecca D.; Dodge, Kenneth A.

    2011-01-01

    This randomized trial tested the efficacy of an intensive, four-week summer program designed to enhance low-income children's transition to kindergarten (n's = 60 program children, 40 controls). Administered in four public schools, the program focused on social competence, pre-literacy and pre-numeracy skills, school routines, and parental…

  16. Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action.

    PubMed

    Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Akdemir, Atilla; Isik, Semra; Lanzi, Cecilia; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T

    2015-05-15

    A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. PMID:25846066

  17. The efficacy of CHK1 inhibitors is not altered by hypoxia, but is enhanced after reoxygenation.

    PubMed

    Hasvold, Grete; Nähse-Kumpf, Viola; Tkacz-Stachowska, Kinga; Rofstad, Einar K; Syljuåsen, Randi G

    2013-05-01

    Inhibitors of CHK1 are in clinical trials for cancer treatment in combination with DNA-damaging agents. Importantly, it was previously suggested that hypoxic cancer cells may be particularly sensitive to CHK1 inhibition. However, this suggestion was based on studies in severe, toxic levels of hypoxia (anoxia). The influence of less severe hypoxia on the efficacy of CHK1 inhibitors, administered either as single agents or in combination with other treatments, remains to be investigated. Here, we have assayed the effects of the CHK1 inhibitors, AZD7762 and UCN-01, during various hypoxic conditions and after reoxygenation in the absence and presence of ionizing radiation. Treatment with CHK1 inhibitors during acute or prolonged hypoxia (< 0.03%, 0.2%, and 1% O2; 3 h or 20-24 h) gave similar effects on cell survival as treatment with these inhibitors during normoxia. CHK1 inhibitors combined with ionizing radiation showed similar radiosensitization in hypoxic and normoxic cells. However, when the inhibitors were administered after reoxygenation following prolonged hypoxia (< 0.03% and 0.2%; 20-24 h), we observed decreased cell survival and stronger induction of the DNA damage marker, γH2AX, in S-phase cells. This was accompanied by enhanced phosphorylation of the single-stranded DNA-binding replication protein A. These results suggest that the cytotoxic effects of CHK1 inhibitors are enhanced after reoxygenation following prolonged hypoxia, most likely due to the increased replication-associated DNA damage. Combining CHK1 inhibitors with other treatments that cause increased reoxygenation, such as fractionated radiotherapy, might therefore be beneficial. PMID:23635654

  18. Enhanced protective efficacy of a chimeric form of the schistosomiasis vaccine antigen Sm-TSP-2.

    PubMed

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

    2012-01-01

    The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG(1) and IgG(3) from putatively resistant individuals resident in S. mansoni endemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to the immunogenic 5B region of the hookworm aspartic protease and vaccine antigen, Na-APR-1. Sm-TSP-2 formulated with alum/CpG showed significant reductions in adult worm and liver egg burdens in two separate murine schistosomiasis challenge studies. Sm-TSP-2/5B afforded significantly greater protection than Sm-TSP-2 alone when both antigens were formulated with alum/CpG. The enhanced protection obtained with the chimeric fusion protein was associated with increased production of anti-Sm-TSP-2 antibodies and IL-4, IL-10 and IFN-γ from spleen cells of vaccinated animals. Sera from 666 individuals from Brazil who were infected with S. mansoni were screened for potentially deleterious IgE responses to Sm-TSP-2. Anti-Sm-TSP-2 IgE to this protein was not detected (also shown previously for Na-APR-1), suggesting that the chimeric antigen Sm-TSP-2/5B could be used to safely and effectively vaccinate people in areas where schistosomes and hookworms are endemic. PMID:22428079

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

    PubMed Central

    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. PMID:26457052

  20. 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.

  1. Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy.

    PubMed

    Heffler, Melissa; Golubovskaya, Vita M; Dunn, Kelli M Bullard; Cance, William

    2013-08-01

    Focal adhesion kinase (FAK) increasingly has been implicated in cancer growth and progression. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) is a small molecule FAK inhibitor that blocks the Y397 autophosphorylation site. FAK inhibitor, Y15 decreased Y397 FAK in different colon cancer cells lines in a dose-dependent manner. In addition, Y15 decreased phosphorylated Src in SW480 and SW620 cells. Y15 decreased cell viability, increased detachment, and increased apoptosis in SW480 and SW620 cells in vitro. Combination of FAK inhibitor Y15 and Src inhibitor PP2 decreased colon cancer cell viability more effectively than each agent alone. In addition, when combined with 5-FU, oxaliplatin or 5-FU and oxaliplatin, colon cancer viability was decreased further, demonstrating that dual and triple therapy synergistically inhibits cell viability. In vivo, Y15 decreased subcutaneous SW620 tumor growth by 28%. Combination of oral Y15 with 5-FU/or oxaliplatin decreased tumor growth by 48% more effectively than each inhibitor alone. Finally, tumors treated with Y15 expressed less Y397 phosphorylation, Src phosphorylation and had greater apoptosis than controls. Thus, the small molecule FAK inhibitor, Y15, inhibits cell growth in vitro and in vivo and enhances the efficacy of chemotherapy, demonstrating that it can be an effective therapeutic inhibitor for treating colon cancer. PMID:23792569

  2. PDE5 Inhibitors Enhance Tumor Permeability and Efficacy of Chemotherapy in a Rat Brain Tumor Model

    PubMed Central

    Black, Keith L.; Yin, Dali; Ong, John M.; Hu, Jinwei; Konda, Bindu M.; Wang, Xiao; Ko, MinHee K.; Bayan, Jennifer-Ann; Sacapano, Manuel R.; Espinoza, Andreas; Morris-Irvin, Dwain K; Shu, Yan

    2008-01-01

    The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (KCa) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB “opener”, bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhance anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors. PMID:18674521

  3. 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

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

    PubMed

    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

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

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

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

  6. Strategies to enhance the therapeutic efficacy of antidepressants: targeting residual symptoms

    PubMed Central

    Kurian, Benji T; Greer, Tracy L; Trivedi, Madhukar H

    2009-01-01

    Major depressive disorder (MDD) is an illness of great morbidity that affects many people across the world. The current goal for treatment of MDD is to achieve remission (i.e., no depressive symptoms). However, despite scientific advances in the treatment for MDD, antidepressants as first-line agents yield only modest remission rates. In fact, a recent study indicated that only one out of three subjects who received a standard, first-line antidepressant attained remission. Not achieving remission from depressive symptoms increases the risk of a more chronic and debilitating course of illness with frequent recurrences. Although a number of reasons contribute to these modest outcomes, the presence of residual symptoms is a major problem. Residual symptoms are defined as symptoms that linger despite an adequate dose and duration of an antidepressant medication. This article reviews the prevalence and clinical impact of common residual symptoms and discusses the utility of aggressively addressing residual symptoms to enhance the efficacy of antidepressant medications. PMID:19589048

  7. Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation.

    PubMed

    Broxmeyer, Hal E

    2016-06-01

    Clinical cord blood (CB) hematopoietic cell transplantation (HCT) has progressed well since the initial successful CB HCT that saved the life of a young boy with Fanconi anemia. The recipient is alive and well now 28 years out since that first transplant with CB cells from his HLA-matched sister. CB HCT has now been used to treat over 35,000 patients with various malignant and non-malignant disorders mainly using HLA-matched or partially HLA-disparate allogeneic CB cells. There are advantages and disadvantages to using CB for HCT compared to other sources of transplantable hematopoietic stem (HSC) and progenitor (HPC) cells. One disadvantage of the use of CB as a source of transplantable HSC and HPC is the limited number of these cells in a single CB collected, and slower time to neutrophil, platelet and immune cell recovery. This review describes current attempts to: increase the collection of HSC/HPC from CB, enhance the homing of the infused cells, ex-vivo expand numbers of collected HSC/HPC and increase production of the infused CB cells that reach the marrow. The ultimate goal is to manipulate efficiency and efficacy for safe and economical use of single unit CB HCT. PMID:27211041

  8. Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism.

    PubMed

    Sun, Meiyan; Zhang, Qunshu; Yang, Xiaoyu; Qian, Steven Y; Guo, Bin

    2016-09-01

    Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D-regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer cells. We show that calcitriol enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. When miR-627 is inhibited, calcitriol fails to enhance the activity of irinotecan. In addition, overexpression of miR-627 or siRNA knockdown of CYP3A4 enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. In contrast, overexpression of CYP3A4 abolished the effects of calcitriol on the activity of irinotecan. Using a nude mouse xenograft model, we demonstrated that calcitriol inhibited CYP3A4 and enhanced the in vivo antitumor activity of irinotecan without causing side effects. Our study identified a novel target for improving cancer therapy, i.e., modulating the intratumoral CYP3A4-mediated drug metabolism with vitamin D. This strategy could enhance the therapeutic efficacy without eliciting the side effects. Mol Cancer Ther; 15(9); 2086-95. ©2016 AACR. PMID:27458137

  9. 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. PMID:21397538

  10. 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

  11. Using Microteaching to Enhance Teacher Efficacy in Pre-Service Teachers

    ERIC Educational Resources Information Center

    Mergler, Amanda G.; Tangen, D.

    2010-01-01

    This study examined pre-service teachers' efficacy in relation to the utilisation of microteaching as an assessment tool for postgraduate education students in Australia. Three hundred and fifteen pre-service teachers completed the teacher efficacy survey and additional qualitative questions at Time 1 and 208 completed the survey and questions at…

  12. 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…

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

    PubMed Central

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

    2009-01-01

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

  14. Randomized controlled trial of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients with myocardial infarction.

    PubMed

    Vibulchai, Nisakorn; Thanasilp, Sureeporn; Preechawong, Sunida

    2016-06-01

    This study examined the effects of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients who had a myocardial infarction. Sixty-six hospitalized patients of various ages and both genders were randomly assigned to either an experimental or a control group. Participants in the experimental group took part in three individualized in-hospital education sessions and three weekly sessions of telephone counseling. The control group primarily engaged in a supervised exercise and activities of a daily living performance regimen, and received education in this regard. Self-efficacy and functional status were measured via questionnaire. Four weeks after discharge, the experimental group was found to have significantly higher total self-efficacy and functional status scores than the control group. In addition, the experimental group exhibited significantly higher subscale scores on social activity, household tasks, occupation, and exercise self-efficacy than the control group. These results indicate that the program is effective in improving the self-efficacy and functional status of Thai patients who have had a myocardial infarction. PMID:26415520

  15. Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo

    PubMed Central

    Zhao, Hongliang; Verma, Deeptak; Li, Wen; Choi, Yoonjoo; Ndong, Christian; Fiering, Steven N.; Bailey-Kellogg, Chris; Griswold, Karl E.

