Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents

PubMed Central

Dewal, Mahender B.; Wani, Amit S.; Vidaillac, Celine; Oupicky, David; Rybak, Michael J.

2012-01-01

Several thieno[2,3-d]pyrimidinediones have been synthesized and examined for antibacterial activity against a range of Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2–16 mg/L) against multi-drug resistant Gram-positive organisms, including methicillin, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus (MRSA, VISA, VRSA) and vancomycin-resistant enterococci (VRE). Only one of these agents possessed moderate activity (16–32 mg/L) against Gram-negative strains. An examination of the cytotoxicity of these agents revealed that they displayed low toxicity (40–50 mg/L) against mammalian cell and very low hemolytic activity (2–7%). Taken together, these studies suggest that thieno[2,3-d]pyrimidinediones are interesting scaffolds for the development of novel Gram-positive antibacterial agents. PMID:22405289

Development of Intra-Articular Drug Delivery to Alter Progression of Arthritis Following Joint Injury

DTIC Science & Technology

2012-04-01

2012Revised AnnualApril 2012 DESIGN: A novel injectable and in situ forming drug depot based on thermally-responsive elastin -like polypeptide (ELP) will... Elastin -like polypeptide, Drug Depot – technology allowing sustained release of biologically active agent , Active agents used include IL1Ra...The abstract has been removed and an appendix has been included. In brief this protocol explores the use of elastin like polypeptide (ELP) as a

Loading, Release, Biodegradation, and Biocompatibility of a Nanovector Delivery System

NASA Technical Reports Server (NTRS)

Ferrai, Mauro; Tasciotti, Ennio

2012-01-01

A nanovector multistage system has been created to overcome or bypass sequential barriers within the human body, in order to deliver a therapeutic or imaging agent to a specific location. This innovation consists of a composition that includes two or more stages of particles, such that smaller, later-stage particles are contained in the larger, early-stage particles. An active agent, such as a therapeutic agent or imaging agent, is preferentially delivered and/or localized to a particular target site in the body of a subject. The multistage composition overcomes multiple biological barriers in the body. The multistage composition also allows for simultaneous delivery and localization at the same or different target sites of multiple active agents.

Influence of anionic surface-active agents on the uptake of heavy metals by water hyacinth (Eichhornia crassipes)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muramoto, S.; Oki, Y.

1984-10-01

In a previous paper, the ability of water hyacinth to remove toxic heavy metals, cadmium, lead, and mercury, from a metal-containing solution was reported. However, information on the effects of surface-active agents on the metal uptake from waste water by water hyacinth is insufficient. Surface-active agents including anionic detergents have been found in lake, ponds, and rivers polluted by waste from industry and municipal sewage treatment plants. The present study examines the uptake of cadmium or nickel in the presence of the anionic detergent sodium dedecyl sulfate.

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure.

PubMed

Keskin, O; Bahar, I; Jernigan, R L; Beutler, J A; Shoemaker, R H; Sausville, E A; Covell, D G

2000-04-01

An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposition (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity distances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against 60 human cancer cell lines. Cluster analysis divides the 122 standard agents into 25 statistically distinct groups. The first eight groups include structurally diverse compounds with reactive functionalities that act as DNA-damaging agents while the remaining 17 groups include compounds that inhibit nucleic acid biosynthesis and mitosis. Examination of the average activity patterns across the 60 tumor cell lines reveals unique 'fingerprints' associated with each group. A diverse set of structural features are observed for compounds within these groups, with frequent occurrences of strong within-group structural similarities. Clustering of cell types by their response to the 122 anticancer agents divides the 60 cell types into 21 groups. The strongest within-panel groupings were found for the renal, leukemia and ovarian cell panels. These results contribute to the basis for comparisons between log(GI(50)) screening patterns of the 122 anticancer agents and additional tested compounds.

Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment

PubMed Central

Li, Dongqi; Li, Huiling; Ren, Mingyan; Liao, Yedan; Yu, Shunling; Chen, Yanjin; Yang, Yihao; Zhang, Ya

2016-01-01

Osteosarcoma is the most common primary bone tumor in children and adolescents. Although combined therapy including surgery and multi-agent chemotherapy have resulted in great improvements in the overall survival of patients, chemoresistance remains an obstacle for the treatment of osteosarcoma. Molecular targets or effective agents that are actively involved in cell death including apoptosis, autophagy and necroptosis have been studied. We summarized how these agents (novel compounds, miRNAs, or proteins) regulate apoptotic, autophagic and necroptotic pathways; and discussed the current knowledge on the role of these new agents in chemotherapy resistance in osteosarcoma. PMID:27007056

A review of responsive MRI contrast agents: 2005–2014

PubMed Central

Hingorani, Dina V.; Bernstein, Adam S.; Pagel, Mark D.

2014-01-01

This review focuses on MRI contrast agents that are responsive to a change in a physiological biomarker. The response mechanisms are dependent on six physicochemical characteristics, including the accessibility of water to the agent, tumbling time, proton exchange rate, electron spin state, MR frequency, or superparamagnetism of the agent. These characteristics can be affected by changes in concentrations or activities of enzymes, proteins, nucleic acids, metabolites, or metal ions, or changes in redox state, pH, temperature, or light. A total of 117 examples are presented, including examples that employ nuclei other than 1H, which attests to the creativity of multidisciplinary research efforts to develop responsive MRI contrast agents. PMID:25355685

Effects of Antiparasite Chemotherapeutic Agents on Immune Functions.

DTIC Science & Technology

1984-05-01

OF ALKYLATING AGENTS AGAINST CELLS PARTICIPATING IN SUPPRESSION OF ANTIBODY RESPONSES* RONALD D. PAUL, ABOUL GHAFFARt and M. MICHAEL SIGEL Department... alkylating agents on the induction and expression of specific suppressor cell activity induced by supraoptimal immunization (SO[) with (4x 109) SRBC was...including 1982b). different subsets of T cells (Cantor & Gershon, A number of alkylating agents which are used as 1979). It is therefore necessary to

Survey of Chemical Compounds Tested In Vitro against Rumen Protozoa for Possible Control of Bloat

PubMed Central

Willard, F. L.; Kodras, Rudolph

1967-01-01

Over 170 chemical agents were screened for antiprotozoal action in bovine ruminal fluid. Compounds were tested at 0.1 and 0.05% concentrations. Tested compounds included inorganic compounds, antibiotics, biocides, neuromuscular agents, arsenicals, plant and animal hormones, antimalarials, surface-active agents, anthelmintics, and many others. The most active compounds were cupric sulfate, nickel sulfate, nitrofurazone, hydrogen peroxide, dodecyl sodium sulfate, pelargonic acid, iodoacetic acid, 1-diethylaminoethylamino-4-methylthiaxanthrone, sodium arsanilate, sodium arsenate, bismuth glycolyl arsanilate, 1-β-hydroxyethyl-2-methyl-5-nitroimidazole, and p-nitroaniline. Copper ion was not particularly effective against entodinia; nickel ion had no effect on holotrichs. Hydrogen peroxide and iodoacetic acid were effective at a concentration of 0.005%. Anionic surface-active agents were very effective, especially long-chain sulfates and phosphates. These antiprotozoal agents warrant further in vivo studies for possible use in treating or curing bloat in ruminants. PMID:6077407

Survey of chemical compounds tested in vitro against rumen protozoa for possible control of bloat.

PubMed

Willard, F L; Kodras, R

1967-09-01

Over 170 chemical agents were screened for antiprotozoal action in bovine ruminal fluid. Compounds were tested at 0.1 and 0.05% concentrations. Tested compounds included inorganic compounds, antibiotics, biocides, neuromuscular agents, arsenicals, plant and animal hormones, antimalarials, surface-active agents, anthelmintics, and many others. The most active compounds were cupric sulfate, nickel sulfate, nitrofurazone, hydrogen peroxide, dodecyl sodium sulfate, pelargonic acid, iodoacetic acid, 1-diethylaminoethylamino-4-methylthiaxanthrone, sodium arsanilate, sodium arsenate, bismuth glycolyl arsanilate, 1-beta-hydroxyethyl-2-methyl-5-nitroimidazole, and p-nitroaniline. Copper ion was not particularly effective against entodinia; nickel ion had no effect on holotrichs. Hydrogen peroxide and iodoacetic acid were effective at a concentration of 0.005%. Anionic surface-active agents were very effective, especially long-chain sulfates and phosphates. These antiprotozoal agents warrant further in vivo studies for possible use in treating or curing bloat in ruminants.

Essential oils and their principal constituents as antimicrobial agents for synthetic packaging films.

PubMed

Kuorwel, Kuorwel K; Cran, Marlene J; Sonneveld, Kees; Miltz, Joseph; Bigger, Stephen W

2011-01-01

Spices and herbal plant species have been recognized to possess a broad spectrum of active constituents that exhibit antimicrobial (AM) activity. These active compounds are produced as secondary metabolites associated with the volatile essential oil (EO) fraction of these plants. A wide range of AM agents derived from EOs have the potential to be used in AM packaging systems which is one of the promising forms of active packaging systems aimed at protecting food products from microbial contamination. Many studies have evaluated the AM activity of synthetic AM and/or natural AM agents incorporated into packaging materials and have demonstrated effective AM activity by controlling the growth of microorganisms. This review examines the more common synthetic and natural AM agents incorporated into or coated onto synthetic packaging films for AM packaging applications. The focus is on the widely studied herb varieties including basil, oregano, and thyme and their EOs. © 2011 Institute of Food Technologists®

Cellulosic/wool pigment prints with remarkable antibacterial functionalities.

PubMed

Ibrahim, N A; Eid, B M; Khalil, H M

2015-01-22

Several bio-active agents namely choline chloride, triclosan derivative, PEG-600 and 4-hydroxybenzophenone were successfully included into solvent-free pigment formulations, in a single-stage process, followed by screen printing and microwave-fixation to obtain antibacterial functionalized cellulosic/wool pigment prints. Results obtained signify that both the improvement in functionalization and coloration properties are governed by type of antibacterial agent, kind of substrate as well as pigment colorant. The imparted antibacterial activity of the loaded bio-active agents follows the decreasing order: G+ve (Staphylococcus aureus)>G-ve (Escherichia coli), keeping other parameters constant. The imparted functional and coloration properties showed no significant decrease even after 15 washings. Mode of interactions among the nominated substrates, the pigment paste constituents and the bioactive agents were also proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Susceptibility of Legionella pneumophila to twenty antimicrobial agents.

PubMed Central

Edelstein, P H; Meyer, R D

1980-01-01

Thirty-three isolates of Legionella pneumophila, all except one of which were clinical isolates, were tested against 20 antimicrobial agents by using an agar dilution technique. Erythromycin, rifamp]in, and rosaramycin were the most active agents tested. Aminoglycosides, chloramphenicol, and cefoxitin also inhibited the organisms at low concentrations. Other agents, including moxalactam, cefoperazone, and cephalosporins, exhibited moderate to little activity. Tetracycline, doxycycline and minocyeline were apparently inactivated by charcoal-yeast extract medium. There was slight inoculum dependence noted with most of the antimicrobials tested, particularly the beta-lactam agents. There was no consistent difference in susceptibility between Center for Disease Control-supplied stock strains and recent clinical isolates, but there were marked differences with some agents. Susceptibility testing needs to be standardized in view of the influence of inoculum size, strain variation, and the medium used. PMID:7425611

Antiplaque and antigingivitis toothpastes.