    2015-01-01

    SUMMARY The enzyme lysostaphin possesses potent anti-staphylococcal activity and represents a promising antibacterial drug candidate; however, its immunogenicity poses a barrier to clinical translation. Here, structure-based biomolecular design enabled widespread depletion of lysostaphin’s DRB1*0401 restricted T cell epitopes, and resulting deimmunized variants exhibited striking reductions in anti-drug antibody responses upon administration to humanized HLA-transgenic mice. This reduced immunogenicity translated into improved efficacy in the form of protection against repeated challenges with methicillin-resistant Staphylococcus aureus, or MRSA. In contrast, while wild type lysostaphin was efficacious against the initial MRSA infection, it failed to clear subsequent bacterial challenges that were coincident with escalating anti-drug antibody titers. These results extend the existing deimmunization literature, in which reduced immunogenicity and retained efficacy are assessed independently of each other. By correlating in vivo efficacy with longitudinal measures of anti-drug antibody development, we provide the first direct evidence that T cell epitope depletion manifests enhanced biotherapeutic efficacy. PMID:26000749

  16. Lactobacillus casei Shirota enhances the preventive efficacy of soymilk in chemically induced breast cancer.

    PubMed

    Kaga, Chiaki; Takagi, Akimitsu; Kano, Mitsuyoshi; Kado, Shoichi; Kato, Ikuo; Sakai, Masashi; Miyazaki, Kouji; Nanno, Masanobu; Ishikawa, Fumiyasu; Ohashi, Yasuo; Toi, Masakazu

    2013-11-01

    Soy foods are known to be effective for breast cancer prevention. The habitual consumption of soy isoflavones in combination with the probiotic Lactobacillus casei Shirota (LcS) was shown to decrease the risk of breast cancer occurrence in our previous population-based case-controlled study among Japanese women. The present study aimed to elucidate the cooperative prevention mechanism of soymilk and LcS using an animal carcinogenic model. Female Sprague-Dawley rats received a high-fat, AIN-76A diet containing soymilk, LcS, both soymilk and LcS, or none and were orally exposed to 2-amino-1-methyl-6-penylimidazo[4,5-b]pyridine at a dose of 85 mg/kg bodyweight eight times for 2 weeks. The development of palpable mammary tumors was monitored for 17 weeks. Tumor tissues were immunohistochemically examined for estrogen receptor (ER)-α, Ki-67 and CD34. Compared with the control group, the incidence and multiplicity of mammary tumors were reduced by soymilk alone and soymilk in combination with LcS, while tumor volume was decreased by LcS alone and LcS in combination with soymilk. An immunohistochemical analysis revealed that soymilk in combination with LcS more effectively reduced the numbers of ER-α-positive and Ki-67-positive cells in tumors than soymilk alone and that both soymilk and LcS inhibited tumor angiogenesis. These results demonstrated that soymilk prevents the development of mammary tumors and that LcS suppresses tumor growth, potentially enhancing the preventive efficacy of soymilk. The habitual consumption of LcS in combination with soymilk might be a beneficial dietary style for breast cancer prevention. PMID:23992486

  17. Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.

    PubMed

    Zhou, Hao; Fan, Zhiyuan; Deng, Junjie; Lemons, Pelin K; Arhontoulis, Dimitrios C; Bowne, Wilbur B; Cheng, Hao

    2016-05-11

    One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood. PMID:27057591

  18. Role of contrast-enhanced ultrasonography in percutaneous radiofrequency ablation of liver metastases and efficacy evaluation

    PubMed Central

    Wu, Jie; Yang, Wei; Yin, Shanshan; Wu, Jinyu; Wu, Wei; Yan, Kun

    2013-01-01

    Objective To retrospectively investigate the role of contrast-enhanced ultrasonography (CEUS) in percutaneous radiofrequency ablation (RFA) in patients with liver metastases and evaluate the therapeutic efficacy of RFA assisted by CEUS. Methods From May 2004 to September 2010, 136 patients with 219 liver metastatic lesions received CEUS examination 1 h before RFA (CEUS group), and other 126 patients with 216 lesions without CEUS examination in the earlier period were served as a historical control group. The mean tumor size was 3.2 cm and the mean tumor number was 1.6 in the CEUS group, while 3.4 cm and 1.7 in the control group, respectively (P>0.05). The clinical characteristics, recurrence results and survival outcomes were compared between two groups. Results In the CEUS group, two isoechoic tumors were not demonstrated on unenhanced ultrasonography (US), and 63 (47%) of 134 tumors examined with CEUS were 0.3 cm larger than with unenhanced US. Furthermore, in 18.4% of 136 patients, additional 1-3 tumors were detected on CEUS. The CEUS group showed higher early tumor necrosis and lower intrahepatic recurrence than the control group. The 3-year overall survival (OS) rate and the 3-year local recurrence-free survival (LRFS) rate in the CEUS group were 50.1% and 38.3%, in contrast to 25.3% and 19.3% in the control group, respectively (P=0.002 and P<0.001). Conclusions CEUS provides important information for RFA treatment in patients with liver metastases and better therapeutic effect could be attained. PMID:23592894

  19. Inhibiting cortical protein kinase A in spinal cord injured rats enhances efficacy of rehabilitative training.

    PubMed

    Wei, David; Hurd, Caitlin; Galleguillos, Danny; Singh, Jyoti; Fenrich, Keith K; Webber, Christine A; Sipione, Simonetta; Fouad, Karim

    2016-09-01

    Elevated levels of the second messenger molecule cyclic adenosine monophosphate (cAMP) are often associated with neuron sprouting and neurite extension (i.e., neuroplasticity). Phosphokinase A (PKA) is a prominent downstream target of cAMP that has been associated with neurite outgrowth. We hypothesized that rehabilitative motor training following spinal cord injuries promotes neuroplasticity via PKA activation. However, in two independent experiments, inhibition of cortical PKA using Rp-cAMPS throughout rehabilitative training robustly increased functional recovery and collateral sprouting of injured corticospinal tract axons, an indicator of neuroplasticity. Consistent with these in vivo findings, using cultured STHdh neurons, we found that Rp-cAMPS had no effect on the phosphorylation of CREB (cAMP response element-binding protein), a prominent downstream target of PKA, even with the concomitant application of the adenylate cyclase agonist forskolin to increase cAMP levels. Conversely, when cAMP levels were increased using the phosphodiesterase inhibitor IBMX, Rp-cAMPS potently inhibited CREB phosphorylation. Taken together, our results suggest that an alternate cAMP dependent pathway was involved in increasing CREB phosphorylation and neuroplasticity. This idea was supported by an in vitro neurite outgrowth assay, where inhibiting PKA did enhance neurite outgrowth. However, when PKA inhibition was combined with inhibition of EPAC2 (exchange protein directly activated by cAMP), another downstream target of cAMP in neurons, neurite outgrowth was significantly reduced. In conclusion, blocking PKA in cortical neurons of spinal cord injured rats increases neurite outgrowth of the lesioned corticospinal tract fibres and the efficacy of rehabilitative training, likely via EPAC. PMID:27401133

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

    PubMed

    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; Maus, Marcela V

    2016-03-01

    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

  1. 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

  2. IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy

    PubMed Central

    Helms, Mike W.; Prescher, Jennifer A.; Cao, Yu-An; Schaffert, Steven

    2016-01-01

    Cytokine-induced killer (CIK) cells are T cell derived ex vivo expanded cells with both NK and T cell properties. They exhibit potent anti-tumor efficacy against various malignancies in preclinical models and have proven safe and effective in clinical studies. We combined CIK cell adoptive immunotherapy with IL-12 cytokine immunotherapy in an immunocompetent preclinical breast cancer model. Combining CIK cells with IL-12 increased anti-tumor efficacy in vivo compared to either therapy alone. Combination led to full tumor remission and long-term protection in 75% of animals. IL-12 treatment sharply increased the anti-tumor efficacy of short-term cultured CIK cells that exhibited no therapeutic effect alone. Bioluminescence imaging based in vitro cytotoxicity and in vivo homing assays revealed that short-term cultured CIK cells exhibit full cytotoxicity in vitro, but display different tumor homing properties than fully expanded CIK cells in vivo. Our data suggest that short-term cultured CIK cells can be “educated” in vivo, producing fully expanded CIK cells upon IL-12 administration with anti-tumor efficacy in a mouse model. Our findings demonstrate the potential to improve current CIK cell-based immunotherapy by increasing efficacy and shortening ex vivo expansion time. This holds promise for a highly efficacious cancer therapy utilizing synergistic effects of cytokine and cellular immunotherapy. PMID:20532883

  3. MMP-2/9-oriented combinations enhance antitumor efficacy of EGFR/HER2-targeting fusion proteins and gemcitabine.

    PubMed

    Qin, Ye; Liu, Xiu-Jun; Li, Liang; Liu, Xu-Jie; Li, Yi; Gao, Rui-Juan; Shao, Rong-Guang; Zhen, Yong-Su

    2014-07-01

    To increase the antitumor efficacy, in the present study, we proposed several settings of matrix metalloproteinase (MMP)-2/9-oriented combinations that comprise the MMP-2/9-targeting fusion protein dFv-LDP and the MMP inhibitor doxycycline (DOX) in association with EGFR/HER2-bispecific fusion protein Ec-LDP-Hr, its enediyne-energized analogue Ec-LDP-Hr-AE, and gemcitabine (GEM). The expressions of various fusion proteins were detected by western blot analysis. Proliferation and migration inhibition of cells were determined by MTT and Transwell assay, respectively. The binding capability of dFv-LDP and Ec-LDP-Hr to cancer cells was examined by ELISA, cell immunofluorescence coimmunoprecipitation and confocal assays. Animal experiments were set to investigate the antitumor efficacy of various combinations against colorectal carcinoma HCT-15 xenograft in athymic mice. These two targeting proteins dFv-LDP and Ec-LDP-Hr had strong binding capabilities and antiproliferation effects on various cancer cell lines. Enhanced therapeutic efficacy in vivo was observed in the MMP-2/9-targeting fusion protein dFv-LDP integrated combinations including: i) dFv-LDP and Ec-LDP-Hr, ii) dFv-LDP and enediyne-energized fusion protein Ec-LDP-Hr-AE, iii) dFv-LDP and Ec-LDP-Hr-AE plus DOX, and iv) dFv-LDP and GEM plus DOX against colorectal cancer HCT-15 xenograft in athymic mice. In setting iii, DOX (20 mg/kg), dFv-LDP (20 mg/kg) and Ec-LDP-Hr-AE (0.3 mg/kg) alone suppressed tumor growth by 35, 49.7 and 67.5%, respectively. The combination of dFv-LDP and Ec-LDP-Hr-AE was 75.1%. Furthermore, this combination plus DOX showed stronger efficacy with an inhibitory rate of 82.7%. In setting iv, the combination of dFv-LDP and GEM suppressed tumor growth by 66.3%. Notably, the tumor inhibitory rate of the dFv-LDP/GEM/DOX combination reached 85.5%, producing initial shrinkage after the first administration. The MMP-2/9-oriented combination strategy that employs the MMP-2/9-targeting antibody

  4. Middle School Focus: Examining the Interplay between Middle School Students Achievement Goals and Self-Efficacy in a Technology-Enhanced Learning Environment

    ERIC Educational Resources Information Center

    Hsieh, Peggy; Cho, Yunjoong; Liu, Min; Schallert, Diane L.

    2008-01-01

    Researchers have suggested that self-efficacy and goal orientation are context specific variables. However, few researchers have addressed these variables in technology-enhanced learning environments. This study examined changes in 549 middle school students' goal orientation, self-efficacy, and science knowledge after engaging in science learning…

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

    PubMed

    Matsaganis, Matthew D; Wilkin, Holley A

    2015-04-01

    This article contributes to the burgeoning literature on the social determinants of health disparities. The authors investigate how communication resources and collective efficacy, independently and in combination, shape residents' access to health enhancing resources (including healthcare services, sources of healthier food options, and public recreation spaces) in their communities. Using random digit dial telephone survey data from 833 residents of South Los Angeles communities the authors show that communicative social capital-that is, an information and problem-solving resource that accrues to residents as they become more integrated into their local communication network of neighbors, community organizations, and local media-plays a significant role in access to health resources. This relationship is complicated by individuals' health insurance and health status, as communicative social capital magnifies the sense of absence of resources for those who are in worse health and lack insurance. Communicative social capital builds collective efficacy, which is positively related to access to health-enhancing resources, but it also mediates the negative relationship between communicative social capital and access to health resources. Residents with richer stores of communicative social capital and collective efficacy report better access to health resources. The authors conclude with a discussion of implications of these findings and suggestions for future research. PMID:25529115

  6. Naringenin enhances the efficacy of human embryonic stem cell-derived pancreatic endoderm in treating gestational diabetes mellitus mice.

    PubMed

    Xing, Bao-Heng; Yang, Feng-Zhen; Wu, Xiao-Hua

    2016-06-01

    Gestational diabetes mellitus (GDM) is a disease commonly occurs during mid to late pregnancy with pathologies such as hyperglycemia, hyperinsulinemia and mal-development of fetus. We have previously demonstrated that pancreatic endoderm (PE) derived from human embryonic stem cells (hESCs) effectively alleviated diabetic symptoms in a mouse model of GDM, although the clinical efficacy was limited due to oxidative stress. In this study, using the anti-oxidant agent naringenin, we aimed to further enhance the efficacy of hESC-derived PE transplant. Insulin-secreting PE was differentiated from hESCs, which were then transplanted into GDM mice. Naringenin was administered to mice receiving the PE transplant, with sham operated mice serving as negative control, to assess its effect on alleviation of GDM symptoms. We found that naringenin supplement further improved insulin response, glucose metabolism and reproductive outcome of the PE-transplanted female mice. Our new findings further potentiates the feasibility of using differentiated hESCs to treat GDM, in which anti-oxidative agent such as naringenin could greatly enhance the clinical efficacy of stem cell based therapies. PMID:27156928

  7. Artemether-lumefantrine nanostructured lipid carriers for oral malaria therapy: Enhanced efficacy at reduced dose and dosing frequency.

    PubMed

    Prabhu, Priyanka; Suryavanshi, Shital; Pathak, Sulabha; Sharma, Shobhona; Patravale, Vandana

    2016-09-10

    Artemether-lumefantrine (ARM-LFN) is a World Health Organization (WHO) approved fixed-dose combination having low solubility and poor oral bioavailability. Nanostructured lipid carriers (NLC) were developed to enhance the oral efficacy of this combination using the microemulsion template technique. They were characterized for drug content, entrapment efficiency, size distribution, in vitro release, antimalarial efficacy, and toxicity. The NLC showed sustained drug release. The recommended adult therapeutic dose is 80mg ARM and 480mg LFN (4 tablets) twice a day, which amounts to 160mg ARM and 960mg LFN daily. ARM-LFN NLC given once a day at 1/5 of therapeutic dose (16mg ARM and 96mg LFN) showed complete parasite clearance and 100% survival in Plasmodium berghei-infected mice. 33% of the mice treated with marketed tablets twice a day at the therapeutic dose showed late-stage recrudescence. Thus, NLC showed enhanced efficacy at 1/10 of the daily dose of ARM-LFN. The 10-fold reduced daily dose was formulated in two soft gelatin capsules thus reducing the number of units to be taken at a time by the patient. The capsules showed good stability at room temperature for a year. The NLC were found to be safe in rats. The biocompatible NLC developed using an industrially feasible technique offer a promising solution for oral malaria therapy. PMID:27421912

  8. 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.

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

    PubMed

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

    2013-07-01

    In times of a high-impact safety incident citizens may have a variety of sources available to help them cope with the situation. This research focuses on the interplay of efficacy information in risk communication messages and peer feedback, such as responses on social network sites (SNSs) in the context of a high-impact risk on the intention to engage in self-protective behavior. The study pitted high and low efficacy information messages against supporting and opposing peer feedback (N = 242). Results show a significant interaction effect between efficacy information in a news article and peer feedback from SNS messages on both the intention to engage in self-protective behavior and levels of involvement. Participants who received the article with more efficacy information and also received supportive peer feedback via SNS messages were more likely to express higher levels of involvement and greater intentions to engage in protective behavior. When confronted with a low efficacious news article, the effect of peer feedback on these two variables was significantly stronger. Finally, implications for theory and government risk communication are discussed. PMID:23126483

  10. Biodegradable in situ gelling delivery systems containing pilocarpine as new antiglaucoma formulations: effect of a mercaptoacetic acid/N-isopropylacrylamide molar ratio.

    PubMed

    Lai, Jui-Yang

    2013-01-01

    Ocular drug delivery is one of the most commonly used treatment modalities in the management of glaucoma. We have recently proposed the use of gelatin and poly(N-isopropylacrylamide) (PNIPAAm) graft copolymers as biodegradable in situ forming delivery systems for the intracameral administration of antiglaucoma medications. In this study, we further investigated the influence of carrier characteristics on drug delivery performance. The carboxyl-terminated PNIPAAm samples with different molecular weights were synthesized by varying the molar ratio of mercaptoacetic acid (MAA)/N-isopropylacrylamide (NIPAAm) from 0.05 to 1.25, and were determined by end-group titration. The preparation of gelatin-g-PNIPAAm (GN) copolymers from these thermoresponsive polymers was achieved using carbodiimide chemistry. Our results showed that the carboxylic end-capped PNIPAAm of high molecular weight may lead to the lower thermal phase transition temperature and slower degradation rate of GN vehicles than its low molecular weight counterparts. With a decreasing MAA/NIPAAm molar ratio, the drug encapsulation efficiency of copolymers was increased due to fast temperature-triggered capture of pilocarpine nitrate. The degradation of the gelatin network could greatly affect the drug release profiles. All of the GN copolymeric carriers demonstrated good corneal endothelial cell and tissue compatibility. It is concluded that different types of GN-based delivery systems exhibit noticeably distinct intraocular pressure-lowering effect and miosis action, thereby reflecting the potential value of a MAA/NIPAAm molar ratio in the development of new antiglaucoma formulations. PMID:24187486

  11. Biodegradable in situ gelling delivery systems containing pilocarpine as new antiglaucoma formulations: effect of a mercaptoacetic acid/N-isopropylacrylamide molar ratio

    PubMed Central

    Lai, Jui-Yang

    2013-01-01

    Ocular drug delivery is one of the most commonly used treatment modalities in the management of glaucoma. We have recently proposed the use of gelatin and poly(N-isopropylacrylamide) (PNIPAAm) graft copolymers as biodegradable in situ forming delivery systems for the intracameral administration of antiglaucoma medications. In this study, we further investigated the influence of carrier characteristics on drug delivery performance. The carboxyl-terminated PNIPAAm samples with different molecular weights were synthesized by varying the molar ratio of mercaptoacetic acid (MAA)/N-isopropylacrylamide (NIPAAm) from 0.05 to 1.25, and were determined by end-group titration. The preparation of gelatin-g-PNIPAAm (GN) copolymers from these thermoresponsive polymers was achieved using carbodiimide chemistry. Our results showed that the carboxylic end-capped PNIPAAm of high molecular weight may lead to the lower thermal phase transition temperature and slower degradation rate of GN vehicles than its low molecular weight counterparts. With a decreasing MAA/NIPAAm molar ratio, the drug encapsulation efficiency of copolymers was increased due to fast temperature-triggered capture of pilocarpine nitrate. The degradation of the gelatin network could greatly affect the drug release profiles. All of the GN copolymeric carriers demonstrated good corneal endothelial cell and tissue compatibility. It is concluded that different types of GN-based delivery systems exhibit noticeably distinct intraocular pressure-lowering effect and miosis action, thereby reflecting the potential value of a MAA/NIPAAm molar ratio in the development of new antiglaucoma formulations. PMID:24187486

  12. 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.

  13. Enhancing Drug Treatment Program Staff’s Self-Efficacy to Support Patients’ HCV Needs

    PubMed Central

    STRAUSS, SHIELA M.; MUNOZ-PLAZA, CORRINE; ROSEDALE, MARY T.; RINDSKOPF, DAVID M.; LUNIEVICZ, JOSEPH

    2011-01-01

    To increase HCV-related support for patients in substance abuse treatment programs, we implemented an on-site staff training in 16 programs throughout the United States. It aimed to increase participants’ self-efficacy in assisting patients with their HCV-related needs. Findings indicate that participants’ self-efficacy increased both 1- and 3-months post-training, resulting in providers’ perceptions that they were better able to support patients regarding HCV. Implementing an engaging and interactive HCV training for social workers and other substance abuse treatment program staff has the potential to increase their HCV knowledge, self-efficacy, and the HCV-related assistance provided to patients both in the short- and longer-term. PMID:22102796

  14. Clinical strategies to enhance the efficacy of nicotine replacement therapy for smoking cessation: a review of the literature.

    PubMed

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

    2013-04-01

    A number of smoking cessation pharmacotherapies have led to increases in quitting and thus to significant benefits to public health. Among existing medications, nicotine replacement therapy (NRT) has been available the longest, has the largest literature base in support, and is the only option for over-the-counter access. While the short-term efficacy of NRT is well documented in clinical trials, long-term abstinence rates associated with using NRT are modest, as most smokers will relapse. This literature review examines emerging clinical strategies to improve NRT efficacy. After an initial overview of NRT and its FDA-approved indications for use, we review randomized trials in which clinical delivery of NRT was manipulated and tested, in an attempt to enhance efficacy, through (1) duration of use (pre-quit and extended use), (2) amount of use (high-dose and combination NRT), (3) tailoring to specific smoker groups (genotype and phenotype), or (4) use of NRT for novel purposes (relapse prevention, temporary abstinence, cessation induction). Outcomes vary within and across topic area, and we highlight areas that offer stronger promise. Combination NRT likely represents the most promising strategy moving forward; other clinical strategies offer conflicting evidence but deserve further testing (pre-quit NRT or tailored treatment) or offer potential utility but are in need of further, direct tests. Some areas, though based on a limited set of studies, do not offer great promise (high-dose and extended treatment NRT). We conclude with a brief discussion of emergent NRT products (e.g., oral nicotine spray, among others), which may ultimately offer greater efficacy than current formulations. In order to further lower the prevalence of smoking, novel strategies designed to optimize NRT efficacy are needed. PMID:23572407

  15. 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…

  16. 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…

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

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

    ERIC Educational Resources Information Center

    Susskind, J.E.

    2005-01-01

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

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

    ERIC Educational Resources Information Center

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

    2013-01-01

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

  20. 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…

  1. 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…

  2. 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. PMID:26543027

  3. A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells.

    PubMed

    Lin, Chi-Chen; Yu, Yen-Ling; Shih, Chia-Chiao; Liu, Ko-Jiunn; Ou, Keng-Liang; Hong, Ling-Zong; Chen, Jody D C; Chu, Ching-Liang

    2011-07-01

    DNA vaccine has been suggested to use in cancer therapy, but the efficacy remains to be improved. The immunostimulatory effect of a fungal immunomodulatory protein Ling Zhi-8 (LZ-8) isolated from Ganoderma lucidum has been reported. In this study, we tested the adjuvanticity of LZ-8 for HER-2/neu DNA vaccine against p185(neu) expressing tumor MBT-2 in mice. We found that recombinant LZ-8 stimulated mouse bone marrow-derived dendritic cells (DCs) via TLR4 and its stimulatory effect was not due to any microbe contaminant. In addition, LZ-8 enhanced the ability of DCs to induce antigen-specific T cell activation in vitro and in a subunit vaccine model in vivo. Surprisingly, LZ-8 cotreatment strongly improved the therapeutic effect of DNA vaccine against MBT-2 tumor in mice. This increase in antitumor activity was attributed to the enhancement of vaccine-induced Th1 and CTL responses. Consistent with the results from DCs, the promoting effect of LZ-8 on DNA vaccine was diminished when the MBT-2 tumor cells were grown in TLR4 mutant mice. Thus, we concluded that LZ-8 may be a promising adjuvant to enhance the efficacy of DNA vaccine by activating DCs via TLR4. PMID:21499904

  4. 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

  5. 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. PMID:26829221

  6. The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine.

    PubMed

    Lee, Mi Jin; Woo, Min-Yeong; Heo, Yoo Mi; Kim, Jung Sik; Kwon, Myung-Hee; Kim, Kyongmin; Park, Sun

    2010-11-01

    T-cell immunoglobulin and mucin domain 3 (Tim3) plays an important role in the Th1-mediated immune response; however, its effect on the efficacy of tumor vaccines has not been fully evaluated. Here, we demonstrate the effect of Tim3 pathway inhibition on tumor growth in mice. Lewis lung carcinoma (3LL) cells expressing a Tim3 pathway inhibitor, when injected into mice, showed suppressed tumor growth and a reduced frequency of CD4(+)CD25(+)Foxp3(+) T-cells. Furthermore, Tim3 pathway inhibition significantly enhanced the efficacy of a prophylactic tumor vaccine and marginally enhanced the efficacy of a therapeutic tumor vaccine. However, when given in combination with the chemotherapeutic agent, 5-fluorouracil, the therapeutic tumor vaccine capable of Tim3 pathway inhibition had no additional anti-tumor effect. Our results show that Tim3 pathway inhibition can enhance tumor vaccine efficacy. PMID:20920468

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

    PubMed

    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

  8. 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

  9. Luminous efficacy enhancement of ultraviolet-excited white light-emitting diodes through multilayered phosphor-in-glass.