PubMed

Sanz, Mariano; Serrano, Jorge; Iniesta, Margarita; Santa Cruz, Isabel; Herrera, David

2013-01-01

Dentifrices are a general term used to describe preparations that are used together with a toothbrush with the purpose to clean and/or polish the teeth. Active toothpastes were first formulated in the 1950s and included ingredients such as urea, enzymes, ammonium phosphate, sodium lauryl sarcosinate and stannous fluoride. Later, therapeutic agents were included. Today's toothpastes have two objectives: to help the toothbrush in cleaning the tooth surface and to provide a therapeutic effect. The therapeutic effect may have an antiplaque or anti-inflammatory basis when the nature of the agents is antimicrobial. Plaque inhibitory and antiplaque activity of toothpastes used for chemical plaque control is evaluated in distinct consecutive stages, the last being home use randomized clinical trials of at least 6 months' duration. In this chapter, the scientific evidence supporting the use of the most common antiplaque agents, included in toothpaste formulations, is reviewed, with a special emphasis on 6-month clinical trials, and systematic reviews with meta-analyses of the mentioned studies. Among the active agents, the following have been included in toothpastes: enzymes, amine alcohols, herbal or natural products, triclosan, bisbiguanides (chlorhexidine), quaternary ammonium compounds (cetylpyridinium chloride) and different metal salts (zinc salts, stannous fluoride, stannous fluoride with amine fluoride). Dentifrices are the ideal vehicles for any active ingredient used as an oral health preventive measure since they are used in combination with toothbrushing, which is the most frequently employed oral hygiene method. The most important indications of dentifrices with active ingredients are associated with long-term use to prevent bacterial biofilm formation, mostly in gingivitis patients or in patients on supportive periodontal therapy. Copyright © 2013 S. Karger AG, Basel.

Updating the carbon footprint of the Galician fishing activity (NW Spain).

PubMed

Iribarren, Diego; Vázquez-Rowe, Ian; Hospido, Almudena; Moreira, María Teresa; Feijoo, Gumersindo

2011-03-15

Recent life cycle assessment studies have revealed the relevance of cooling agent leakage when assessing the greenhouse gas (GHG) emissions generated by fishing vessel operations. The goal of this communication is to update the carbon footprinting of the Galician fishing activity (NW Spain) by including the GHG emissions from cooling agent leakage. Results proved the relevant role played by refrigerants regarding their contribution to the carbon footprint of fishing activities. Thus, an overall increase of 13% was found when comparing the final global carbon footprint for the Galician fishing activity with previous calculations that did not include these emissions. Nevertheless, further efforts should be made in order to provide robust data in this respect. Copyright © 2011 Elsevier B.V. All rights reserved.

Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-03-01

A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.

Thiazole containing Heterocycles with CNS activity.

PubMed

Kalal, Priyanka; Gandhi, Divyani; Prajapat, Prakash; Agarwal, Shikha

2017-07-24

Thiazoles are promising scaffolds in the area of medicinal and pharmaceutical chemistry and have accounted to show different pharmacophoric properties. For the last years, thiazole derivatives have focused too much attention to develop different new CNS active agents. It has been broadly used to generate diverse therapeutic agents against various CNS targets. Histamine H3 receptors are seriously involved in the pathophysiology of numerous disorders of the central nervous system. The literature survey has been done using different database from peer-reviewed journals. The quality of repossessed papers was evaluated using standard tools. The details of important papers were described to focus on the potency of thiazole containing heterocycles with CNS activity. Eighty nine papers were included in the review indicating thiazole containing heterocycles with CNS activity. (1) to (30) papers included different thiazole derivatives impregnated withCNS activity. Different CNS agents have been shown in references (37) to (56). The remaining papers have been searched for anticonvulsant agents (57) to (78) and other miscellaneous activities from (79) to (89). A detailed investigation has been carried out on thiazoles and its derivatives to judge its efficacy to overcome several CNS disorders. This article covers the recent updates of thiazole and its derivative with CNS activity already present in literature and will definitely provide a better platform for the production and development of potent thiazole based CNS vigorous drugs in near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

ERLN Activities Details

EPA Pesticide Factsheets

Environmental Response Laboratory Network activities include the All Hazard Receipt Facility and Screening Protocol, standardizing chemical methods, Chemical Warfare Agent Fixed Laboratory Pilot Project, microbial efforts, and WLA response plan.

State-level legal preparedness for nuclear and radiological emergencies in the U.S.: a network analysis of state laws and regulations.

PubMed

Guclu, Hasan; Ferrell Bjerke, Elizabeth; Galvan, Jared; Sweeney, Patricia; Potter, Margaret A

2014-01-01

This study explored if and to what extent the laws of U.S. states mirrored the U.S. federal laws for responding to nuclear-radiological emergencies (NREs). Emergency laws from a 12-state sample and the federal government were retrieved and translated into numeric codes representing acting agents, their partner agents, and the purposes of activity in terms of preparedness, response, and recovery. We used network analysis to explore the relationships among agents in terms of legally directed NRE activities. States' legal networks for NREs appear as not highly inclusive, involving an average of 28% of agents among those specified in the federal laws. Certain agents are highly central in NRE networks, so that their capacity and effectiveness might strongly influence an NRE response. State-level lawmakers and planners might consider whether or not greater inclusion of agents, modeled on the federal government laws, would enhance their NRE laws and if more agents should be engaged in planning and policy-making for NRE incidents. Further research should explore if and to what extent legislated NRE directives impose constraints on practical response activities including emergency planning.

Tissue-based water quality biosensors for detecting chemical warfare agents

DOEpatents

Greenbaum, Elias [Oak Ridge, TN; Sanders, Charlene A [Knoxville, TN

2003-05-27

A water quality sensor for detecting the presence of at least one chemical or biological warfare agent includes: a cell; apparatus for introducing water into the cell and discharging water from the cell adapted for analyzing photosynthetic activity of naturally occurring, free-living, indigenous photosynthetic organisms in water; a fluorometer for measuring photosynthetic activity of naturally occurring, free-living, indigenous photosynthetic organisms drawn into the cell; and an electronics package that analyzes raw data from the fluorometer and emits a signal indicating the presence of at least one chemical or biological warfare agent in the water.

Allergic Contact Dermatitis to Ophthalmic Medications: Relevant Allergens and Alternative Testing Methods.

PubMed

Grey, Katherine R; Warshaw, Erin M

Allergic contact dermatitis is an important cause of periorbital dermatitis. Topical ophthalmic agents are relevant sensitizers. Contact dermatitis to ophthalmic medications can be challenging to diagnose and manage given the numerous possible offending agents, including both active and inactive ingredients. Furthermore, a substantial body of literature reports false-negative patch test results to ophthalmic agents. Subsequently, numerous alternative testing methods have been described. This review outlines the periorbital manifestations, causative agents, and alternative testing methods of allergic contact dermatitis to ophthalmic medications.

Mechanochemical processing for metals and metal alloys

DOEpatents

Froes, Francis H.; Eranezhuth, Baburaj G.; Prisbrey, Keith

2001-01-01

A set of processes for preparing metal powders, including metal alloy powders, by ambient temperature reduction of a reducible metal compound by a reactive metal or metal hydride through mechanochemical processing. The reduction process includes milling reactants to induce and complete the reduction reaction. The preferred reducing agents include magnesium and calcium hydride powders. A process of pre-milling magnesium as a reducing agent to increase the activity of the magnesium has been established as one part of the invention.

Maintaining Fluoroquinolone Class Efficacy: Review of Influencing Factors

PubMed Central

2003-01-01

Previous experience with antimicrobial resistance has emphasized the importance of appropriate stewardship of these pharmacotherapeutic agents. The introduction of fluoroquinolones provided potent new drugs directed primarily against gram-negative pathogens, while the newer members of this class demonstrate more activity against gram-positive species, including Streptococcus pneumoniae. Although these agents are clinically effective against a broad range of infectious agents, emergence of resistance and associated clinical failures have prompted reexamination of their use. Appropriate use revolves around two key objectives: 1) only prescribing antimicrobial therapy when it is beneficial and 2) using the agents(s) with optimal activity against the expected pathogens(s). Pharmacodynamic principles and properties can be applied to achieve the latter objective when prescribing agents belonging to the fluoroquinolone class. A focused approach emphasizing “correct-spectrum” coverage may reduce development of antimicrobial resistance and maintain class efficacy. PMID:12533274

Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents

PubMed Central

Wink, Michael; Ashour, Mohamed L.; El-Readi, Mahmoud Zaki

2012-01-01

Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion. PMID:22536197

Antimicrobial susceptibility of Gram-negative bacteria causing intra-abdominal infections in China: SMART China 2011.

PubMed

Zhang, Hui; Yang, Qiwen; Xiao, Meng; Chen, Minjun; Badal, Robert E; Xu, Yingchun

2014-01-01

The Study for Monitoring Antimicrobial Resistance Trends program monitors the activity of antibiotics against aerobic and facultative Gram-negative bacilli (GNBs) from intra-abdominal infections (IAIs) in patients worldwide. In 2011, 1 929 aerobic and facultative GNBs from 21 hospitals in 16 cities in China were collected. All isolates were tested using a panel of 12 antimicrobial agents, and susceptibility was determined following the Clinical Laboratory Standards Institute guidelines. Among the Gram-negative pathogens causing IAIs, Escherichia coli (47.3%) was the most commonly isolated, followed by Klebsiella pneumoniae (17.2%), Pseudomonas aeruginosa (10.1%), and Acinetobacter baumannii (8.3%). Enterobacteriaceae comprised 78.8% (1521/1929) of the total isolates. Among the antimicrobial agents tested, ertapenem and imipenem were the most active agents against Enterobacteriaceae, with susceptibility rates of 95.1% and 94.4%, followed by amikacin (93.9%) and piperacillin/tazobactam (87.7%). Susceptibility rates of ceftriaxone, cefotaxime, ceftazidime, and cefepime against Enterobacteriaceae were 38.3%, 38.3%, 61.1%, and 50.8%, respectively. The leastactive agent against Enterobacteriaceae was ampicillin/sulbactam (25.9%). The extended-spectrum β-lactamase (ESBL) rates among E. coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis were 68.8%, 38.1%, 41.2%, and 57.7%, respectively. Enterobacteriaceae were the major pathogens causing IAIs, and the most active agents against the study isolates (including those producing ESBLs) were ertapenem, imipenem, and amikacin. Including the carbapenems, most agents exhibited reduced susceptibility against ESBL-positive and multidrug-resistant isolates.

Evaluation of Foaming Performance of Bitumen Modified with the Addition of Surface Active Agent

NASA Astrophysics Data System (ADS)

Chomicz-Kowalska, Anna; Mrugała, Justyna; Maciejewski, Krzysztof

2017-10-01

The article presents the analysis of the performance of foamed bitumen modified using surface active agents. Although, bitumen foaming permits production of asphalt concrete and other asphalt mix types without using chemical additives in significantly reduced temperatures, the decrease in processing temperatures still impacts the adhesion performance and bitumen coating of aggregates in final mixes. Therefore, in some cases it may be feasible to incorporate adhesion promoters and surface active agents into warm and half-warm mixes with foamed bitumen to increase their service life and resilience. Because of the various nature of the available surface active agents, varying bitumen compatibility and their possible impact on the rheological properties of bitumen, the introduction of surface active agents may significantly alter the bitumen foaming performance. The tests included basic performance tests of bitumen before and after foaming. The two tested bitumen were designated as 35/50 and 50/70 penetration grade binders, which were modified with a surface active agent widely used for improving mixture workability, compactibility and adhesion in a wide range of asphalt mixes and techniques, specifically Warm Mix Asphalt. Alongside to the reference unmodified bitumen, binders with 0.2%, 0.4% and 0.6% surface active agent concentration were tested. The analysis has shown a positive influence of the modifier on the foaming performance of both of the base bitumen increasing their maximum expansion ratio and bitumen foam halflife. In the investigations, it was found that the improvement was dependent on the bitumen type and modifier content. The improved expansion ratio and foam half-life has a positive impact on the aggregate coating and adhesion, which together with the adhesion promoting action of the modifier will have a combined positive effect on the quality of produced final asphalt mixes.

Anti-inflammatory Agents: Present and Future

PubMed Central

Dinarello, Charles A.

2012-01-01

Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, when allowed to continue unchecked, inflammation may result in autoimmune or autoinflammatory disorders, neurodegenerative disease, or cancer. A variety of safe and effective anti-inflammatory agents are available, including aspirin and other nonsteroidal anti-inflammatories, with many more drugs under development. In particular, the new era of anti-inflammatory agents includes “biologicals” such as anticytokine therapies and small molecules that block the activity of kinases. Other anti-inflammatories currently in use or under development include statins, histone deacetylase inhibitors, PPAR agonists, and small RNAs. This Review discusses the current status of anti-inflammatory drug research and the development of new anti-inflammatory therapeutics. PMID:20303881

A framework for the use of agent based modeling to simulate ...

EPA Pesticide Factsheets

Simulation of human behavior in exposure modeling is a complex task. Traditionally, inter-individual variation in human activity has been modeled by drawing from a pool of single day time-activity diaries such as the US EPA Consolidated Human Activity Database (CHAD). Here, an agent-based model (ABM) is used to simulate population distributions of longitudinal patterns of four macro activities (sleeping, eating, working, and commuting) in populations of adults over a period of one year. In this ABM, an individual is modeled as an agent whose movement through time and space is determined by a set of decision rules. The rules are based on the agent having time-varying “needs” that are satisfied by performing actions. Needs are modeled as increasing over time, and taking an action reduces the need. Need-satisfying actions include sleeping (meeting the need for rest), eating (meeting the need for food), and commuting/working (meeting the need for income). Every time an action is completed, the model determines the next action the agent will take based on the magnitude of each of the agent’s needs at that point in time. Different activities advertise their ability to satisfy various needs of the agent (such as food to eat or sleeping in a bed or on a couch). The model then chooses the activity that satisfies the greatest of the agent’s needs. When multiple actions could address a need, the model will choose the most effective of the actions (bed over the couc

Antiseptics and Disinfectants: Activity, Action, and Resistance

PubMed Central

McDonnell, Gerald; Russell, A. Denver

1999-01-01

Antiseptics and disinfectants are extensively used in hospitals and other health care settings for a variety of topical and hard-surface applications. A wide variety of active chemical agents (biocides) are found in these products, many of which have been used for hundreds of years, including alcohols, phenols, iodine, and chlorine. Most of these active agents demonstrate broad-spectrum antimicrobial activity; however, little is known about the mode of action of these agents in comparison to antibiotics. This review considers what is known about the mode of action and spectrum of activity of antiseptics and disinfectants. The widespread use of these products has prompted some speculation on the development of microbial resistance, in particular whether antibiotic resistance is induced by antiseptics or disinfectants. Known mechanisms of microbial resistance (both intrinsic and acquired) to biocides are reviewed, with emphasis on the clinical implications of these reports. PMID:9880479

Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halbrook, R.S.; Shugart, L.R.; Watson, A.P.

1992-09-01

A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. Amore » framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.« less

PPARγ and Apoptosis in Cancer

PubMed Central

Elrod, Heath A.; Sun, Shi-Yong

2008-01-01

Peroxisome proliferator-activated receptors (PPARs) are ligand binding transcription factors which function in many physiological roles including lipid metabolism, cell growth, differentiation, and apoptosis. PPARs and their ligands have been shown to play a role in cancer. In particular, PPARγ ligands including endogenous prostaglandins and the synthetic thiazolidinediones (TZDs) can induce apoptosis of cancer cells with antitumor activity. Thus, PPARγ ligands have a potential in both chemoprevention and therapy of several types of cancer either as single agents or in combination with other antitumor agents. Accordingly, the involvement of PPARγ and its ligands in regulation of apoptosis of cancer cells have been extensively studied. Depending on cell types or ligands, induction of apoptosis in cancer cells by PPARγ ligands can be either PPARγ-dependent or -independent. Through increasing our understanding of the mechanisms of PPARγ ligand-induced apoptosis, we can develop better strategies which may include combining other antitumor agents for PPARγ-targeted cancer chemoprevention and therapy. This review will highlight recent research advances on PPARγ and apoptosis in cancer. PMID:18615184

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

PubMed

Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D

2015-11-05

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

PubMed Central

Lefranc, Florence; Carbone, Marianna; Mollo, Ernesto; Gavagnin, Margherita; Betancourt, Tania; Dasari, Ramesh

2016-01-01

Abstract The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as “chemotaxonomic markers” for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk‐derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen‐containing compounds. The “promise” of a mollusk‐derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk‐derived anticancer agents and solutions to their procurement in quantity. PMID:27925266

Emerging drug treatments for solid tumours.

PubMed

Schellens, J H; Pronk, L C; Verweij, J

1996-01-01

A number of novel anticancer agents have emerged during the past few decades, which show high activity in preclinical tumour models and promising activity in early trials in patients with solid tumours. Most of the agents have novel and unique mechanisms of action, and show activity against a variety of malignancies, including tumours which are notoriously resistant to systemic treatment. Recently, our understanding of the molecular basis of cancer has increased considerably. This is reflected in the development of agents that are directed at well defined molecular targets, such as the mitotic tubulin/microtubuli system (taxoids), nuclear enzymes (topoisomerase I inhibitors) and cell signal transduction pathways (protein kinase C inhibitors). In addition, significant advances have been made in our understanding of mechanisms of toxicity, especially of cisplatin. This has resulted in the development of agents modulating cisplatin toxicity, among which amifostine (WR-2721) is one of the most promising. The outlined emerging drug therapies with novel anticancer agents and treatment modalities will, it is hoped, result in increased response rates of advanced tumours, longer disease-free and total survival and better palliative care.

The role of toxicological science in meeting the challenges and opportunities of hydraulic fracturing.

PubMed

Goldstein, Bernard D; Brooks, Bryan W; Cohen, Steven D; Gates, Alexander E; Honeycutt, Michael E; Morris, John B; Orme-Zavaleta, Jennifer; Penning, Trevor M; Snawder, John

2014-06-01

We briefly describe how toxicology can inform the discussion and debate of the merits of hydraulic fracturing by providing information on the potential toxicity of the chemical and physical agents associated with this process, individually and in combination. We consider upstream activities related to bringing chemical and physical agents to the site, on-site activities including drilling of wells and containment of agents injected into or produced from the well, and downstream activities including the flow/removal of hydrocarbon products and of produced water from the site. A broad variety of chemical and physical agents are involved. As the industry expands this has raised concern about the potential for toxicological effects on ecosystems, workers, and the general public. Response to these concerns requires a concerted and collaborative toxicological assessment. This assessment should take into account the different geology in areas newly subjected to hydraulic fracturing as well as evolving industrial practices that can alter the chemical and physical agents of toxicological interest. The potential for ecosystem or human exposure to mixtures of these agents presents a particular toxicological and public health challenge. These data are essential for developing a reliable assessment of the potential risks to the environment and to human health of the rapidly increasing use of hydraulic fracturing and deep underground horizontal drilling techniques for tightly bound shale gas and other fossil fuels. Input from toxicologists will be most effective when employed early in the process, before there are unwanted consequences to the environment and human health, or economic losses due to the need to abandon or rework costly initiatives.

The Role of Toxicological Science in Meeting the Challenges and Opportunities of Hydraulic Fracturing

PubMed Central

Goldstein, Bernard D.; Brooks, Bryan W.; Cohen, Steven D.; Gates, Alexander E.; Honeycutt, Michael E.; Morris, John B.; Orme-Zavaleta, Jennifer; Penning, Trevor M.; Snawder, John

2014-01-01

We briefly describe how toxicology can inform the discussion and debate of the merits of hydraulic fracturing by providing information on the potential toxicity of the chemical and physical agents associated with this process, individually and in combination. We consider upstream activities related to bringing chemical and physical agents to the site, on-site activities including drilling of wells and containment of agents injected into or produced from the well, and downstream activities including the flow/removal of hydrocarbon products and of produced water from the site. A broad variety of chemical and physical agents are involved. As the industry expands this has raised concern about the potential for toxicological effects on ecosystems, workers, and the general public. Response to these concerns requires a concerted and collaborative toxicological assessment. This assessment should take into account the different geology in areas newly subjected to hydraulic fracturing as well as evolving industrial practices that can alter the chemical and physical agents of toxicological interest. The potential for ecosystem or human exposure to mixtures of these agents presents a particular toxicological and public health challenge. These data are essential for developing a reliable assessment of the potential risks to the environment and to human health of the rapidly increasing use of hydraulic fracturing and deep underground horizontal drilling techniques for tightly bound shale gas and other fossil fuels. Input from toxicologists will be most effective when employed early in the process, before there are unwanted consequences to the environment and human health, or economic losses due to the need to abandon or rework costly initiatives. PMID:24706166

Preliminary assessment of the health and environmental impacts of transporting M55 rockets from Lexington-Blue Grass Depot activity, Anniston Army depot, and Umatilla depot activity to alternative disposal facilities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carnes, S.A.; Breck, J.E.; Copenhaver, E.D.

1986-03-01

This assessment discusses the potential health and environmental impacts of transporting M55 rockets filled with nerve agent GB or VX from various existing Army storage depots to alternative Army depots for disposal. The origin depots include Anniston Army Depot in Alabama, Lexington-Blue Grass Depot Activity in Kentucky, and Umatilla Depot Activity in Oregon. The destination depots include Pine Bluff Arsenal in Arkansas, Tooele Army Depot in Utah, and the facility on Johnston Island in the central Pacific Ocean. This assessment considers the possible impacts of normal transport operations and of two postulated accident scenarios on the air quality, ground andmore » surface water, aquatic ecology, terrestrial ecology, human health, and cultural and socioeconomic resources of the various transport corridors involved. The impacts of these scenarios are assessed for truck, train, and air transport for each orgin-destination pair. The analysis considers three basic scenario during transport: (1) normal operations with no atmospheric release of nerve agent; (2) a minor agent spill (the contents of one rocket being released to the biosphere); and (3) a worst-case accident involving the release of a large, specified quantity of nerve agent to the biosphere. The extremely low probabilities of such accidents, which are reported elsewhere, are noted.« less

Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU.

PubMed Central

Workman, P.; Twentyman, P. R.

1982-01-01

Using a regrowth-delay assay, we investigated structure/activity relationships for the enhancement by electron-affinic agents of the anti-tumour effect of the nitrosourea CCNU against the KHT sarcoma in C3H mice. A series of neutral 2-nitroimidazoles similar in electron affinity but varying in octanol/water partition coefficient (PC) over 4 orders of magnitude (0.016- greater than 200, Misonidazole = 0.43) were examined at a fixed dose of 2.5 mmol/kg. A parabolic (quadratic) dependence of activity on log PC was observed. Analogues more hydrophilic than misonidazole (MISO) were inactive as were those with very high PCs (greater than 20). Those with PC 0.43--20 were usually more active than MISO, some considerably so. The fairly lipophilic 5-nitroimidazoles nimorazole and metronidazole (METRO) had similar activity to MISO, despite their reduced electron affinity. Two basic 2-nitroimidazoles more efficient as radiosensitizers in vitro likewise showed activity comparable to MISO. We also investigated several agents more electron-affinic than MISO, including some non-nitro compounds. Most were inactive at maximum tolerated doses, but nitrofurazone showed reasonable activity. Sensitizer dose-response curves were obtained for MISO, METRO and two of the most effective agents, benznidazole (Ro 07-1051) and Ro 07-1902. The two latter agents were both considerably more active than MISO at low doses (0.1--0.9 mmol/kg). These studies indicate that the structural features of electron-affinic agents responsible for the enhancement of KHT tumour response to CCNU, are quite different from those affecting radiosensitization, lipophilicity being particularly important. The microsomal enzyme-inhibitor SKF 525A increased the anti-tumour effect of CCNU, suggesting inhibition of CCNU metabolism as one possible mechanism contributing to chemosensitization by lipophilic electron-affinic agents in mice. PMID:7150475

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond.

PubMed

Boldescu, Veaceslav; Behnam, Mira A M; Vasilakis, Nikos; Klein, Christian D

2017-08-01

Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk. This Review summarizes and comments on the opportunities for broad-spectrum agents that are active against multiple flaviviruses. Broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic, which could emerge from as-yet unknown or neglected viruses. Potential molecular targets for broad-spectrum antiflaviviral compounds include viral proteins, such as the viral protease or polymerase, and host targets that are exploited by these viruses during entry and replication, including α-glucosidase and proteins involved in nucleoside biosynthesis. Numerous compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For other compounds, broad-spectrum activity can be anticipated because of their mode of action and molecular targets.