    PubMed

    Peng, Yang; Wang, Sinmin; Li, Ruixin; Li, Hong; Cheng, Hao; Chen, Mingxiang; Liu, Sheng

    2016-06-20

    To enhance the luminous efficacy of ultraviolet-excited white light-emitting diodes (WLEDs), a novel packaging structure that is based on a multilayered red, green, and blue (RGB) phosphor-in-glass (PiG) was proposed. The RGB PiG was prepared by screenprinting and low temperature sintering, and the effects of different configuration orders of RGB phosphor layers on the optical performance of WLEDs were studied. Compared with the conventional mixed-RGB PiG, the luminous efficacy of WLEDs packaged by the multilayered PiG with the order of R-G-B is increased by 8.2% at the driving current of 500 mA, and the corresponding correlated color temperature (CCT) and color rendering index (CRI) are 2984 K and 86.8, respectively. Moreover, the WLEDs packaged by multilayered G-R-B PiG yield the highest luminous efficacy of 27.19 lm/W at the expense of color quality, which is still an acceptable warm light, with a CCT of 3326 K and a CRI of 84.2. PMID:27409121

  10. Enhanced tumor targeting and antitumor efficacy via hydroxycamptothecin-encapsulated folate-modified N-succinyl-N'-octyl chitosan micelles.

    PubMed

    Zhu, Hongyan; Cao, Jie; Cui, Sisi; Qian, Zhiyu; Gu, Yueqing

    2013-04-01

    10-Hydroxycamptothecin (HCPT) is an effective anticancer drug against various types of solid tumors. But the antitumor efficacy of HCPT is far from satisfactory because of its poor physicochemical properties, short circulating half-life, low stability, and nonspecific toxicity to normal tissues. Therefore, a targeted delivery strategy for HCPT to pathological sites is eagerly needed to overcome these limitations. The folate-modified N-succinyl-N'-octyl chitosan (folate-SOC) micelle was chosen in this study and served as the targeted delivery system for HCPT to improve the antitumor efficacy. The water-insoluble anticancer drug HCPT was encapsulated into the folate-SOC micelles by the dialysis method. The near-spherical HCPT-loaded folate-SOC (HCPT/folate-SOC) micelles were formed in aqueous media with diameter of about 100-200 nm. The HCPT/folate-SOC micelles displayed a good stability, reasonable drug-loading content (about 10%), and sustained release behavior for the water-insoluble HCPT. Compared with free HCPT, HCPT/folate-SOC micelles exhibited a significant enhancement of cellular uptake, higher cytotoxicity against folate receptor positive tumor cell (Bel-7402), excellent tumor-targeting capability and substantially better antitumor efficacy on the nude mice bearing Bel-7402 xenografts. These results demonstrate the potential of folate-SOC micelles as long-term stable and effective drug delivery systems in cancer therapy. PMID:23400693

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

    PubMed

    Parker, S K

    1998-12-01

    Role breadth self-efficacy (RBSE) refers to employees' perceived capability of carrying out a broader and more proactive set of work tasks that extend beyond prescribed technical requirements. A newly developed scale of RBSE was internally consistent and distinct from the related concepts of proactive personality and self-esteem. In an initial cross-sectional study (N = 580), work design variables (job enrichment, job enlargement, and membership of improvement groups) were the key organizational predictors of RBSE. These investigations were repeated in a second cross-sectional study (N = 622) and extended by examining change over time (N = 459). The longitudinal analysis showed that increased job enrichment and increased quality of communication predicted the development of greater self-efficacy. PMID:9885197

  12. Immune Activation Efficacy of Indolicidin Is Enhanced upon Conjugation with Carbon Nanotubes and Gold Nanoparticles

    PubMed Central

    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. PMID:25876153

  13. Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer.

    PubMed

    Li, Xin; Xun, Zhe; Yang, Yong

    2016-09-01

    Most colorectal cancer (CRC) cell lines are identified to overexpress phosphoserine phosphatase (PSPH), which regulates the intracellular synthesis of serine and glycine, and supports tumor growth. In this study, the effect of PSPH on 5-fluorouracil (5-FU) efficacy was evaluated. CRC cells exposed to 5-FU acquire metabolic remodeling, resulting in increased glucose flux for PSPH-mediated serine synthesis. Then serine is converted into GSH, which promotes cell survival through the detoxification of 5-FU-induced reactive oxygen species (ROS). Consequently, repression of PSPH by the use of shRNAs for PSPH impaired the defense against drug-induced oxidative stress, thereby sensitizing cells to 5-FU. The importance of the PSPH in supporting tumor growth during 5-FU treatment was also demonstrated in an in vivo tumor model of CRC. These findings indicate that the PSPH could serve as a target for increasing the anticancer efficacy of conventional therapy in patients with CRC. PMID:27349874

  14. Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models.

    PubMed

    Yamazaki, Hiroki; Takagi, Satoshi; Hosoya, Kenji; Okumura, Masahiro

    2015-04-01

    Histiocytic sarcoma (HS) in dogs exhibits aggressive clinical and biological behavior. Currently, no effective treatments are available for dogs with HS. Survivin, a member of a family of apoptosis protein inhibitors, could serve as a potential therapeutic target in several canine cancers. Sepantronium bromide (YM155) has recently been established as a novel survivin-targeting agent. The aim of this study was to use YM155 as a tool for evaluating survivin-targeted therapies against dogs with HS, and to investigate how YM155 treatment affects antitumor and chemotherapeutic efficacies in murine xenograft models using canine HS cells. The results showed that in HS cells with lomustine (CCNU) resistance, YM155 treatment suppressed both the cell-growth potential and cell resistance to CCNU, which essentially increases the chemotherapy efficacy in the murine models. The evidence presented here supports the favorable preclinical evaluation that survivin-targeted therapies might be effective against HS in dogs. PMID:25744435

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

    PubMed

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

    2015-01-01

    Antibiotic resistance is concern of today's world. Search for alternative molecules, for treatment and immune stimulation, remains at the forefront. One such group of biomolecules with promise, along the line of immune stimulation or therapy, is host defense peptide (HDP). These molecules, however, are required at a higher dose to be effective which leads to high cost. To alleviate such problems, an aid can be used to achieve similar efficacy but at a smaller effective dose of the immune stimulant. We hypothesised that by conjugating HDPs with carbon nanotubes and/or gold nanoparticles, it would be possible to stimulate a protective immune response in host system at a lower dosage of HDP. In this report, we characterized, using biophysical methodologies, conjugation of Indolicidin, as a representative of HDP. We further established efficacy of peptide-nanomaterial conjugates in activating innate immunity and protecting against pathogen infection in vitro at a significantly small dose. PMID:25876153

  16. Enhanced Efficacy of Combinations of Pexiganan with Colistin Versus Acinetobacter Baumannii in Experimental Sepsis.

    PubMed

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

    2016-08-01

    We investigated the efficacy of colistin combined with pexiganan in experimental mouse models of Acinetobacter baumannii infection.Adult male BALB/c mice received intraperitoneally 1 mL saline containing 2 × 10 CFU of susceptible and multiresistant A. baumannii. Two hours after bacterial challenge, animals received 1 mg/kg of colistin, 1 mg/kg of pexiganan, or 1 mg/kg of colistin plus 1 mg/kg of pexiganan.Blood culture positivity, the quantities of bacteria in the intra-abdominal fluid, the rate of lethality and immunological studies, such as immunophenotyping and NK cytotoxicity, were evaluated.In the in vitro study, A. baumannii showed susceptibility to colistin and pexiganan and a strong synergy was observed by testing colistin combined with pexiganan with fractionary inhibitory concentration index of 0.312 for both strains.In the in vivo study colistin or pexiganan alone showed a good antimicrobial efficacy. When colistin was combined with pexiganan, the positive interaction produced low bacterial counts that were statistically significant versus singly treated groups. For both strains the highest rate of survival was observed in combined-treated groups (90%).Pexiganan increased NK cytotoxic activity over the levels of infected and colistin-treated animals.In conclusion, pexiganan combined with colistin was found to be efficacious against A. baumannii infection. PMID:26849630

  17. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    PubMed Central

    Lee, Gyeong Jin; Kang, Joo-Hee

    2014-01-01

    Objective. Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy. PMID:24860812

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

    PubMed

    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. PMID:25463615

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

    PubMed Central

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

    2014-01-01

    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. PMID:25463615

  20. Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals.

    PubMed

    Shi, Liang; Lin, Hui; Li, Gonghui; Sun, Yin; Shen, Jiliang; Xu, Junjie; Lin, Changyi; Yeh, Shuyuan; Cai, Xiujun; Chang, Chawnshang

    2016-04-01

    The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy. PMID:26805759

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

    PubMed

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

    2015-12-01

    Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE. PMID:26409727

  2. CD226 as a genetic adjuvant to enhance immune efficacy induced by Ag85A DNA vaccination.

    PubMed

    Li, Yan; Yang, Fangli; Zhu, Junfeng; Sang, Lixuan; Han, Xue; Wang, Danan; Shan, Fengping; Li, Shengjun; Sun, Xun; Lu, Changlong

    2015-03-01

    Antigen-85A (Ag85A) is one of the major proteins secreted by Mycobacterium tuberculosis. Many studies on animal models have shown that vaccination with the recombinant Ag85A-DNA or Ag85A protein induces powerful immune response. However, these vaccines cannot generate sufficient protective immunity in the systemic compartment. CD226, a member of the immunoglobulin superfamily, is expressed in the majority of NK cells, T cells, monocytes, and platelets, and can be served as a co-stimulator that contributes to multiple innate and adaptive responses. However, there has been no study where either CD226 protein or DNA has been used as an adjuvant for vaccine development. The aim of this study was to develop a novel Ag85A DNA vaccine with CD226 as the genetic adjuvant to increase the immune efficacy induced by Ag85A. Oral vaccination with pcDNA3.1-Ag85A-CD226 DNA induced potent immune responses in mice. CD226 was an effective genetic adjuvant that improved the immune efficacy induced by Ag85A and enhanced the activity of cytotoxic T lymphocytes (CTL) and NK cells in mice. Th1 dominant cytokines (i.e. IL-2, IFN-γ and TNF-α), cellular immunity (i.e. CD4(+)IFN-γ(+)T cells and CD8(+)IFN-γ(+)T cells in splenocytes) and MLNs were also significantly elevated by pcDNA3.1-Ag85A-CD226 DNA vaccination. Our results suggest that CD226 is an effective adjuvant to enhance the immune efficacy induced by Ag85A. Our findings provide a new strategy for the development of a DNA vaccine co-expressing Ag85A and CD226. PMID:25582686

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

    PubMed Central

    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. PMID:25996044

  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. PMID:26886318

  5. Enhanced Antitumor Efficacy of Vasculostatin (Vstat120) Expressing Oncolytic HSV-1

    PubMed Central

    Hardcastle, Jayson; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P; Ahmad, Sarwat; Waterman, Peter; Weissleder, Ralph; Chiocca, E Antonio; Kaur, Balveen

    2009-01-01

    Oncolytic viral (OV) therapy is a promising therapeutic modality for brain tumors. Vasculostatin (Vstat120) is the cleaved and secreted extracellular fragment of brain-specific angiogenesis inhibitor 1 (BAI1), a brain-specific receptor. To date, the therapeutic efficacy of Vstat120 delivery into established tumors has not been investigated. Here we tested the therapeutic efficacy of combining Vstat120 gene delivery in conjunction with OV therapy. We constructed RAMBO (Rapid Antiangiogenesis Mediated By Oncolytic virus), which expresses Vstat120 under the control of the herpes simplex virus (HSV) IE4/5 promoter. Secreted Vstat120 was detected as soon as 4 hours postinfection in vitro and was retained for up to 13 days after OV therapy in subcutaneous tumors. RAMBO-produced Vstat120 efficiently inhibited endothelial cell migration and tube formation in vitro (P = 0.0005 and P = 0.0184, respectively) and inhibited angiogenesis (P = 0.007) in vivo. There was a significant suppression of intracranial and subcutaneous glioma growth in mice treated with RAMBO compared to the control virus, HSVQ (P = 0.0021 and P < 0.05, respectively). Statistically significant reduction in tumor vascular volume fraction (VVF) and microvessel density (MVD) was observed in tumors treated with RAMBO. This is the first study to report the antitumor effects of Vstat120 delivery into established tumors and supports the further development of RAMBO as a possible cancer therapy. PMID:19844198