Current and Novel Therapeutic Options for Irritable Bowel Syndrome Management

PubMed Central

Camilleri, Michael; Andresen, Viola

2009-01-01

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting up to 3-15% of the general population in western countries. It is characterized by unexplained abdominal pain, discomfort, and bloating in association with altered bowel habits. The pathophysiology of IBS is multifactorial involving disturbances of the brain-gut-axis. The pathophysiology provides the rationale for pharmacotherapy: abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction, and mucosal immune activation. Understanding the mechanisms, and their mediators or modulators including neurotransmitters and receptors have led to several therapeutic approaches including agents acting on the serotonin receptor or serotonin transporter system, antidepressants, novel selective anticholinergics, α-adrenergic agonists, opioid agents, cholecystokinin-antagonists, neurokinin-antagonists, somatostatin receptor agonists, corticotropin releasing factor antagonists, chloride-channel activators, guanylate-cyclase-c agonists, melatonin, atypical benzodiazepines, antibiotics, immune modulators and probiotics. The mechanisms and current evidence regarding efficacy of these agents are reviewed. PMID:19665953

In vitro activity of Tedizolid phosphate against multidrug-resistant Streptococcus pneumoniae isolates from Asian countries.

PubMed

Baek, Jin Yang; Kang, Cheol-In; Kim, So Hyun; Ko, Kwan Soo; Chung, Doo Ryeon; Peck, Kyong Ran; Hsueh, Po-Ren; Thamlikitkul, Visanu; So, Thomas Man-Kit; Lee, Nam Yong; Song, Jae-Hoon

2016-06-01

Tedizolid phosphate is a second-generation oxazolidinone prodrug that is potential activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, penicillin-resistant streptococci, and vancomycin-resistant enterococci. The in vitro activity of tedizolid and other comparator agents against multidrug-resistant (MDR) pneumococci from various Asian countries were evaluated. Of the S. pneumoniae clinical pneumonia isolates collected during 2008 and 2009 from 8 Asian countries (Korea, Taiwan, Thailand, Hong Kong, Vietnam, Malaysia, Philippines, and Sri Lanka), 104 isolates of MDR pneumococci were included in this study. Antimicrobial susceptibility testing for 18 antimicrobial agents was performed by broth microdilution method. Tedizolid was highly active against pneumococci. All isolates tested were inhibited at a tedizolid minimum inhibitory concentration (MIC) value of ≤0.25μg/ml (ranged from ≤0.03μg/ml to 0.25μg/ml). The MIC50 and MIC90 of tedizolid against MDR pneumococci were both 0.12μg/ml, while MIC50 and MIC90 of linezolid were 0.5μg/ml and 1μg/ml, respectively. In addition, tedizolid maintained the activity against S. pneumoniae regardless of the extensively drug-resistant (XDR) phenotype of the isolates. The activity of tedizolid was excellent against all types of MDR pneumococci, exhibiting and maintaining at least 4-fold-greater potency compared to linezolid, regardless of resistance phenotypes to other commonly utilized agents. Tedizolid has the potential to be an agent to treat infections caused by MDR pneumococci in the Asia. Copyright © 2016 Elsevier Inc. All rights reserved.

Microgravity

NASA Image and Video Library

1989-02-03

(PCG) Protein Crystal Growth Gamma-Interferon. Stimulates the body's immune system and is used clinically in the treatment of cancer. Potential as an anti-tumor agent against solid tumors as well as leukemia's and lymphomas. It has additional utility as an anti-ineffective agent, including antiviral, anti-bacterial, and anti-parasitic activities. Principal Investigator on STS-26 was Charles Bugg.

Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)

PubMed Central

Docherty, J R

2008-01-01

This review examines the pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Stimulants that increase alertness/reduce fatigue or activate the cardiovascular system can include drugs like ephedrine available in many over-the-counter medicines. Others such as amphetamines, cocaine and hallucinogenic drugs, available on prescription or illegally, can modify mood. A total of 62 stimulants (61 chemical entities) are listed in the WADA List, prohibited in competition. Athletes may have stimulants in their body for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The majority of stimulants on the list act on the monoaminergic systems: adrenergic (sympathetic, transmitter noradrenaline), dopaminergic (transmitter dopamine) and serotonergic (transmitter serotonin, 5-HT). Sympathomimetic describes agents, which mimic sympathetic responses, and dopaminomimetic and serotoninomimetic can be used to describe actions on the dopamine and serotonin systems. However, many agents act to mimic more than one of these monoamines, so that a collective term of monoaminomimetic may be useful. Monoaminomimietic actions of stimulants can include blockade of re-uptake of neurotransmitter, indirect release of neurotransmitter, direct activation of monoaminergic receptors. Many of the stimulants are amphetamines or amphetamine derivatives, including agents with abuse potential as recreational drugs. A number of agents are metabolized to amphetamine or metamphetamine. In addition to the monoaminomimetic agents, a small number of agents with different modes of action are on the list. A number of commonly used stimulants are not considered as Prohibited Substances. PMID:18500382

Lipopeptides as the Antifungal and Antibacterial Agents: Applications in Food Safety and Therapeutics

PubMed Central

Meena, Khem Raj; Kanwar, Shamsher S.

2015-01-01

A lot of crops are destroyed by the phytopathogens such as fungi, bacteria, and yeast leading to economic losses to the farmers. Members of the Bacillus genus are considered as the factories for the production of biologically active molecules that are potential inhibitors of growth of phytopathogens. Plant diseases constitute an emerging threat to global food security. Many of the currently available antimicrobial agents for agriculture are highly toxic and nonbiodegradable and thus cause extended environmental pollution. Moreover, an increasing number of phytopathogens have developed resistance to antimicrobial agents. The lipopeptides have been tried as potent versatile weapons to deal with a variety of phytopathogens. All the three families of Bacillus lipopeptides, namely, Surfactins, Iturins and Fengycins, have been explored for their antagonistic activities towards a wide range of phytopathogens including bacteria, fungi, and oomycetes. Iturin and Fengycin have antifungal activities, while Surfactin has broad range of potent antibacterial activities and this has also been used as larvicidal agent. Interestingly, lipopeptides being the molecules of biological origin are environmentally acceptable. PMID:25632392

Abstract-Reasoning Software for Coordinating Multiple Agents

NASA Technical Reports Server (NTRS)

Clement, Bradley; Barrett, Anthony; Rabideau, Gregg; Knight, Russell

2003-01-01

A computer program for scheduling the activities of multiple agents that share limited resources has been incorporated into the Automated Scheduling and Planning Environment (ASPEN) software system, aspects of which have been reported in several previous NASA Tech Briefs articles. In the original intended application, the agents would be multiple spacecraft and/or robotic vehicles engaged in scientific exploration of distant planets. The program could also be used on Earth in such diverse settings as production lines and military maneuvers. This program includes a planning/scheduling subprogram of the iterative repair type that reasons about the activities of multiple agents at abstract levels in order to greatly improve the scheduling of their use of shared resources. The program summarizes the information about the constraints on, and resource requirements of, abstract activities on the basis of the constraints and requirements that pertain to their potential refinements (decomposition into less-abstract and ultimately to primitive activities). The advantage of reasoning about summary information is that time needed to find consistent schedules is exponentially smaller than the time that would be needed for reasoning about the same tasks at the primitive level.

Antimalarial and antimicrobial activities of 8-Aminoquinoline-Uracils metal complexes

PubMed Central

Phopin, Kamonrat; Sinthupoom, Nujarin; Treeratanapiboon, Lertyot; Kunwittaya, Sarun; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2016-01-01

8-Aminoquinoline (8AQ) derivatives have been reported to have antimalarial, anticancer, and antioxidant activities. This study investigated the potency of 8AQ-5-substituted (iodo and nitro) uracils metal (Mn, Cu, Ni) complexes (1-6) as antimalarial and antimicrobial agents. Interestingly, all of these metal complexes (1-6) showed fair antimalarial activities. Moreover, Cu complexes 2 (8AQ-Cu-5Iu) and 5 (8AQ-Cu-5Nu) exerted antimicrobial activities against Gram-negative bacteria including P. shigelloides and S. dysenteriae. The results reveal application of 8AQ and its metal complexes as potential compounds to be further developed as novel antimalarial and antibacterial agents. PMID:27103894

Antimalarial and antimicrobial activities of 8-Aminoquinoline-Uracils metal complexes.

PubMed

Phopin, Kamonrat; Sinthupoom, Nujarin; Treeratanapiboon, Lertyot; Kunwittaya, Sarun; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2016-01-01

8-Aminoquinoline (8AQ) derivatives have been reported to have antimalarial, anticancer, and antioxidant activities. This study investigated the potency of 8AQ-5-substituted (iodo and nitro) uracils metal (Mn, Cu, Ni) complexes (1-6) as antimalarial and antimicrobial agents. Interestingly, all of these metal complexes (1-6) showed fair antimalarial activities. Moreover, Cu complexes 2 (8AQ-Cu-5Iu) and 5 (8AQ-Cu-5Nu) exerted antimicrobial activities against Gram-negative bacteria including P. shigelloides and S. dysenteriae. The results reveal application of 8AQ and its metal complexes as potential compounds to be further developed as novel antimalarial and antibacterial agents.

Efficacy of antimicrobial agents incorporated in orthodontic bonding systems: a systematic review and meta-analysis.

PubMed

de Almeida, C M; da Rosa, W L O; Meereis, C T W; de Almeida, S M; Ribeiro, J S; da Silva, A F; Lund, Rafael Guerra

2018-06-01

The purpose of this study was to evaluate the efficacy of orthodontic bonding systems containing different antimicrobial agents, as well as the influence of antimicrobial agent incorporation in the bonding properties of these materials. Eight databases were searched: PubMed (Medline), Web of Science, Scopus, Lilacs, Ibecs, BBO, Scielo and Google Scholar. Any study that evaluated antimicrobial activity in experimental or commercial orthodontic bonding systems was included. Data were tabulated independently and in duplicated by two authors on pre-designed data collection form. The global analysis was carried out using a random-effects model, and pooled-effect estimates were obtained by comparing the standardised mean difference of each antimicrobial orthodontic adhesive with the respective control group. A p-value < .05 was considered as statistically significant. Thirty-two studies were included in the qualitative analysis; of these, 22 studies were included in the meta-analysis. Antimicrobial agents such as silver nanoparticles, benzalkonium chloride, chlorhexidine, triclosan, cetylpyridinium chloride, Galla chinensis extract, acid ursolic, dimethylaminododecyl methacrylate, dimethylaminohexadecyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine, 1,3,5-triacryloylhexahydro-1,3,5-triazine, zinc oxide and titanium oxide have been incorporated into orthodontic bonding systems. The antimicrobial agent incorporation in orthodontic bonding systems showed higher antimicrobial activity than the control group in agar diffusion (overall standardised mean difference: 3.71; 95% CI 2.98 to 4.43) and optical density tests (0.41; 95% CI -0.05 to 0.86) (p < .05). However, for biofilm, the materials did not present antimicrobial activity (6.78; 95% CI 4.78 to 8.77). Regarding bond strength, the global analysis showed antimicrobial orthodontic bonding systems were statistically similar to the control. Although there is evidence of antibacterial activity from in vitro studies, clinical and long-term studies are still necessary to confirm the effectiveness of antibacterial orthodontic bonding systems in preventing caries disease.

Amino acid–based surfactants: New antimicrobial agents.

PubMed

Pinazo, A; Manresa, M A; Marques, A M; Bustelo, M; Espuny, M J; Pérez, L

2016-02-01

The rapid increase of drug resistant bacteria makes necessary the development of new antimicrobial agents. Synthetic amino acid-based surfactants constitute a promising alternative to conventional antimicrobial compounds given that they can be prepared from renewable raw materials. In this review, we discuss the structural features that promote antimicrobial activity of amino acid-based surfactants. Monocatenary, dicatenary and gemini surfactants that contain different amino acids on the polar head and show activity against bacteria are revised. The synthesis and basic physico-chemical properties have also been included.

Integrating planning and reactive control

NASA Technical Reports Server (NTRS)

Wilkins, David E.; Myers, Karen L.