  6. Enhancing Resilience Among New Nurses: Feasibility and Efficacy of a Pilot Intervention

    PubMed Central

    Chesak, Sherry S.; Bhagra, Anjali; Schroeder, Darrell R.; Foy, Denise A.; Cutshall, Susanne M.; Sood, Amit

    2015-01-01

    Background Orientation is one of the most stressful times in a registered nurse's career. Little information is available regarding the efficacy of stress management approaches among new nurses. The purpose of this study was to examine outcomes of the implementation of a brief Stress Management and Resiliency Training (SMART) program within a nurse orientation program. Methods In this randomized controlled pilot study, self-reported measures of stress, mindfulness, anxiety, and resilience were measured at baseline and 12 weeks following the intervention. For each group, the mean change from baseline to week 12 was evaluated using the paired t test. The change from baseline was compared between groups using the 2-sample t test. Feasibility of integrating the SMART program into the nurse orientation program was also analyzed. Results Of the 55 participants enrolled, 40 (73%) completed the study. Mindfulness and resilience scores improved in the intervention group and declined in the control group, while stress and anxiety scores decreased in the intervention group and increased in the control group. The between-group change in each outcome, however, was not statistically significant. Conclusions Integrating the SMART program within the nurse orientation program is feasible. While changes between groups were not significant, trends in the results indicate that the program has the potential for efficacy. Future research with larger numbers is indicated with a revised version of the program to increase its effect size. PMID:25829879

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

    PubMed Central

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

    2009-01-01

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

  8. Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases

    PubMed Central

    Newton, Robert

    2015-01-01

    Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called “combination therapy” is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical

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

    PubMed Central

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

    2014-01-01

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

  10. 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. PMID:25278753

  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. 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

  13. Simultaneous determination of timolol maleate in combination with some other anti-glaucoma drugs in rabbit aqueous humor by high performance liquid chromatography-tandem mass spectroscopy.

    PubMed

    Hassib, Sonia T; Elkady, Ehab F; Sayed, Rawda M

    2016-06-01

    In this work, a sensitive, selective, accurate and precise LC-MS/MS method has been developed for the simultaneous determination of an anti-glaucoma ß-blocker, timolol maleate (TIM) with other co-administered anti-glaucoma drugs of different classes, namely; dorzolamide hydrochloride (DOR), brinzolamide (BRZ) and brimonidine tartrate (BRM) in rabbit aqueous humor (AH) using eslicarbazepine as an internal standard (IS). Liquid-liquid extraction was used for the purification and pre-concentration of analytes from rabbit AH matrix. The chromatographic separation was achieved using a mobile phase consisting of 10mM ammonium formate pH=7: methanol: acetonitrile (5: 50: 45, v/v/v) in isocratic mode of elution at a flow rate of 0.8mL/min on an INERTSIL(®) C18 ODS-3 column (150mm×4.6mm, 3.5μm). The method was operated using electrospray ionization source in the positive ionization mode prior to detection by multiple reaction monitoring (MRM) at the following transitions: m/z 317.2→261.0 for TIM, m/z 325.1→199.0 for DOR, m/z 384.2→281.0 for BRZ, m/z 292.1→212.0 for BRM and m/z 255.0→237.0 for IS. The separation was done in only 3min and the lower limit of quantitation (LLOQ) was (50ng/ml) for all cited drugs. A detailed validation of the bio-analytical method was performed as mentioned in US-FDA and EMA guidelines and the standard calibration curves were found to be linear in the range (50-5000ng/ml) for all drugs with good mean regression coefficient for all drugs. PMID:27085020

  14. Increasing the efficacy of tumor cell vaccines by enhancing cross priming

    PubMed Central

    Andersen, Brian M.; Ohlfest, John R.

    2012-01-01

    Cancer immunotherapy has been attempted for more than a century, and investment has intensified in the last 20 years. The complexity of the immune system is exemplified by the myriad of immunotherapeutic approaches under investigation. While anti-tumor immunity has been achieved experimentally with multiple effector cells and molecules, particular promise is shown for harnessing the CD8 T cell response. Tumor cell-based vaccines have been employed in hundreds of clinical trials to date and offer several advantages over subunit and peptide vaccines. However, tumor cell-based vaccines, often aimed at cross priming tumor-reactive CD8 T cells, have shown modest success in clinical trials. Here we review the mechanisms of cross priming and discuss strategies to increase the efficacy of tumor cell-based vaccines. A synthesis of recent findings on tissue culture conditions, cell death, and dendritic cell activation reveals promising new avenues for clinical investigation. PMID:22809568

  15. The potential of radiotherapy to enhance the efficacy of renal cell carcinoma therapy

    PubMed Central

    De Wolf, Katrien; Vermaelen, Karim; De Meerleer, Gert; Lambrecht, Bart N; Ost, Piet

    2015-01-01

    Renal cell carcinoma (RCC) is an immunogenic tumor, but uses several immune-suppressive mechanisms to shift the balance from tumor immune response toward tumor growth. Although RCC has traditionally been considered to be radiation resistant, recent evidence suggests that hypofractionated radiotherapy contributes to systemic antitumor immunity. Because the efficacy of antitumor immune responses depends on the complex balance between diverse immune cells and progressing tumor cells, radiotherapy alone is unlikely to induce persistent antitumor immunity. Therefore, the combination of radiotherapy with drugs having synergistic immunomodulatory properties holds great promise with the optimal timing and sequence of modalities depending on the agent used. We highlight the immunomodulatory properties of targeted therapies, such as tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF) neutralizing antibodies, and will suggest a combination schedule with radiotherapy based on the available literature. We also address the combination of radiotherapy with innovative treatments in the field of immunotherapy. PMID:26464810

  16. Microwell array-mediated delivery of lipoplexes containing nucleic acids for enhanced therapeutic efficacy.

    PubMed

    Wu, Yun; Gallego-Perez, Daniel; Lee, L James

    2015-01-01

    Many delivery methods have been developed to improve the therapeutic efficacy and facilitate the clinical translation of nucleic acids-based therapeutics. We present a facile microwell array to mediate the delivery of nucleic acids carried by lipoplexes, which combines the advantages of lipoplexes as an efficient carrier system, the surface mediated delivery, and the control of surface topography. This method shows much higher transfection efficiency than conventional transfection method for oligodeoxynucleotides and microRNAs, and thus significantly reduces the effective therapeutic dosages. Microwell array is also a very flexible platform. Multifunctional lipoplexes containing both nucleic acid therapeutics and imaging reagents can be easily prepared in the microwell array and efficiently delivered to cells, demonstrating its potential applications in theranostic medicine. PMID:25319649

  17. 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

  18. 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.

  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 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. PMID:22970742

  1. Newcastle disease virus chimeras expressing the Hemagglutinin- Neuraminidase protein of mesogenic strain exhibits an enhanced anti-hepatoma efficacy.

    PubMed

    He, Jinjiao; Pan, Ziye; Tian, Guiyou; Liu, Xin; Liu, Yunye; Guo, Xiaochen; An, Ying; Song, Liying; Wu, Hongsong; Cao, Hongwei; Yu, Dan; Che, Ruixiang; Xu, Pengfei; Rasoul, Lubna M; Li, Deshan; Yin, Jiechao

    2016-08-01

    Newcastle disease virus (NDV) is an intrinsically tumor-specific virus, many researchers have reported that lentogenic NDV is a safe and effective agent for human cancer therapy. It had been demonstrated that the amino acid sequence of the fusion protein cleavage site is a major factor in the pathogenicity and anti-tumor efficacy of rNDV. However, the role of Hemagglutinin-Neuraminidase (HN) gene that contributes to virulence and anti-tumor efficacy remains undefined. To assess the role of HN gene in virus pathogenicity and anti-tumor efficacy, a reverse genetic system was developed using the lentogenic NDV Clone30 strain to provide backbone for gene exchange. Chimeric virus (rClone30-Anh(HN)) created by exchange of the HN gene of lentogenic strain Clone30 with HN gene of mesogenic strain produce no significant changes in virus pathogenicity as assessed by conducting the mean death time (MDT) and intracerebral pathogenicity index (ICPI) assays. In vitro, infection with chimeras could induce the formation of syncytium relative significantly in HepG2 cells. Furthermore, chimeras was shown to induce the cell apoptosis via MTT and Annexin V-PI assays, reduce mitochondrial membrane potential and increase the mRNA transcription level of caspase 3. In vivo, ICR mice carrying tumor of hepatoma H22 cells were treated via intratumoral injection of chimeric virus. The treatment of chimera shows an obvious suppression in tumor volume. These results suggest that it could be an ideal approach to enhance the antitumor ability of Newcastle disease virus and highlighted the potential therapeutic application of rClone30-Anh(HN) as a viral vector to deliver foreign genes for treatment of cancers. PMID:27164362

  2. Proteasomal Degradation of Mcl-1 by Maritoclax Induces Apoptosis and Enhances the Efficacy of ABT-737 in Melanoma Cells

    PubMed Central

    Doi, Kenichiro; Sharma, Arun K.; Wang, Hong-Gang; Amin, Shantu

    2013-01-01

    Background and purpose Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. Experimental approach For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis. Key results The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2–5.0 µM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids. Conclusions and implications Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors. PMID:24223823

  3. Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA

    PubMed Central

    Evers, B. Mark

    2012-01-01

    Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis and metastasis of CRCs, indicating that mTOR inhibition may have therapeutic potential. Notwithstanding, many cancers, including CRC, demonstrate resistance to the antitumorigenic effects of rapamycin. In this study, we show that inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance. Combination with the multikinase inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib synergistically inhibits proliferation of CRC cells. CRCs harboring coexistent KRAS and PIK3CA mutations are partially sensitive to either rapamycin or sorafenib monotherapy, but highly sensitive to combination treatment with rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant treatment with rapamycin and sorafenib at inhibiting growth of xenografts from CRC cells with coexistent mutations in KRAS and PIK3CA. The efficacy and tolerability of combined treatment with rapamycin and sorafenib provides rationale for use in treating CRC patients, particularly those with tumors harboring coexistent KRAS and PIK3CA mutations. Abbreviations:CIcombination indexCRCcolorectal cancerIHCimmunohistochemistryMAPKmitogen activated protein kinasemTORmammalian target of rapamycinPI3Kphosphatidylinositol 3-kinase. PMID:22696593

  4. 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. PMID:25933159

  5. 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. PMID:27063964

  6. Effects of Population Type on Mail Survey Response Rates and on the Efficacy of Response Enhancers.

    ERIC Educational Resources Information Center

    Green, Kathy E.; And Others

    Experimental studies of response rates to mail surveys were reviewed and differences in response by population type were described. Cases were selected for review if they were experimental studies that manipulated a response enhancement factor. Results suggest significant differences in typical response rates for different populations. Higher…

  7. Investing in Administrator Efficacy: An Examination of Professional Development as a Tool for Enhancing Principal Effectiveness

    ERIC Educational Resources Information Center

    Grissom, Jason A.; Harrington, James R.

    2010-01-01

    A primary goal of school districts' investments in professional development for principals is to enhance their effectiveness. This study examines the connection between administrator professional development and performance in a national sample of schools. We show that not all types of administrator professional development participation correlate…

  8. 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…

  9. Hsp90 inhibitor geldanamycin enhances the antitumor efficacy of enediyne lidamycin in association with reduced DNA damage repair.

    PubMed

    Han, Fei-Fei; Li, Liang; Shang, Bo-Yang; Shao, Rong-Guang; Zhen, Yong-Su

    2014-01-01

    Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio- and chemo-therapy sensitivity. To investigate the potentiation of antitumor efficacy of lidamycin (LDM), an enediyne agent by the Hsp90 inhibitor geldanamycin (GDM), and possible mechanisms, we have determined effects on ovarian cancer SKOV- 3, hepatoma Bel-7402 and HepG2 cells by MTT assay, apoptosis assay, and cell cycle analysis. DNA damage was investigated with H2AX C-terminal phosphorylation (γH2AX) assays. We found that GDM synergistically sensitized SKOV-3 and Bel-7402 cells to the enediyne LDM, and this was accompanied by increased apoptosis. GDM pretreatment resulted in a greater LDM-induced DNA damage and reduced DNA repair as compared with LDM alone. However, in HepG2 cells GDM did not show significant sensitizing effects both in MTT assay and in DNA damage repair. Abrogation of LDM-induced G2/M arrest by GDM was found in SKOV-3 but not in HepG2 cells. Furthermore, the expression of ATM, related to DNA damage repair responses, was also decreased by GDM in SKOV-3 and Bel-7402 cells but not in HepG2 cells. These results demonstrate that Hsp90 inhibitors may potentiate the antitumor efficacy of LDM, possibly by reducing the repair of LDM-induced DNA damage. PMID:25227788

  10. Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy with Bromodomain Inhibition

    PubMed Central

    Taylor, Isabella C.; Hütt-Cabezas, Marianne; Brandt, William D.; Kambhampati, Madhuri; Nazarian, Javad; Chang, Howard T.; Warren, Katherine E.; Eberhart, Charles G.; Raabe, Eric H.

    2015-01-01

    NOTCH regulates stem cells during normal development and stem-like cells in cancer but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, HES5, inhibited DIPG growth by 75%, and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pre-treatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during re-irradiation. PMID:26115193

  11. Enhancement of DNA cancer vaccine efficacy by combination with anti-angiogenesis in regression of established subcutaneous B16 melanoma.

    PubMed

    Chan, Ray Chun-Fai; Gutierrez, Benjamin; Ichim, Thomas E; Lin, Feng

    2009-11-01

    Immunotherapy of cancer offers great promise, however translation into human studies has yielded relatively poor results to date. The concept of combining cancer vaccination with angiogenesis inhibition is appealing, due to favorable safety profile of both approaches, as well as possible biological synergies. Here we studied the anti-tumor effects of combining plasmid DNA (pDNA) vaccination and anti-angiogenesis in B16F10 murine model. By using electroporation-mediated gene/pDNA delivery, the anti-tumor efficacy of vaccination with pDNAs encoding gp100, TRP2 and Ii-PADRE was facilitated by administration of soluble form of EphB4 fused with human serum albumin (sEphB4-HSA), or by co-delivery of pDNAs encoding Angiostatin and/or Endostatin. In an optimized administration protocol, melanoma vaccination together with intratumoral delivery of pDNAs encoding Angiostatin and Endostatin resulted in 57% tumor-free survival over 90 days after challenge. These data support the general concept that suppression of angiogenesis may allow for enhanced efficacy of anti-tumor immunity, suggesting the synergetic effects of therapeutic pDNA vaccination and angiogenesis inhibition in cancer therapy. PMID:19787240

  12. Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.

    PubMed

    Taylor, Isabella C; Hütt-Cabezas, Marianne; Brandt, William D; Kambhampati, Madhuri; Nazarian, Javad; Chang, Howard T; Warren, Katherine E; Eberhart, Charles G; Raabe, Eric H

    2015-08-01

    NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation. PMID:26115193

  13. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model

    PubMed Central

    Zeng, Wen; Xiao, Jia; Zheng, Gang; Xing, Feiyue; Tipoe, George L.; Wang, Xiaogang; He, Chengyi; Chen, Zhi-Ying; Liu, Yingxia

    2015-01-01

    One of the major problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is partly attributed to insufficient resistance of transplanted stem cells to oxidative and inflammatory stresses at the injured sites. In the current study, we demonstrated the pivotal role of antioxidant levels in human umbilical cord mesenchymal stem cells (hUCMSCs) dynamic in vitro anti-stress abilities against lipopolysaccharide (LPS)/H2O2 intoxication and in vivo therapeutic efficacy in a murine acute liver failure model induced by D-galactosamine/LPS (Gal/LPS) by either reducing the antioxidant levels with diethyl maleate (DEM) or increasing antioxidant levels with edaravone. Both the anti- and pro-oxidant treatments dramatically influenced the survival, apoptosis, and reactive oxygen species (ROS) production of hUCMSCs through the MAPK-PKC-Nrf2 pathway in vitro. When compared with untreated and DEM-treated cells, edaravone-treated hUCMSCs rescued NOD/SCID mice from Gal/LPS-induced death, significantly improved hepatic functions and promoted host liver regeneration. These effects were probably from increased stem cell homing, promoted proliferation, decreased apoptosis and enhanced secretion of hepatocyte growth factor (HGF) under hepatic stress environment. In conclusion, elevating levels of antioxidants in hUCMSCs with edaravone can significantly influence their hepatic tissue repair capacity. PMID:26057841

  14. 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

  15. The cathelicidin-derived tritrpticin enhances the efficacy of ertapenem in experimental rat models of septic shock.

    PubMed

    Ghiselli, Roberto; Cirioni, Oscar; Giacometti, Andrea; Mocchegiani, Federico; Orlando, Fiorenza; Silvestri, Carmela; Licci, Alberto; Della Vittoria, Agnese; Scalise, Giorgio; Saba, Vittorio

    2006-08-01

    Sepsis remains a serious clinical problem despite intense efforts to improve survival. In this study, the efficacy of ertapenem combined with the cathelicidin tritrpticin was investigated in two rat models of septic shock. Main outcome measures were bacterial growth in blood, peritoneum, spleen, liver, and mesenteric lymph nodes; endotoxin, interleukin 6, and tumor necrosis factor alpha concentrations in plasma; and lethality. Adult male Wistar rats were given (1) an intraperitoneal injection of 1 mg Escherichia coli serotype 0111:B4 LPS or (2) intra-abdominal sepsis induced via cecal ligation and puncture. For each model, all animals were randomized to receive intraperitoneally isotonic sodium chloride solution, 1 mg/kg tritrpticin, 15 mg/kg ertapenem, and 1 mg/kg tritrpticin combined with 15 mg/kg ertapenem. Each group included 20 animals. All compounds significantly reduced bacterial growth and lethality as compared with saline treatment. Treatment with tritrpticin resulted in significant decrease in plasma endotoxin and cytokine levels, whereas ertapenem exerted opposite effect. The combination between tritrpticin and ertapenem proved to be the most effective treatment in reducing all variables measured. In conclusion, tritrpticin enhances ertapenem efficacy in gram-negative septic shock rat models. PMID:16878029

  16. Dexamethasone-loaded Block Copolymer Nanoparticles Induce Leukemia Cell Death and Enhances Therapeutic Efficacy: A Novel Application in Pediatric Nanomedicine

    PubMed Central

    Krishnan, Vinu; Xu, Xian; Barwe, Sonali P.; Yang, Xiaowei; Czymmek, Kirk; Waldman, Scott A.; Mason, Robert W.; Jia, Xinqiao; Rajasekaran, Ayyappan K.

    2014-01-01

    Nanotechnology approaches have tremendous potential for enhancing treatment efficacy with lower doses of chemotherapeutics. Nanoparticle-based drug delivery approaches are poorly developed for childhood leukemia. Dexamethasone (Dex) is one of the most common chemotherapeutic drugs used in the treatment of childhood leukemia. In this study, we encapsulated Dex in polymeric nanoparticles and validated their anti-leukemic potential in vitro and in vivo. Nanoparticles (NPs) with an average diameter of 110 nm were assembled from amphiphilic block copolymers poly (ethylene glycol) (PEG) and poly (ε-caprolactone) (PCL) bearing pendant cyclic ketals. The blank nanoparticles were non-toxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the nanoparticles (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to the free Dex in leukemic cells. Studies using nanoparticles labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of the particles with time. In a pre-clinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the free drug. To our knowledge, this is the first report showing the efficacy of polymeric nanoparticles to deliver Dex to potentially treat childhood leukemia and reveals that low dose of Dex should be sufficient for inducing cell death and improve survival. PMID:23194373

  17. Enhancing the Transition to Kindergarten: A Randomized Trial to Test the Efficacy of the "Stars" Summer Kindergarten Orientation Program.

    PubMed

    Berlin, Lisa J; Dunning, Rebecca D; Dodge, Kenneth A

    2011-01-01

    This randomized trial tested the efficacy of an intensive, four-week summer program designed to enhance low-income children's transition to kindergarten (n's = 60 program children, 40 controls). Administered in four public schools, the program focused on social competence, pre-literacy and pre-numeracy skills, school routines, and parental involvement. Hierarchical linear modeling indicated that the program significantly improved teachers' ratings of (a) the transition to the social aspect of kindergarten for girls (but not boys); and (b) the transition to kindergarten routines for the subgroup of children who had the same teacher for kindergarten as for the summer program. Findings are discussed in terms of practices and policies for supporting children's transition to school. PMID:21969767

  18. [Evaluating the efficacy of a program to enhance college students' self-regulation learning processes and learning strategies].

    PubMed

    Rosário, Pedro; Mourao, Rosa; Núñez, José C; González-Pienda, Julio; Solano, Paula; Valle, Antonio

    2007-08-01

    The present study examines the efficacy of a program designed to enhance college students'learning processes and study strategies. The program was organised around a number of letters written by a freshman, Gervásio (Rosário, Núñez, & González-Pienda, 2006), telling about his new experiences, troubles, and successes in the university. This intervention program is intended to promote a series of strategies (cognitive, meta-cognitive, and supportive) which allow students to manage their learning processes in a more proficient, successful, and autonomous way. The collected data suggest that students who had the opportunity to follow the program significantly improved their declarative knowledge about learning strategies, reduced their use of surface approaches to study, and extended the newly acquired skills to new and different tasks and assignments. PMID:17617980

  19. Plasmid containing CpG motifs enhances the efficacy of porcine reproductive and respiratory syndrome live attenuated vaccine.

    PubMed

    Guo, Xiaoyu; Zhang, Quan; Hou, Shaohua; Zhai, Guoqin; Zhu, Hongfei; Sánchez-Vizcaíno, J M

    2011-12-15

    Porcine reproductive and respiratory syndrome (PRRS) is now among the most important swine diseases that affect the Chinese swine industry. Both killed and live attenuated vaccines are currently used against the disease, but neither of them could provide full protection after vaccination. In the present study, the adjuvanticity of a plasmid containing CpG motifs (pUC18-CpG) was introduced to enhance the efficacy of a commercial PRRS live attenuated vaccine. After vaccination, PRRSV-specific antibodies, PRRSV-specific cytokines, and clinical parameters were studied and compared between different vaccinated groups. During a following challenge study, co-administration of pUC18-CpG with the vaccine could confer higher protection rate. Our results have shown that co-administration of pUC18-CpG with the vaccine could elicit more potent adaptive immune response and provide better protection. PMID:21917319

  20. Immunotherapy with mutated onchocystatin fails to enhance the efficacy of a sub-lethal oxytetracycline regimen against Onchocerca ochengi.