1994-01-01

Our research is developing persistent agents that can achieve complex tasks in dynamic and uncertain environments. We refer to such agents as taskable, reactive agents. An agent of this type requires a number of capabilities. The ability to execute complex tasks necessitates the use of strategic plans for accomplishing tasks; hence, the agent must be able to synthesize new plans at run time. The dynamic nature of the environment requires that the agent be able to deal with unpredictable changes in its world. As such, agents must be able to react to unanticipated events by taking appropriate actions in a timely manner, while continuing activities that support current goals. The unpredictability of the world could lead to failure of plans generated for individual tasks. Agents must have the ability to recover from failures by adapting their activities to the new situation, or replanning if the world changes sufficiently. Finally, the agent should be able to perform in the face of uncertainty. The Cypress system, described here, provides a framework for creating taskable, reactive agents. Several features distinguish our approach: (1) the generation and execution of complex plans with parallel actions; (2) the integration of goal-driven and event driven activities during execution; (3) the use of evidential reasoning for dealing with uncertainty; and (4) the use of replanning to handle run-time execution problems. Our model for a taskable, reactive agent has two main intelligent components, an executor and a planner. The two components share a library of possible actions that the system can take. The library encompasses a full range of action representations, including plans, planning operators, and executable procedures such as predefined standard operating procedures (SOP's). These three classes of actions span multiple levels of abstraction.

Integrating planning and reactive control

NASA Astrophysics Data System (ADS)

Wilkins, David E.; Myers, Karen L.

1994-10-01

Our research is developing persistent agents that can achieve complex tasks in dynamic and uncertain environments. We refer to such agents as taskable, reactive agents. An agent of this type requires a number of capabilities. The ability to execute complex tasks necessitates the use of strategic plans for accomplishing tasks; hence, the agent must be able to synthesize new plans at run time. The dynamic nature of the environment requires that the agent be able to deal with unpredictable changes in its world. As such, agents must be able to react to unanticipated events by taking appropriate actions in a timely manner, while continuing activities that support current goals. The unpredictability of the world could lead to failure of plans generated for individual tasks. Agents must have the ability to recover from failures by adapting their activities to the new situation, or replanning if the world changes sufficiently. Finally, the agent should be able to perform in the face of uncertainty. The Cypress system, described here, provides a framework for creating taskable, reactive agents. Several features distinguish our approach: (1) the generation and execution of complex plans with parallel actions; (2) the integration of goal-driven and event driven activities during execution; (3) the use of evidential reasoning for dealing with uncertainty; and (4) the use of replanning to handle run-time execution problems. Our model for a taskable, reactive agent has two main intelligent components, an executor and a planner. The two components share a library of possible actions that the system can take. The library encompasses a full range of action representations, including plans, planning operators, and executable procedures such as predefined standard operating procedures (SOP's). These three classes of actions span multiple levels of abstraction.

Antioxidant agents against trichothecenes: new hints for oxidative stress treatment

PubMed Central

Nepovimova, Eugenie; Wang, Yun; Yang, Hualin; Li, Li; Zhang, Xiujuan; Kuca, Kamil

2017-01-01

Trichothecenes are a group of mycotoxins mainly produced by fungi of genus Fusarium. Due to high toxicity and widespread dissemination, T-2 toxin and deoxynivalenol (DON) are considered to be the most important compounds of this class. Trichothecenes generate free radicals, including reactive oxygen species (ROS), which induce lipid peroxidation, decrease levels of antioxidant enzymes, and ultimately lead to apoptosis. Consequently, oxidative stress is an active area of research on the toxic mechanisms of trichothecenes, and identification of antioxidant agents that could be used against trichothecenes is crucial for human health. Numerous natural compounds have been analyzed and have shown to function very effectively as antioxidants against trichothecenes. In this review, we summarize the molecular mechanisms underlying oxidative stress induced by these compounds, and discuss current knowledge regarding such antioxidant agents as vitamins, quercetin, selenium, glucomannan, nucleotides, antimicrobial peptides, bacteria, polyunsaturated fatty acids, oligosaccharides, and plant extracts. These products inhibit trichothecene-induced oxidative stress by (1) inhibiting ROS generation and induced DNA damage and lipid peroxidation; (2) increasing antioxidant enzyme activity; (3) blocking the MAPK and NF-κB signaling pathways; (4) inhibiting caspase activity and apoptosis; (5) protecting mitochondria; and (6) regulating anti-inflammatory actions. Finally, we summarize some decontamination methods, including bacterial and yeast biotransformation and degradation, as well as mycotoxin-binding agents. This review provides a comprehensive overview of antioxidant agents against trichothecenes and casts new light on the attenuation of oxidative stress. PMID:29299181

Antibacterial activity of essential oils from Australian native plants.

PubMed

Wilkinson, Jenny M; Cavanagh, Heather M A

2005-07-01

To date, of the Australian essential oils, only tea tree (Melaleuca alternifolia) and Eucalyptus spp. have undergone extensive investigation. In this study a range of Australian essential oils, including those from Anethole anisata, Callistris glaucophyllia, Melaleuca spp. and Thyptomine calycina, were assayed for in vitro antibacterial activity. M. alternifolia was also included for comparison purposes. Activity was determined using standard disc diffusion assays with each oil assayed at 100%, 10% and 1% against five bacteria (Escherichia coli, Salmonella typhimurium, Staphylococcus aureus, Pseudomonas aeruginosa and Alcaligenes faecalis) and the yeast, Candida albicans. All bacteria, with the exception of Ps. aeruginosa, were susceptible to one or more of the essential oils at 100%, with only Eremophilia mitchelli inhibiting the growth of any bacteria at 1% (inhibition of Sal. typhimurium). Where multiple samples of a single oil variety were tested variability in activity profiles were noted. This suggests that different methods of preparation of essential oils, together with variability in plant chemical profiles has an impact on whether or not the essential oil is of use as an antimicrobial agent. These results show that essential oils from Australian plants may be valuable antimicrobial agents for use alone or incorporated into cosmetics, cleaning agents and pharmaceutical products.

Tissue-based standoff biosensors for detecting chemical warfare agents

DOEpatents

Greenbaum, Elias; Sanders, Charlene A.

2003-11-18

A tissue-based, deployable, standoff air quality sensor for detecting the presence of at least one chemical or biological warfare agent, includes: a cell containing entrapped photosynthetic tissue, the cell adapted for analyzing photosynthetic activity of the entrapped photosynthetic tissue; means for introducing an air sample into the cell and contacting the air sample with the entrapped photosynthetic tissue; a fluorometer in operable relationship with the cell for measuring photosynthetic activity of the entrapped photosynthetic tissue; and transmitting means for transmitting analytical data generated by the fluorometer relating to the presence of at least one chemical or biological warfare agent in the air sample, the sensor adapted for deployment into a selected area.

Method and system for real-time analysis of biosensor data

DOEpatents

Greenbaum, Elias; Rodriguez, Jr., Miguel

2014-08-19

A method of biosensor-based detection of toxins includes the steps of providing a fluid to be analyzed having a plurality of photosynthetic organisms therein, wherein chemical, biological or radiological agents alter a nominal photosynthetic activity of the photosynthetic organisms. At a first time a measured photosynthetic activity curve is obtained from the photosynthetic organisms. The measured curve is automatically compared to a reference photosynthetic activity curve to determine differences therebetween. The presence of the chemical, biological or radiological agents, or precursors thereof, are then identified if present in the fluid using the differences.

New antibiotics for healthcare-associated pneumonia.

PubMed

Neuner, Elizabeth A; Ritchie, David J; Micek, Scott T

2009-02-01

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Effect of ionic detergents, nonionic detergents, and chaotropic agents on polyphenol oxidase activity from dormant saffron (Crocus sativus L.) corms.

PubMed

Saeidian, Shahriar; Keyhani, Ezzatollah; Keyhani, Jacqueline

2007-05-02

Polyphenol oxidase (PPO; EC 1.14.18.1) catalyzes the hydroxylation of monophenols to o-diphenols (cresolase activity) and the oxidation of o-diphenols to o-quinones (catecholase activity), leading to browning in plants and produce. Further interest in the enzyme has been triggered by the active role that it plays in plant defense systems. PPO can be found in latent forms and is activated in vitro by various agents including urea, detergents, and proteases. The activation of PPO from several sources by sodium dodecyl sulfate (SDS) has been extensively investigated, but reports on the effect of other detergents or on the differential effect of detergents on each of PPO's activities are scarce. In addition, investigations on the enzyme in other plant parts besides fruits and vegetables are also scarce. Here, the effect of various detergents and chaotropic agents on PPO from dormant saffron (Crocus sativus L.) corm extract was investigated. SDS and sarkosyl activated the cresolase activity, while only SDS activated the catecholase activity. All other detergents tested, in milli- or micromolar concentrations, inhibited the cresolase activity but barely affected the catecholase activity. In contrast, urea and guanidine-HCl drastically inhibited the catecholase activity but moderately inhibited the cresolase activity. The same effects were obtained on the partially purified enzyme. Results identified a PPO, present in dormant corms, which was activated only by anionic detergents and was inhibited by other reputed activating agents such as urea. Results also emphasized the differences in structure and accessibility of the active sites for cresolase and catecholase activities.

Ant-Based Cyber Defense (also known as

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glenn Fink, PNNL

2015-09-29

ABCD is a four-level hierarchy with human supervisors at the top, a top-level agent called a Sergeant controlling each enclave, Sentinel agents located at each monitored host, and mobile Sensor agents that swarm through the enclaves to detect cyber malice and misconfigurations. The code comprises four parts: (1) the core agent framework, (2) the user interface and visualization, (3) test-range software to create a network of virtual machines including a simulated Internet and user and host activity emulation scripts, and (4) a test harness to allow the safe running of adversarial code within the framework of monitored virtual machines.

Reactive decontamination formulation

DOEpatents

Giletto, Anthony [College Station, TX; White, William [College Station, TX; Cisar, Alan J [Cypress, TX; Hitchens, G Duncan [Bryan, TX; Fyffe, James [Bryan, TX

2003-05-27

The present invention provides a universal decontamination formulation and method for detoxifying chemical warfare agents (CWA's) and biological warfare agents (BWA's) without producing any toxic by-products, as well as, decontaminating surfaces that have come into contact with these agents. The formulation includes a sorbent material or gel, a peroxide source, a peroxide activator, and a compound containing a mixture of KHSO.sub.5, KHSO.sub.4 and K.sub.2 SO.sub.4. The formulation is self-decontaminating and once dried can easily be wiped from the surface being decontaminated. A method for decontaminating a surface exposed to chemical or biological agents is also disclosed.

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

PubMed Central

Deng, Liting; Ng, Lindsay; Ozawa, Tatsuya

2017-01-01

Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs. PMID:27821713

Shaping the Landscape.

ERIC Educational Resources Information Center

Naturescope, 1987

1987-01-01

Provides background information on various agents that change the landscape. Includes teaching activities on weathering, water, wind and ice erosion, plate tectonics, sedimentation, deposition, mountain building, and determining contour lines. Contains reproducible handouts and worksheets for two of the activities. (TW)

Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

PubMed Central

Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

2013-01-01

Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

(PCG) Protein Crystal Growth Gamma-Interferon

NASA Technical Reports Server (NTRS)

1989-01-01

(PCG) Protein Crystal Growth Gamma-Interferon. Stimulates the body's immune system and is used clinically in the treatment of cancer. Potential as an anti-tumor agent against solid tumors as well as leukemia's and lymphomas. It has additional utility as an anti-ineffective agent, including antiviral, anti-bacterial, and anti-parasitic activities. Principal Investigator on STS-26 was Charles Bugg.

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

PubMed Central

Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

PubMed

Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Beyond Ketamine: New Approaches to the Development of Safer Antidepressants.