    PubMed

    Bah, Germanus S; Tanya, Vincent N; Makepeace, Benjamin L

    2015-08-15

    Human onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, has been successfully controlled by a single drug, ivermectin, for over 25 years. Ivermectin prevents the disease symptoms of severe itching and visual impairment by killing the microfilarial stage, but does not eliminate the adult parasites, necessitating repeated annual treatments. Mass drug administration with ivermectin does not always break transmission in forest zones and is contraindicated in individuals heavily co-infected with Loa loa, while reports of reduced drug efficacy in Ghana and Cameroon may signal the development of resistance. An alternative treatment for onchocerciasis involves targeting the essential Wolbachia symbiont with tetracycline or its derivatives, which are adulticidal. However, implementation of antibiotic therapy has not occurred on a wide scale due to the prolonged treatment regimen required (several weeks). In the bovine Onchocerca ochengi system, it has been shown previously that prolonged oxytetracycline therapy increases eosinophil counts in intradermal nodules, which kill the adult worms by degranulating on their surface. Here, in an "immunochemotherapeutic" approach, we sought to enhance the efficacy of a short, sub-lethal antibiotic regimen against O. ochengi by prior immunotherapy targeting onchocystatin, an immunomodulatory protein located in the adult female worm cuticle. A key asparagine residue in onchocystatin was mutated to ablate immunomodulatory activity, which has been demonstrated previously to markedly improve the protective efficacy of this vaccine candidate when used as an immunoprophylactic. The immunochemotherapeutic regimen was compared with sub-lethal oxytetracycline therapy alone; onchocystatin immunotherapy alone; a gold-standard prolonged, intermittent oxytetracycline regimen; and no treatment (negative control) in naturally infected Cameroonian cattle. Readouts were collected over one year and comprised adult

  1. A Non-invasive Real-time Localization System for Enhanced Efficacy in Nasogastric Intubation.

    PubMed

    Sun, Zhenglong; Foong, Shaohui; Maréchal, Luc; Tan, U-Xuan; Teo, Tee Hui; Shabbir, Asim

    2015-12-01

    Nasogastric (NG) intubation is one of the most commonly performed clinical procedures. Real-time localization and tracking of the NG tube passage at the larynx region into the esophagus is crucial for safety, but is lacking in current practice. In this paper, we present the design, analysis and evaluation of a non-invasive real-time localization system using passive magnetic tracking techniques to improve efficacy of the clinical NG intubation process. By embedding a small permanent magnet at the insertion tip of the NG tube, a wearable system containing embedded sensors around the neck can determine the absolute position of the NG tube inside the body in real-time to assist in insertion. In order to validate the feasibility of the proposed system in detecting erroneous tube placement, typical reference intubation trajectories are first analyzed using anatomically correct models and localization accuracy of the system are evaluated using a precise robotic platform. It is found that the root-mean-squared tracking accuracy is within 5.3 mm for both the esophagus and trachea intubation pathways. Experiments were also designed and performed to demonstrate that the system is capable of tracking the NG tube accurately in biological environments even in presence of stationary ferromagnetic objects (such as clinical instruments). With minimal physical modification to the NG tube and clinical process, this system allows accurate and efficient localization and confirmation of correct NG tube placement without supplemental radiographic methods which is considered the current clinical standard. PMID:26108204

  2. Berberine Nanosuspension Enhances Hypoglycemic Efficacy on Streptozotocin Induced Diabetic C57BL/6 Mice

    PubMed Central

    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. PMID:25866534

  3. Enhanced sialylation and in vivo efficacy of recombinant human α-galactosidase through in vitro glycosylation

    PubMed Central

    Sohn, Youngsoo; Lee, Jung Mi; Park, Heung-Rok; Jung, Sung-Chul; Park, Tai Hyun; Oh, Doo-Byoung

    2013-01-01

    Human α-galactosidase A (GLA) has been used in enzyme replacement therapy for patients with Fabry disease. We expressed recombinant GLA from Chinese hamster ovary cells with very high productivity. When compared to an approved GLA (agalsidase beta), its size and charge were found to be smaller and more neutral. These differences resulted from the lack of terminal sialic acids playing essential roles in the serum half-life and proper tissue targeting. Because a simple sialylation reaction was not enough to increase the sialic acid content, a combined reaction using galactosyltransferase, sialyltransferase, and their sugar substrates at the same time was developed and optimized to reduce the incubation time. The product generated by this reaction had nearly the same size, isoelectric points, and sialic acid content as agalsidase beta. Furthermore, it had better in vivo efficacy to degrade the accumulated globotriaosylceramide in target organs of Fabry mice compared to an unmodified version. [BMB Reports 2013; 46(3): 157-162] PMID:23527859

  4. CD19-Targeted Nanodelivery of Doxorubicin Enhances Therapeutic Efficacy in B-cell Acute Lymphoblastic Leukemia

    PubMed Central

    Krishnan, Vinu; Xu, Xian; Kelly, Dakota; Snook, Adam; Waldman, Scott A.; Mason, Robert W.; Jia, Xinqiao; Rajasekaran, Ayyappan K.

    2015-01-01

    Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is still in its infancy for treatment of childhood malignancies such as acute lymphoblastic leukemia (ALL). Nanotherapy offers multiple advantages over conventional therapy. It facilitates targeted delivery and enables controlled release of drugs to reduce treatment-related side effects. Here, we demonstrate, that doxorubicin (DOX) encapsulated in polymeric nanoparticles (NPs) modified with targeting ligands against CD19 (CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive ALL cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. We suggest that targeted delivery of drugs used in childhood cancer treatment should improve therapeutic efficacy and reduce treatment-related side effects in children. PMID:25898125

  5. 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.

  6. CD19-Targeted Nanodelivery of Doxorubicin Enhances Therapeutic Efficacy in B-Cell Acute Lymphoblastic Leukemia.

    PubMed

    Krishnan, Vinu; Xu, Xian; Kelly, Dakota; Snook, Adam; Waldman, Scott A; Mason, Robert W; Jia, Xinqiao; Rajasekaran, Ayyappan K

    2015-06-01

    Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is still in its infancy for treatment of childhood malignancies such as acute lymphoblastic leukemia (ALL). Nanotherapy offers multiple advantages over conventional therapy. It facilitates targeted delivery and enables controlled release of drugs to reduce treatment-related side effects. Here, we demonstrate that doxorubicin (DOX) encapsulated in polymeric nanoparticles (NPs) modified with targeting ligands against CD19 (CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19-positive ALL cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility, indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. We suggest that targeted delivery of drugs used in childhood cancer treatment should improve therapeutic efficacy and reduce treatment-related side effects in children. PMID:25898125

  7. 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

  8. Immobilized Silver Nanoparticles on Chitosan with Special Surface State-Enhanced Antimicrobial Efficacy and Reduced Cytotoxicity.

    PubMed

    He, Miao; Lu, Liying; Zhang, Jinchi; Li, Danzhen

    2015-09-01

    Immobilized chitosan-Ag nanoparticles (CTS-Ag NPs) with special surface state have been synthesized successfully through immobilizing Ag NPs on the amino-enriched surface of CTS by reducing Ag (I) in situ. The antimicrobial efficiency and potency of CTS-Ag NPs against Escherichia coli and Staphylococcus aureus were studied. Our results reveal that surface-immobilized CTS-Ag NPs show better antimicrobial efficacy than several other reported monodisperse colloidal Ag NPs, because the unique surface state of our CTS-Ag NPs leads to both "contact killing" and "ion mediated killing" functions. Due to the synergetic effect of CTS and Ag NPs, the immobilized CTS-Ag NPs present a broader antimicrobial spectrum and a more effective antifungal activity against Monilia albican. In addition, CTS as an environment friendly dispersant can help to reduce the cytotoxicity of Ag NPs on higher organisms. The immobilized CTS-Ag NPs are stable and can maintain good disinfection potential after 6 months' shelf-time. PMID:26716197

  9. Enhanced efficacy (intrinsic activity) of cyclic opioid peptide analogs at the. mu. -receptor

    SciTech Connect

    Schiller, P.W.; Lemieux, C.; Nguyen, T.M.D.; Maziak, L.A.

    1986-05-01

    Side-chain to end group cyclized enkephalin analogs (e.g. H-Tyr-cyclo(-D-Lys-Gly-Phe-Leu-) and cyclic opioid peptide analogs obtained through covalent linkage of two side-chains (e.g. H-Tyr-D-Cys-Gly-Phe-Cys-NH/sub 2/ or H-Tyr-D-Lys-Gly-Phe-Glu-NH/sub 3/) were tested in the ..mu..-receptor-representative guinea pig ileum (GPI) bioassay and in a binding assay based on displacement of the ..mu..-ligand (/sup 3/H)DAGO from rat brain membranes. The cyclic analogs were 5 to 70 times more potent in the GPI assay than in the binding assay, whereas linear analogs showed equal potency in the two assays. These results suggest that the efficacy (intrinsic activity) of cyclic opioid peptide analogs at the ..mu..-receptor is increased as a consequence of the conformation constraint imposed through ring closure. This effect was most pronounced in analogs containing a long hydrophobic sidechain as part of the ring structure in the 2-position of the peptide sequence. Further experimental evidence ruled out the possibilities that these potency discrepancies may be due to differences in enzymatic degradation, dissimilar exposure of the receptors in their lipid environment or interaction with different receptor types in the two assay systems. It can be hypothesized that the semi-rigid cyclic analogs may induce a more productive conformational change in the receptor protein than the linear peptides.

  10. Enhanced in vitro and in vivo therapeutic efficacy of codrug-loaded nanoparticles against liver cancer

    PubMed Central

    Li, Xiaolin; Xu, Hua’e; Dai, Xinzheng; Zhu, Zhenshu; Liu, Baorui; Lu, Xiaowei

    2012-01-01

    Paclitaxel (Ptx), one of the most widely used anticancer agents, has demonstrated extraordinary activities against a variety of solid tumors. However, the therapeutic response of Ptx is often associated with severe side effects caused by its nonspecific cytotoxic effects and special solvents (Cremophor EL®). The current study reports the stable controlled release of Ptx/tetrandrine (Tet)-coloaded nanoparticles by amphilic methoxy poly(ethylene glycol)–poly(caprolactone) block copolymers. There were three significant findings. Firstly, Tet could effectively stabilize Ptx-loaded nanoparticles with the coencapsulation of Tet and Ptx. The influence of different Ptx/Tet feeding ratios on the size and loading efficiency of the nanoparticles was also explored. Secondly, the encapsulation of Tet and Ptx into nanoparticles retains the synergistic anticancer efficiency of Tet and Ptx against mice hepatoma H22 cells. Thirdly, in the in vivo evaluation, intratumoral administration was adopted to increase the site-specific delivery. Ptx/Tet nanoparticles, when delivered intratumorally, exhibited significantly improved antitumor efficacy; moreover, they substantially increased the overall survival in an established H22-transplanted mice model. Further investigation into the anticancer mechanisms of this nanodelivery system is under active consideration as a part of this ongoing research. The results suggest that Ptx/Tet-coloaded nanoparticles could be a potential useful chemotherapeutic formulation for liver cancer therapy. PMID:23055730

  11. 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

  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. Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin

    PubMed Central

    Reddy, Cheruku Apoorva; Somepalli, Venkateswarlu; Golakoti, Trimurtulu; Kanugula, Anantha KoteswaraRao; Karnewar, Santosh; Rajendiran, Karthikraj; Vasagiri, Nagarjuna; Prabhakar, Sripadi; Kuppusamy, Periannan; Kotamraju, Srigiridhar; Kutala, Vijay Kumar

    2014-01-01

    Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers. PMID:24622734

  14. 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

  15. Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade.

    PubMed

    Han, Sang-oh; Li, Songtao; Brooks, Elizabeth D; Masat, Elisa; Leborgne, Christian; Banugaria, Suhrad; Bird, Andrew; Mingozzi, Federico; Waldmann, Herman; Koeberl, Dwight

    2015-01-01

    Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease. PMID:25382056

  16. Mitochondrial-targeted curcuminoids: a strategy to enhance bioavailability and anticancer efficacy of curcumin.

    PubMed

    Reddy, Cheruku Apoorva; Somepalli, Venkateswarlu; Golakoti, Trimurtulu; Kanugula, Anantha KoteswaraRao; Karnewar, Santosh; Rajendiran, Karthikraj; Vasagiri, Nagarjuna; Prabhakar, Sripadi; Kuppusamy, Periannan; Kotamraju, Srigiridhar; Kutala, Vijay Kumar

    2014-01-01

    Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers. PMID:24622734

  17. Safety and Efficacy of Stabilized Hyaluronic Acid Gel for Breast Enhancement

    PubMed Central

    Sarfati, Isabelle; Clough, Krishna; Olenius, Michael; Sellman, Gabriella; Trevidic, Patrick

    2015-01-01

    Summary: Long-term follow-up data following 2 breast enhancement treatments with stabilized hyaluronic acid (HA) gel are limited. Although HA gel is no longer marketed for breast enhancement, there is a clinical need for information about follow-up of previously treated women. A multicenter, noncomparative study was conducted in women seeking breast enhancement. Subjects received 1 treatment of HA gel (maximum, 100 mL/breast); a subgroup underwent retreatment 9 months later. Follow-up was conducted for 24 months after last treatment; endpoints included magnetic resonance imaging for estimation of gel degradation, adverse events, breast examinations, Global Esthetic Improvement Scale, and satisfaction ratings. Seventy-one subjects received 1 treatment, with 22 (31%) receiving retreatment after 9 months. Twenty-four months after last treatment, the mean percentage of remaining gel was 17% in the single-treatment group and 21% in the retreatment group; complete degradation had not occurred in any subject. The most commonly reported treatment-related adverse events were implant-site nodules, medical device implantation events, capsular contracture associated with breast implant, and injection-site nodules; most were mild to moderate and required no intervention. Based on subject Global Esthetic Improvement Scale ratings, 36% of breasts in the single- treatment group and 50% of breasts in the retreatment group were improved 24 months after last treatment, but subject satisfaction had returned to baseline levels. Some gel remained in all subjects 24 months after last treatment. Although single treatment and retreatment were generally well tolerated, physicians need to be aware of common treatment-related complications to manage them adequately. PMID:26894000

  18. 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

  19. An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy.

    PubMed

    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

    2016-07-01

    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 culture. Here we describe an artificial niche 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 engineered muscle fibers that mimic the native myofiber of the MuSC niche. Mouse MuSCs maintained in QM on engineered fibers showed enhanced potential for engraftment, tissue regeneration and self-renewal after transplantation in mice. An artificial niche adapted to human cells similarly extended the quiescence of human MuSCs in vitro and enhanced their potency in vivo. Our approach for maintaining quiescence may be applicable to stem cells isolated from other tissues. PMID:27240197

  20. Enhanced efficacy of clindamycin hydrochloride encapsulated in PLA/PLGA based nanoparticle system for oral delivery.

    PubMed

    Rauta, Pradipta Ranjan; Das, Niladri Mohan; Nayak, Debasis; Ashe, Sarbani; Nayak, Bismita

    2016-08-01

    Clindamycin hydrochloride (CLH) is a clinically important oral antibiotic with wide spectrum of antimicrobial activity that includes gram-positive aerobes (staphylococci, streptococci etc.), most anaerobic bacteria, Chlamydia and certain protozoa. The current study was focused to develop a stabilised clindamycin encapsulated poly lactic acid (PLA)/poly (D,L-lactide-co-glycolide) (PLGA) nano-formulation with better drug bioavailability at molecular level. Various nanoparticle (NPs) formulations of PLA and PLGA loaded with CLH were prepared by solvent evaporation method varying drug: polymer concentration (1:20, 1:10 and 1:5) and characterised (size, encapsulation efficiency, drug loading, scanning electron microscope, differential scanning calorimetry [DSC] and Fourier transform infrared [FTIR] studies). The ratio 1:10 was found to be optimal for a monodispersed and stable nano formulation for both the polymers. NP formulations demonstrated a significant controlled release profile extended up to 144 h (both CLH-PLA and CLH-PLGA). The thermal behaviour (DSC) studies confirmed the molecular dispersion of the drug within the system. The FTIR studies revealed the intactness as well as unaltered structure of drug. The CLH-PLA NPs showed enhanced antimicrobial activity against two pathogenic bacteria Streptococcus faecalis and Bacillus cereus. The results notably suggest that encapsulation of CLH into PLA/PLGA significantly increases the bioavailability of the drug and due to this enhanced drug activity; it can be widely applied for number of therapies. PMID:27463797

  1. Postoperative intrapleural BCG in lung cancer: lack of efficacy and possible enhancement of tumour growth.

    PubMed Central

    Bakker, W; Nijhuis-Heddes, J M; Wever, A M; Brutel de la Rivière, A; van der Velde, E A; Dijkman, J H

    1981-01-01

    Fifty-six patients out of a group of 99 with lung cancer received postoperative intrapleural BCG (Pasteur strain) in three different dosages (16 X 10(6) culturable particles (cp), 32 X 10(6) cp, and 64 X 10(6) cp). When comparing the whole group of 99 patients with a historical control group of 126 patients no statistically significant differences were found in survival and disease-free interval. The two groups were well matched in respect of age, sex, histology, stage of disease, and type of operation. Patients with epidermoid carcinoma stage I receiving BCG, however, did significantly worse than those who had not received BCG in terms of disease-free interval. This unfavourable trend was caused by earlier local recurrences rather than metastases. The possible phenomenon of enhanced tumour growth noted in or patients with epidermoid carcinoma stage I might be related to the dosages used in this study, but the different BCG strain used hinders comparison with other studies. We conclude that BCG has no beneficial effect on survival or on disease-free interval; possible enhancement of tumour growth in stage I epidermoid carcinoma was found. PMID:7330812

  2. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles.

    PubMed

    Gao, Yajie; Zhou, Yanxia; Zhao, Lei; Zhang, Chao; Li, Yushu; Li, Jinwen; Li, Xinru; Liu, Yan

    2015-09-01

    Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH-sensitive copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin αvβ3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK-conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin αvβ3-rich prostate cancers. PMID:26013038

  3. Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts.

    PubMed

    Moschetta, Michele; Pretto, Francesca; Berndt, Alexander; Galler, Kerstin; Richter, Petra; Bassi, Andrea; Oliva, Paolo; Micotti, Edoardo; Valbusa, Giovanni; Schwager, Kathrin; Kaspar, Manuela; Trachsel, Eveline; Kosmehl, Hartwig; Bani, Maria Rosa; Neri, Dario; Giavazzi, Raffaella

    2012-04-01

    The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma. PMID:22392081

  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. PMID:16987711

  5. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell

    PubMed Central

    Bu, Lin-Lin; Zhao, Zhi-Li; Liu, Jian-Feng; Ma, Si-Rui; Huang, Cong-Fa; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2015-01-01

    Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. PMID:26556875

  6. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer.

    PubMed

    Kohrt, Holbrook E; Houot, Roch; Weiskopf, Kipp; Goldstein, Matthew J; Scheeren, Ferenc; Czerwinski, Debra; Colevas, A Dimitrios; Weng, Wen-Kai; Clarke, Michael F; Carlson, Robert W; Stockdale, Frank E; Mollick, Joseph A; Chen, Lieping; Levy, Ronald

    2012-03-01

    Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors. PMID:22326955

  7. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell.

    PubMed

    Bu, Lin-Lin; Zhao, Zhi-Li; Liu, Jian-Feng; Ma, Si-Rui; Huang, Cong-Fa; Liu, Bing; Zhang, Wen-Feng; Sun, Zhi-Jun

    2015-12-01

    Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC. PMID:26556875

  8. Enhancing the efficacy of heart surgery by optimizing patients' preoperative expectations: study protocol of a randomized controlled trial.

    PubMed

    Laferton, Johannes A C; Shedden Mora, Meike; Auer, Charlotte J; Moosdorf, Rainer; Rief, Winfried

    2013-01-01

    In coronary heart disease (CHD) and heart surgery, there is sound evidence for the relationship between patients' expectations and treatment outcome, especially for outcome variables such as disability and quality of life. In addition, patients' expectations have been shown to be modifiable through psychological interventions. Therefore, targeting patients' expectations might offer a promising opportunity to enhance heart surgery outcome. However, few studies have tried to actively change patients' expectations before surgery. The purpose of this clinical trial is to optimize patients' outcome expectations before undergoing coronary artery bypass graft surgery (CABG) through a brief psychoeducational program. The present article describes the study protocol and reports preliminary data on feasibility. Using a randomized controlled design, 180 patients who are scheduled to undergo elective CABG are randomly assigned to either (1) standard medical care (SMC) alone, (2) to an additional expectation manipulation intervention during the 2 weeks before surgery, and (3) to an additional attention-control group ("supportive therapy"). The main goal is to test (a) whether expectation manipulation intervention can optimize patients' expectations and (b) whether optimized expectations lead to enhanced surgery efficacy. The primary outcome variable is illness-related disability 6 months after surgery, whereas secondary outcome variables will be quality of life, return to work, physical activity, and medical outcome variables. First, feasibility data of 36 patients show that the patients appreciated the additional psychological intervention before CABG. Satisfaction of those who received psychological interventions was very high. PMID:23237127

  9. Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells.

    PubMed

    Wang, Jizhong; Tan, Xiangpeng; Yang, Qi; Zeng, Xiangfeng; Zhou, Yuying; Luo, Wu; Lin, Xiaomian; Song, Li; Cai, Jialong; Wang, Tianxiang; Wu, Xiaoping

    2016-08-01

    The interplay between autophagy and apoptosis response to chemotherapy is still a subject of intense debate in recent years. More efforts have focused on the regulation effects of apoptosis on autophagy, whereas how autophagy affects apoptosis remains poorly understood. In this study performed on prostate cancer cells, we investigated the role of autophagy in adriamycin-induced apoptosis, as well as the mechanisms mediating the effects of autophagy on apoptosis response to adriamycin (ADM). The results show that ADM not only inhibited cell viability and enhanced apoptosis, but also promoted autophagy via PI3K/Akt(T308)/mTOR signal pathway. Inhibition of autophagy by either pharmacological inhibitor chloroquine (CQ) or RNA interference of Atg5 increased ADM-induced apoptosis and enhanced the chemosensitivity of prostate cancer cells. Moreover, blockade of autophagy augmented reactive oxygen species (ROS) generation induced by ADM. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the strengthened effects of CQ on ADM-induced apoptosis and rescued the cells from apoptosis. The results identified ROS as a potential mediator directing the modulation effects of the protective autophagy on apoptosis response to ADM. Suppression of the protective autophagy might provide a promising strategy to increase the anticancer efficacy of agents in the treatment of prostate cancer. PMID:27247025

  10. Etoposide enhances antitumor efficacy of MDR1-driven oncolytic adenovirus through autoupregulation of the MDR1 promoter activity.

    PubMed

    Su, Bing-Hua; Shieh, Gia-Shing; Tseng, Yau-Lin; Shiau, Ai-Li; Wu, Chao-Liang

    2015-11-10

    Conditionally replicating adenoviruses (CRAds), or oncolytic adenoviruses, such as E1B55K-deleted adenovirus, are attractive anticancer agents. However, the therapeutic efficacy of E1B55K-deleted adenovirus for refractory solid tumors has been limited. Environmental stress conditions may induce nuclear accumulation of YB-1, which occurs in multidrug-resistant and adenovirus-infected cancer cells. Overexpression and nuclear localization of YB-1 are associated with poor prognosis and tumor recurrence in various cancers. Nuclear YB-1 transactivates the multidrug resistance 1 (MDR1) genes through the Y-box. Here, we developed a novel E1B55K-deleted adenovirus driven by the MDR1 promoter, designed Ad5GS3. We tested the feasibility of using YB-1 to transcriptionally regulate Ad5GS3 replication in cancer cells and thereby to enhance antitumor efficacy. We evaluated synergistic antitumor effects of oncolytic virotherapy in combination with chemotherapy. Our results show that adenovirus E1A induced E2F-1 activity to augment YB-1 expression, which shut down host protein synthesis in cancer cells during adenovirus replication. In cancer cells infected with Ad5WS1, an E1B55K-deleted adenovirus driven by the E1 promoter, E1A enhanced YB-1 expression, and then further phosphorylated Akt, which, in turn, triggered nuclear translocation of YB-1. Ad5GS3 in combination with chemotherapeutic agents facilitated nuclear localization of YB-1 and, in turn, upregulated the MDR1 promoter activity and enhanced Ad5GS3 replication in cancer cells. Thus, E1A, YB-1, and the MDR1 promoter form a positive feedback loop to promote Ad5GS3 replication in cancer cells, and this regulation can be further augmented when chemotherapeutic agents are added. In the in vivo study, Ad5GS3 in combination with etoposide synergistically suppressed tumor growth and prolonged survival in NOD/SCID mice bearing human lung tumor xenografts. More importantly, Ad5GS3 exerted potent oncolytic activity against clinical