PubMed

Chaki, Shigeyuki

2017-01-01

Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention. The first approach includes stereoisomers of ketamine, (R)-ketamine and (S)-ketamine. Although (S)-ketamine has been considered as the active stereoisomer of racemic ketamine, recently, (R)-ketamine has been demonstrated to exert even more prolonged antidepressant effects in animal models than (S)-ketamine. Moreover, ketamine is rapidly metabolized into several metabolites, and some metabolites are speculated as being active substances exerting antidepressant effects. Of such metabolites, one in particular, namely, (2R,6R)-hydroxynorketamine, has been reported to be responsible for the antidepressant effects of ketamine. The second approach includes agents acting on the NMDA receptor, such as glycine site modulators and GluN2B subunit-selective antagonists. These agents have been tested in patients with treatment-resistant depression, and have been found to exhibit rapid antidepressant effects like ketamine. The above approaches may be useful to overcome the drawbacks of ketamine. Elucidation of the mechanisms of action of ketamine may pave the way for the development of antidepressant that are safer, but as potent and rapidly acting as ketamine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Beyond Ketamine: New Approaches to the Development of Safer Antidepressants

PubMed Central

Chaki, Shigeyuki

2017-01-01

Background: Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. Methods: Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention. Results: The first approach includes stereoisomers of ketamine, (R)-ketamine and (S)-ketamine. Although (S)-ketamine has been considered as the active stereoisomer of racemic ketamine, recently, (R)-ketamine has been demonstrated to exert even more prolonged antidepressant effects in animal models than (S)-ketamine. Moreover, ketamine is rapidly metabolized into several metabolites, and some metabolites are speculated as being active substances exerting antidepressant effects. Of such metabolites, one in particular, namely, (2R,6R)-hydroxynorketamine, has been reported to be responsible for the antidepressant effects of ketamine. The second approach includes agents acting on the NMDA receptor, such as glycine site modulators and GluN2B subunit-selective antagonists. These agents have been tested in patients with treatment-resistant depression, and have been found to exhibit rapid antidepressant effects like ketamine. Conclusion: The above approaches may be useful to overcome the drawbacks of ketamine. Elucidation of the mechanisms of action of ketamine may pave the way for the development of antidepressant that are safer, but as potent and rapidly acting as ketamine. PMID:28228087

Balancing repair and tolerance of DNA damage caused by alkylating agents.

PubMed

Fu, Dragony; Calvo, Jennifer A; Samson, Leona D

2012-01-12

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

PubMed Central

Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

2013-01-01

Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID:22237395

Anesthetic Agents and Neuronal Autophagy. What We Know and What We Don't.

PubMed

Xu, Lili; Shen, Jianjun; McQuillan, Patrick M; Hu, Zhiyong

2018-01-01

Ethanol is known to have both γ-Aminobutyric acid agonist and Nmethyl- D-aspartate antagonist characteristics similar to commonly used volatile anesthetic agents. Recent evidence demonstrates that autophagy can reduce the development of ethanol induced neurotoxicity. Recent studies have found that general anesthesia can cause longterm impairment of both mitochondrial morphogenesis and synaptic transmission in the developing rat brain, both of which are accompanied by enhanced autophagy activity. Autophagy may play an important role in general anesthetic mediated neurotoxicity. This review outlines the role of autophagy in the development of anesthetic related neurotoxicity and includes an explanation of the role of autophagy in neuronal cell survival and death, the relationship between anesthetic agents and neuronal autophagy, possible molecular and cellular mechanisms underlying general anesthetic agent induced activation of neuronal autophagy in the developing brain, and potential therapeutic approaches aimed at modulating autophagic pathways. In a time- and concentration-dependent pattern, general anesthetic agents can disrupt intracellular calcium homeostasis which enhances both autophagy and apoptosis activation. The degree of neural cell injury may be ultimately determined by the interplay between autophagy and apoptosis. It appears likely that the increase in calcium flux associated with some anesthetic agents disrupts lysosomal function. This results in an over-activation of endosomal- lysosomal trafficking causing mitochondrial damage, reactive oxygen species upregulation, and lipid peroxidation. Autophagy may play a role in the development of anesthetic related neurotoxicity. Understanding this may lead to strategies or therapies aimed at preventing or ameliorating general anesthetic agent mediated neurotoxicity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Influence of the activating agent and the inert gas (type and flow) used in an activation process for the porosity development of carbon nanofibers.

PubMed

Jiménez, Vicente; Sánchez, Paula; Valverde, José Luis; Romero, Amaya

2009-08-15

Carbon nanofibers (CNFs) were activated with different activating agents (KOH, KHCO(3) and K(2)CO(3)). The effects of different activations conditions, including type of protector gas (He, Ar and N(2)) and helium flow rate on the properties of activated carbon nanofibers were studied. The structural changes in activated CNFs were investigated using the following characterization techniques: N(2) adsorption isotherms at 77K, XRD, temperature-programmed desorption of hydrogen, TEM, TPO and elemental composition. The results showed that the surface area increased by a factor of 3.3, 2.0 and 1.8 referred to the parent CNFs after the treatment with KOH, K(2)CO(3) and KHCO(3), respectively. In addition, KOH generated a greater pore volume than the other activating agents; micropores were mainly generated during the process. Finally, different carrier gases were added during the activation in order to study their influence on the pore opening behavior of CNFs. It was found that the activation degree increased in the following order: Ar

Indoor air pollution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, D.R.

1992-06-01

This article summarizes the health effects of indoor air pollutants and the modalities available to control them. The pollutants discussed include active and passive exposure to tobacco smoke; combustion products of carbon monoxide; nitrogen dioxide; products of biofuels, including wood and coal; biologic agents leading to immune responses, such as house dust mites, cockroaches, fungi, animal dander, and urine; biologic agents associated with infection such as Legionella and tuberculosis; formaldehyde; and volatile organic compounds. An approach to assessing building-related illness and tight building' syndrome is presented. Finally, the article reviews recent data on hospital-related asthma and exposures to potential respiratorymore » hazards such as antineoplastic agents, anesthetic gases, and ethylene oxide.88 references.« less

Collagenase Santyl ointment: a selective agent for wound debridement.

PubMed

Shi, Lei; Carson, Dennis

2009-01-01

Enzymatic debridement is a frequently used technique for removal of necrotic tissue from wounds. Proteases with specificity to break down the collagenous materials in necrotic tissues can achieve selective debridement, digesting denatured collagen in eschar while sparing nonnecrotic tissues. This article provides information about the selectivity of a collagenase-based debriding agent, including evidence of its safe and efficacious uses. Recent research has been conducted, investigating the chemical and biological properties of collagenase ointment, including healing in animal models, digestion power on different collagen types, cell migration activity from collagen degradation products, and compatibility with various wound dressings and metal ions. Evidence presented demonstrates that collagenase ointment is an effective, selective, and safe wound debriding agent.

Design and Implementation of Context-Aware Musuem Guide Agents

NASA Astrophysics Data System (ADS)

Satoh, Ichiro

This paper presents an agent-based system for building and operating context-aware services in public spaces, including museums. The system provides users with agents and detects the locations of users and deploys location-aware user-assistant agents at computers near the their current locations by using active RFID-tags. When a visitor moves between exhibits in a museum, this dynamically deploys his/her agent at the computers close to the exhibits by using mobile agent technology. It annotates the exhibits in his/her personalized form and navigate him/her user to the next exhibits along his/her routes. It also introduces user movement as a natural approach to interacting between users and agents. To demonstrate the utility and effectiveness of the system, we constructed location/user-aware visitor-guide services and experimented them for two weeks in a public museum.

[Obesity: a review of currently used antiobesity drugs and new compounds in clinical development].

PubMed

Zieba, Remigiusz

2007-10-19

This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed. Rimonabant is an endocannabinoid CB1 receptor antagonist which induces a 4-5 kg mean weight loss and improves glycemic and lipid profiles, but it induces anxiety and depressive disorders. Unfortunately, there are no data on the chronic administration of these drugs. Other drugs can induce weight loss, e.g. some antidepressants, antiseizure agents, and antidiabetic drugs. The moderate efficacy of currently used antiobesity drugs has led to an intense effort to identify new, safe antiobesity drugs with better therapeutic profiles. The new antiobesity drugs under clinical development include: 1) agents that affect neurotransmitters in the central nervous system, including noradrenaline and dopamine reuptake inhibitors (bupropion, radafaxine), selective 5HT2C receptor agonists (lorcaserin), and selective 5HT6 receptor antagonists, 2) agents that modulate the activity of neuropeptides influencing food intake, including leptin analogues, human ciliary neurotrophic factor (Axokine), neuropeptide Y antagonists, and melanine-concentrating hormone antagonists, 3) agents that affect the peripheral satiety signals and brain-gut axis, e.g. selective cholecystokinin receptor A agonists, PYY3-36, agents decreasing ghrelin activity, 4) thermogenic agents, e.g. selective beta3 receptor agonists and selective thyroid hormone receptor beta agonists, and 5) others, e.g. human growth hormone fragment (AOD9604) and gastrointestinal lipase inhibitor (cetilistat).

A fluorogenic near-infrared imaging agent for quantifying plasma and local tissue renin activity in vivo and ex vivo

PubMed Central

Zhang, Jun; Preda, Dorin V.; Vasquez, Kristine O.; Morin, Jeff; Delaney, Jeannine; Bao, Bagna; Percival, M. David; Xu, Daigen; McKay, Dan; Klimas, Michael; Bednar, Bohumil; Sur, Cyrille; Gao, David Z.; Madden, Karen; Yared, Wael; Rajopadhye, Milind

2012-01-01

The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a renin-activatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments. PMID:22674025

Adenylate Kinase Release as a High-Throughput-Screening-Compatible Reporter of Bacterial Lysis for Identification of Antibacterial Agents

PubMed Central

Jacobs, Anna C.; DiDone, Louis; Jobson, Jennielle; Sofia, Madeline K.

2013-01-01

Adenylate kinase (AK) is a ubiquitous intracellular enzyme that is released into the extracellular space upon cell lysis. We have shown that AK release serves as a useful reporter of bactericidal agent activity and can be exploited for antimicrobial screening purposes. The AK assay exhibits improved sensitivity over that of growth-based assays and can detect agents that are active against bacteria in clinically relevant growth states that are difficult to screen using conventional approaches, such as small colony variants (SCV) and bacteria within established biofilms. The usefulness of the AK assay was validated by screening a library of off-patent drugs for agents that exhibit antimicrobial properties toward a variety of bacterial species, including Escherichia coli and all members of the “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The assay detected antibiotics within the library that were expected to be active against the organism screened. Moreover, 38 drugs with no previously reported antibacterial activity elicited AK release. Four of these were acquired, and all were verified to exhibit antimicrobial activity by standard susceptibility testing. Two of these molecules were further characterized. The antihistamine, terfenadine, was active against S. aureus planktonic, SCV population, and biofilm-associated cells. Tamoxifen, an estrogen receptor antagonist, was active toward E. faecium in vitro and also reduced E. faecium pathogenesis in a Galleria mellonella infection model. Our data demonstrate that the AK assay provides an attractive screening approach for identifying new antimicrobial agents. Further, terfenadine and tamoxifen may represent novel antimicrobial drug development scaffolds. PMID:23027196

The standoff aerosol active signature testbed (SAAST) at MIT Lincoln Laboratory

NASA Astrophysics Data System (ADS)

Richardson, Jonathan M.; Aldridge, John C.

2005-11-01

Standoff LIDAR detection of BW agents depends on accurate knowledge of the infrared and ultraviolet optical elastic scatter (ES) and ultraviolet fluorescence (UVF) signatures of bio-agents and interferents. MIT Lincoln Laboratory has developed the Standoff Aerosol Active Signature Testbed (SAAST) for measuring ES cross sections from BW simulants and interferents at all angles including 180º (direct backscatter). Measurements of interest include the dependence of the ES and UVF signatures on several spore production parameters including growth medium, sporulation protocol, washing protocol, fluidizing additives, and degree of aggregation. Using SAAST, we have made measurements of the ES signature of Bacillus globigii (atropheaus, Bg) spores grown under different growth methods. We have also investigated one common interferent (Arizona Test Dust). Future samples will include pollen and diesel exhaust. This paper presents the details of the SAAST apparatus along with the results of recent measurements.

A Potential Adjuvant Agent of Chemotherapy: Sepia Ink Polysaccharides

PubMed Central

Li, Fangping; Luo, Ping; Liu, Huazhong

2018-01-01

Sepia ink polysaccharide (SIP) isolated from squid and cuttlefish ink is a kind of acid mucopolysaccharide that has been identified in three types of primary structures from squid (Illex argentinus and Ommastrephes bartrami), cuttlefish Sepiella maindroni, and cuttlefish Sepia esculenta ink. Although SIP has been proved to be multifaceted, most of the reported evidence has illuminated its chemopreventive and antineoplastic activities. As a natural product playing a role in cancer treatment, SIP may be used as chemotherapeutic ancillary agent or functional food. Based on the current findings on SIP, we have summarized four topics in this review, including: chemopreventive, antineoplastic, chemosensitive, and procoagulant and anticoagulant activities, which are correlative closely with the actions of anticancer agents on cancer patients, such as anticancer, toxicity and thrombogenesis, with the latter two actions being common causes of death in cancer cases exposed to chemotherapeutic agents. PMID:29597272

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadav, N.; Kumar, S.; Marlowe, T.

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

DOE PAGES

Yadav, N.; Kumar, S.; Marlowe, T.; ...

2015-11-05

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.« less

Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations.

PubMed

Mutyam, Venkateshwar; Du, Ming; Xue, Xiaojiao; Keeling, Kim M; White, E Lucile; Bostwick, J Robert; Rasmussen, Lynn; Liu, Bo; Mazur, Marina; Hong, Jeong S; Falk Libby, Emily; Liang, Feng; Shang, Haibo; Mense, Martin; Suto, Mark J; Bedwell, David M; Rowe, Steven M

2016-11-01

Premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF). Several agents are known to suppress PTCs but are poorly efficacious or toxic. To determine whether there are clinically available agents that elicit translational readthrough and improve CFTR function sufficient to confer therapeutic benefit to patients with CF with PTCs. Two independent screens, firefly luciferase and CFTR-mediated transepithelial chloride conductance assay, were performed on a library of 1,600 clinically approved compounds using fisher rat thyroid cells stably transfected with stop codons. Select agents were further evaluated using secondary screening assays including short circuit current analysis on primary cells from patients with CF. In addition, the effect of CFTR modulators (ivacaftor) was tested in combination with the most efficacious agents. From the primary screen, 48 agents were selected as potentially active. Following confirmatory tests in the transepithelial chloride conductance assay and prioritizing agents based on favorable pharmacologic properties, eight agents were advanced for secondary screening. Ivacaftor significantly increased short circuit current following forskolin stimulation in cells treated with pyranoradine tetraphosphate, potassium p-aminobenzoate, and escin as compared with vehicle control. Escin, an herbal agent, consistently induced readthrough activity as demonstrated by enhanced CFTR expression and function in vitro. Clinically approved drugs identified as potential readthrough agents, in combination with ivacaftor, may induce nonsense suppression to restore therapeutic levels of CFTR function. One or more agents may be suitable to advance to human testing.

Preapproval and postapproval availability of published comparative efficacy research on biological agents.

PubMed

Thomas, Rachel Hutchins; Freeman, Maisha Kelly; Hughes, Peter J

2013-07-15

Preapproval and postapproval availability of published comparative efficacy studies on biological agents approved between 2000 and 2010 was investigated. Approval packages published on the Food and Drug Administration (FDA) website were examined for all biological agents approved between 2000 and 2010 to determine if comparative efficacy studies were available at the time of FDA approval. The availability of comparative efficacy studies published subsequent to approval was determined by searching PubMed for randomized, active-controlled experimental or observational study designs that measured efficacy as the primary endpoint and were relevant to the original FDA-approved indication. From 2000 to 2010, 107 biological agents were approved by FDA. Of the biological agents with alternative treatments, 54.6% had comparative efficacy data available at the time of approval. Although standard-reviewed biological agents were more likely to have comparative efficacy trials included in the FDA approval packages than priority-reviewed biological agents, statistically significant differences are unlikely. Subsequent to approval, 58.1% of biological agents had at least one published comparative efficacy trial, representing a 3.5% absolute increase in the availability of comparative efficacy studies since the time of approval. Vaccines and biological agents in the hematologic diseases, oncology, and miscellaneous diseases classes had fewer published postapproval comparative efficacy studies per agent compared with the overall group of biological agents. Nearly half of all biological agents approved for marketing between 2000 and 2010 lacked publicly accessible, active-controlled efficacy studies at the time of drug approval; a slightly greater proportion of biological agents had comparative efficacy data published subsequent to their approval.

Role of Combination Antimicrobial Therapy for Vancomycin-Resistant Enterococcus faecium Infections: Review of the Current Evidence.

PubMed

Yim, Juwon; Smith, Jordan R; Rybak, Michael J

2017-05-01

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed. © 2017 Pharmacotherapy Publications, Inc.

Mind your salts: when the inactive constituent isn't.

PubMed

Neubig, Richard R

2010-10-01

Many pharmacological agents include "inactive" constituents that are used to alter the solubility, stability, or pharmaceutical properties of a drug. These "salts" are often ignored, and the "active ingredient" gets all of the attention. Pamoic acid (4-[(3-carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid) has been used in formulations of several drugs as pamoate salts. This Perspective highlights an Accelerated Communication in this issue (p. 560) that identifies pamoic acid as a potent activator of the orphan G protein-coupled receptor GPR35. This effect may contribute to the pharmacological actions of some agents that are prepared as pamoate salts. Thus, pharmacologists, regulators, and clinicians should "mind their salts" in considering differences among supposedly equivalent agents.

The effect of antimicrobial agents on bond strength of orthodontic adhesives: a meta-analysis of in vitro studies.

PubMed

Altmann, A S P; Collares, F M; Leitune, V C B; Samuel, S M W

2016-02-01

Antimicrobial orthodontic adhesives aim to reduce white spot lesions' incidence in orthodontic patients, but they should not jeopardizing its properties. Systematic review and meta-analysis were performed to answer the question whether the association of antimicrobial agents with orthodontic adhesives compromises its mechanical properties and whether there is a superior antimicrobial agent. PubMed and Scopus databases. In vitro studies comparing shear bond strength of conventional photo-activated orthodontic adhesives to antimicrobial photo-activated orthodontic adhesives were considered eligible. Search terms included the following: orthodontics, orthodontic, antimicrobial, antibacterial, bactericidal, adhesive, resin, resin composite, bonding agent, bonding system, and bond strength. The searches yielded 494 citations, which turned into 467 after duplicates were discarded. Titles and abstracts were read and 13 publications were selected for full-text reading. Twelve studies were included in the meta-analysis. The global analysis showed no statistically significant difference between control and experimental groups. In the subgroup analysis, only the chlorhexidine subgroup showed a statistically significant difference, where the control groups had higher bond strength than the experimental groups. Many studies on in vitro orthodontic bond strength fail to report test conditions that could affect their outcomes. The pooled in vitro data suggest that adding an antimicrobial agent to an orthodontic adhesive system does not influence bond strength to enamel. It is not possible to state which antimicrobial agent is better to be associated. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mannich bases in medicinal chemistry and drug design.

PubMed

Roman, Gheorghe

2015-01-07

The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. The review covers extensively the literature reports that have disclosed Mannich bases as anticancer and cytotoxic agents, or compounds with potential antibacterial and antifungal activity in the last decade. The most relevant studies on the activity of Mannich bases as antimycobacterial agents, antimalarials, or antiviral candidates have been included as well. The review contains also a thorough coverage of anticonvulsant, anti-inflammatory, analgesic and antioxidant activities of Mannich bases. In addition, several minor biological activities of Mannich bases, such as their ability to regulate blood pressure or inhibit platelet aggregation, their antiparasitic and anti-ulcer effects, as well as their use as agents for the treatment of mental disorders have been presented. The review gives in the end a brief overview of the potential of Mannich bases as inhibitors of various enzymes or ligands for several receptors. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Information for Successful Interaction with Autonomous Systems

NASA Technical Reports Server (NTRS)

Malin, Jane T.; Johnson, Kathy A.

2003-01-01

Interaction in heterogeneous mission operations teams is not well matched to classical models of coordination with autonomous systems. We describe methods of loose coordination and information management in mission operations. We describe an information agent and information management tool suite for managing information from many sources, including autonomous agents. We present an integrated model of levels of complexity of agent and human behavior, which shows types of information processing and points of potential error in agent activities. We discuss the types of information needed for diagnosing problems and planning interactions with an autonomous system. We discuss types of coordination for which designs are needed for autonomous system functions.

Enhancing biological control of basal stem rot disease (Ganoderma boninense) in oil palm plantations.

PubMed

Susanto, A; Sudharto, P S; Purba, R Y

2005-01-01

Basal Stem Rot (BSR) disease caused by Ganoderma boninense is the most destructive disease in oil palm, especially in Indonesia and Malaysia. The available control measures for BSR disease such as cultural practices and mechanical and chemical treatment have not proved satisfactory due to the fact that Ganoderma has various resting stages such as melanised mycelium, basidiospores and pseudosclerotia. Alternative control measures to overcome the Ganoderma problem are focused on the use of biological control agents and planting resistant material. Present studies conducted at Indonesian Oil Palm Research Institute (IOPRI) are focused on enhancing the use of biological control agents for Ganoderma. These activities include screening biological agents from the oil palm rhizosphere in order to evaluate their effectiveness as biological agents in glasshouse and field trials, testing their antagonistic activities in large scale experiments and eradicating potential disease inoculum with biological agents. Several promising biological agents have been isolated, mainly Trichoderma harzianum, T. viride, Gliocladium viride, Pseudomonas fluorescens, and Bacillus sp. A glasshouse and field trial for Ganoderma control indicated that treatment with T. harzianum and G. viride was superior to Bacillus sp. A large scale trial showed that the disease incidence was lower in a field treated with biological agents than in untreated fields. In a short term programme, research activities at IOPRI are currently focusing on selecting fungi that can completely degrade plant material in order to eradicate inoculum. Digging holes around the palm bole and adding empty fruit bunches have been investigated as ways to stimulate biological agents.

Failures in Phase III: Causes and Consequences.

PubMed

Seruga, Bostjan; Ocana, Alberto; Amir, Eitan; Tannock, Ian F

2015-10-15

Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients. ©2015 American Association for Cancer Research.

A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.

PubMed

Herter, Sylvia; Morra, Laura; Schlenker, Ramona; Sulcova, Jitka; Fahrni, Linda; Waldhauer, Inja; Lehmann, Steffi; Reisländer, Timo; Agarkova, Irina; Kelm, Jens M; Klein, Christian; Umana, Pablo; Bacac, Marina

2017-01-01

The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor-host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB). Following treatment with IgG-IL2v, activation of T cells, NK cells, and NKT cells was demonstrated by increased expression of the activation marker CD69 and enhanced cytokine secretion. The combination of TCBs with IgG-IL2v molecules was more effective than monotherapy, as shown by enhanced effects on immune cell infiltration; activation; increased cytokine secretion; and faster, more efficient elimination of targeted cells. This study demonstrates that the 3D heterotypic spheroid model provides a novel and versatile tool for in vitro evaluation of cancer immunotherapy agents and allows for assessment of additional aspects of the activity of cancer immunotherapy agents, including analysis of immune cell infiltration and drug targeting.

Antimicrobial Substances for Food Packaging Products: The Current Situation.

PubMed

Pellerito, Alessandra; Ameen, Sara M; Micali, Maria; Caruso, Giorgia

2018-04-04

Antimicrobial substances are widely used in many anthropic activities, including sanitary and military services for the human population. These compounds are also known to be used in food production, agricultural activities, and partially correlated industrial sectors. However, there are concerns regarding the link between the abuse of antimicrobial agents in these ambits and the possible detection of antibiotic-resistant microorganisms. Modern food and beverage products are generally found on the market as prepackaged units, with several exceptions. Consequently, positive and negative features of a specific food or beverage should be considered as the result of the synergic action of different components, including the container (or the assembled sum of packaging materials). At present, the meaning of food container also includes the creation and development of new packaging materials that are potentially able to interact with the contained food. "Active" packaging systems can be realized with antimicrobial substances. On the other hand, a careful evaluation of risks and advantages correlated with antimicrobial agents is needed because of possible negative and/or unexpected failures.

Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture.

PubMed

Deng, Liting; Ng, Lindsay; Ozawa, Tatsuya; Stella, Nephi

2017-01-01

Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Discovery and Development of Natural Product-derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach⊥†

PubMed Central

Lee, Kuo-Hsiung

2010-01-01

Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed. PMID:20187635

Redox-activated MRI contrast agents based on lanthanide and transition metal ions.

PubMed

Tsitovich, Pavel B; Burns, Patrick J; McKay, Adam M; Morrow, Janet R

2014-04-01

The reduction/oxidation (redox) potential of tissue is tightly regulated in order to maintain normal physiological processes, but is disrupted in disease states. Thus, the development of new tools to map tissue redox potential may be clinically important for the diagnosis of diseases that lead to redox imbalances. One promising area of chemical research is the development of redox-activated probes for mapping tissue through magnetic resonance imaging (MRI). In this review, we summarize several strategies for the design of redox-responsive MRI contrast agents. Our emphasis is on both lanthanide(III) and transition metal(II/III) ion complexes that provide contrast either as T1 relaxivity MRI contrast agents or as paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents. These agents are redox-triggered by a variety of chemical reactions or switches including redox-activated thiol groups, and heterocyclic groups that interact with the metal ion or influence properties of other ancillary ligands. Metal ion centered redox is an approach which is ripe for development by coordination chemists. Redox-triggered metal ion approaches have great potential for creating large differences in magnetic properties that lead to changes in contrast. An attractive feature of these agents is the ease of fine-tuning the metal ion redox potential over a biologically relevant range. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparative effectiveness of fourth-line anti-hypertensive agents in resistant hypertension: A systematic review and meta-analysis.

PubMed

Sinnott, Sarah-Jo; Tomlinson, Laurie A; Root, Adrian A; Mathur, Rohini; Mansfield, Kathryn E; Smeeth, Liam; Douglas, Ian J

2017-02-01

Aim We assessed the effectiveness of fourth-line mineralocorticoid receptor antagonists in comparison with other fourth-line anti-hypertensive agents in resistant hypertension. Methods and results We systematically searched Medline, EMBASE and the Cochrane library from database inception until January 2016. We included randomised and non-randomised studies that compared mineralocorticoid receptor antagonists with other fourth-line anti-hypertensive agents in patients with resistant hypertension. The outcome was change in systolic blood pressure, measured in the office, at home or by ambulatory blood pressure monitoring. Secondary outcomes were changes in serum potassium and occurrence of hyperkalaemia. We used random effects models and assessed statistical heterogeneity using the I 2 test and corresponding 95% confidence intervals. From 2,506 records, 5 studies met our inclusion criteria with 755 included patients. Two studies were randomised and three were non-randomised. Comparative fourth-line agents included bisoprolol, doxazosin, furosemide and additional blockade of the renin angiotensin-aldosterone system. Using data from randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 7.4 mmHg (95%CI 3.2 - 11.6) more than the active comparator. When limited to non-randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 11.9 mmHg (95% CI 9.3 - 14.4) more than the active comparator. Conclusion On the basis of this meta-analysis, mineralocorticoid receptor antagonists reduce blood pressure more effectively than other fourth-line agents in resistant hypertension. Effectiveness stratified by ethnicity and comorbidities, in addition to information on clinical outcomes such as myocardial infarction and stroke, now needs to be determined.

An in vitro time-kill assessment of linezolid and anaerobic bacteria.

PubMed

Yagi, Betty H; Zurenko, Gary E

2003-02-01

Linezolid is a novel oxazolidinone antibacterial agent active against staphylococci (including methicillin-resistant strains), enterococci (including vancomycin-resistant strains), streptococci (including penicillin-intermediate and -resistant Streptococcus pneumoniae), and other aerobic and facultative bacteria. The agent has also demonstrated activity against a broad spectrum of Gram-positive and Gram-negative anaerobic bacteria. Previous time-kill assessments have shown linezolid to be generally bacteriostatic against staphylococci and enterococci, and bactericidal against streptococci. In this study, an anaerobic glovebox technique was employed to conduct time-kill assessments for four strains of anaerobic Gram-positive, and seven strains of anaerobic Gram-negative bacteria. The time-kill experiment was performed using Anaerobe Broth medium. The drugs were tested at four-fold the minimum inhibitory concentration (MIC), or at the higher concentration of 8mg/L for linezolid, 2mg/L for clindamycin, and 8mg/L for metronidazole. Samples for viable count were taken at 0, 6, and 24h, and plated using the Bioscience International Autospiral DW. Exposure of samples to the aerobic environment during plating was held to less than 30min. Plates were counted after a 48h anaerobic incubation (37 degrees C). The species tested included Bacteroides fragilis (2), B. distasonis, B. thetaiotaomicron, Fusobacterium nucleatum, F. varium, Prevotella melaninogenica, Clostridium perfringens, Eubacterium lentum and Peptostreptococcus anaerobius (2). The activity of linezolid was compared to that of metronidazole and clindamycin, two standard anti-anaerobe agents. As expected, the control agents were very active in these assays. Metronidazole yielded log(10)CFU/mL reductions of 3.0 or greater for nine of ten strains; clindamycin yielded log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for three strains. Linezolid also produced significant in vitro killing in this model achieving log(10)CFU/mL reductions of 2.0 or greater for six of 11 strains, and 3.0 or greater for four strains. The profile of activity was similar to that of clindamycin indicating that additional developmental studies of linezolid with anaerobic bacteria are warranted.

The effect of surface tension reduction on the clinical performance of sodium hypochlorite in endodontics.

PubMed

Rossi-Fedele, G; Prichard, J W; Steier, L; de Figueiredo, J A P

2013-06-01

Sodium hypochlorite (NaOCl) is recommended as an endodontic irrigant in view of its broad antimicrobial and tissue dissolution capacities. To enhance its penetration into inaccessible areas of root canals and to improve its overall effect, the addition of surface-active agents has been suggested. The aim of this investigation was to review the effect of the reduction of the surface tension on the performance of NaOCl in endodontics. A search was performed in the Medline electronic database (articles published up to 28 July 2012, in English) with the search terms and combinations as follows: 'sodium hypochlorite AND surface tension or interfacial force or interfacial tension or surface-active agent or amphiphilic agent or surface active agent or surfactant or tenside or detergent'. The purpose of this search was to identify publications that compared NaOCl alone and NaOCl modified with the addition of a surface-active agent in endodontics. A hand search of articles published online ('in-press' and 'early view'), and appearing in the reference list of the articles included, was further performed, using the same search criteria as the electronic search. The search identified 302 publications, of which 11 fulfilled the inclusion/exclusion criteria of the review. The evidence available suggests that surface-active agents improve the penetration of NaOCl in the main canal and have no effect on its pulp tissue dissolution ability. There are, however, insufficient data to enable a sound conclusion to be drawn regarding the effect of modifying NaOCl's surface tension on lubrication, antimicrobial and smear layer or debris removal abilities. © 2012 International Endodontic Journal.

The development of GADD45α luciferase reporter assays in human cells for assessing the genotoxicity of environmental pollutants.

PubMed

Xin, Lili; Wang, Jianshu; Wu, Yanhu; Guo, Sifan

2015-02-01

In order to assess the potential carcinogenic and genotoxic responses induced by environmental pollutants, genotoxicity test systems based on a GADD45α promoter-driven luciferase reporter in human A549 and HepG2 cells were established. Four different types of environmental toxicants including DNA alkylating agents, precarcinogenic agents, DNA cross-linking agents and non-carcinogenic agents, and three environmental samples collected from a coke oven plant were used to evaluate the test systems. After treated with the tested agents and environmental samples for 12 h, the cell viabilities and luciferase activities of the luciferase reporter cells were determined, respectively. Methyl methanesulfonate, benzo[a]pyrene, formaldehyde and the extractable organic matter (EOM) from coke oven emissions in ambient air generally produced significant induction of relative luciferase activity in a similar dose-dependent manner in A549- and HepG2-luciferase cells. No significant increases in relative luciferase activity were observed in pyrene-treated A549- or HepG2-luciferase cells. Significant increase in relative luciferase activity was already evident after 2.5 µM benzo[a]pyrene, 5 µM formaldehyde, 0.006 µg/L bottom-EOM, 0.10 µg/L side-EOM or 0.06 µg/L top-EOM, where no cytotoxic damage was observed. Compared with the A549-luciferase cells, the tested pollutants produced higher induction of relative luciferase activity in HepG2-luciferase cells. Therefore, the new genotoxicity test systems can detect different types of genotoxic agents and low concentrations of environmental samples. The luciferase reporter cells, especially the HepG2-luciferase cells, could provide a valuable tool for rapid screening of the genotoxic damage of environmental pollutants and their complex mixtures.

Next Generation Remote Agent Planner

NASA Technical Reports Server (NTRS)

Jonsson, Ari K.; Muscettola, Nicola; Morris, Paul H.; Rajan, Kanna

1999-01-01

In May 1999, as part of a unique technology validation experiment onboard the Deep Space One spacecraft, the Remote Agent became the first complete autonomous spacecraft control architecture to run as flight software onboard an active spacecraft. As one of the three components of the architecture, the Remote Agent Planner had the task of laying out the course of action to be taken, which included activities such as turning, thrusting, data gathering, and communicating. Building on the successful approach developed for the Remote Agent Planner, the Next Generation Remote Agent Planner is a completely redesigned and reimplemented version of the planner. The new system provides all the key capabilities of the original planner, while adding functionality, improving performance and providing a modular and extendible implementation. The goal of this ongoing project is to develop a system that provides both a basis for future applications and a framework for further research in the area of autonomous planning for spacecraft. In this article, we present an introductory overview of the Next Generation Remote Agent Planner. We present a new and simplified definition of the planning problem, describe the basics of the planning process, lay out the new system design and examine the functionality of the core reasoning module.

Histone deacetylase inhibitors: current status and overview of recent clinical trials.

PubMed

Ma, Xujun; Ezzeldin, Hany H; Diasio, Robert B

2009-10-01

Histone deacetylase (HDAC) inhibitors are a new group of anticancer agents that have a potential role in the regulation of gene expression, induction of cell death, apoptosis and cell cycle arrest of cancer cells by altering the acetylation status of chromatin and other non-histone proteins. In clinical trials, HDAC inhibitors have demonstrated promising antitumour activity as monotherapy in cutaneous T-cell lymphoma and other haematological malignancies. In solid tumours, several HDAC inhibitors have been shown to be efficacious as single agents; however, results of most clinical trials were in favour of using HDAC inhibitors either prior to the initiation of chemotherapy or in combination with other treatments. Currently, the molecular basis of response to HDAC inhibitors in patients is not fully understood. In this review, we summarize the current status of HDAC inhibitors, as single agents or in combination with other agents in different phases of clinical trials. In most of the clinical trials, HDAC inhibitors were tolerable and exerted biological or antitumor activity. HDAC inhibitors have been studied in phase I, II and III clinical trials with variable efficacy. The combination of HDAC inhibitors with other anticancer agents including epigenetic or chemotherapeutic agents demonstrated favourable clinical outcome.

Agent-based modeling as a tool for program design and evaluation.

PubMed

Lawlor, Jennifer A; McGirr, Sara

2017-12-01

Recently, systems thinking and systems science approaches have gained popularity in the field of evaluation; however, there has been relatively little exploration of how evaluators could use quantitative tools to assist in the implementation of systems approaches therein. The purpose of this paper is to explore potential uses of one such quantitative tool, agent-based modeling, in evaluation practice. To this end, we define agent-based modeling and offer potential uses for it in typical evaluation activities, including: engaging stakeholders, selecting an intervention, modeling program theory, setting performance targets, and interpreting evaluation results. We provide demonstrative examples from published agent-based modeling efforts both inside and outside the field of evaluation for each of the evaluative activities discussed. We further describe potential pitfalls of this tool and offer cautions for evaluators who may chose to implement it in their practice. Finally, the article concludes with a discussion of the future of agent-based modeling in evaluation practice and a call for more formal exploration of this tool as well as other approaches to simulation modeling in the field. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI).

PubMed

Bonhomme, V; Boveroux, P; Brichant, J F; Laureys, S; Boly, M

2012-01-01

This paper reviews the current knowledge about the mechanisms of anesthesia-induced alteration of consciousness. It is now evident that hypnotic anesthetic agents have specific brain targets whose function is hierarchically altered in a dose-dependent manner. Higher order networks, thought to be involved in mental content generation, as well as sub-cortical networks involved in thalamic activity regulation seems to be affected first by increasing concentrations of hypnotic agents that enhance inhibitory neurotransmission. Lower order sensory networks are preserved, including thalamo-cortical connectivity into those networks, even at concentrations that suppress responsiveness, but cross-modal sensory interactions are inhibited. Thalamo-cortical connectivity into the consciousness networks decreases with increasing concentrations of those agents, and is transformed into an anti-correlated activity between the thalamus and the cortex for the deepest levels of sedation, when the subject is non responsive. Future will tell us whether these brain function alterations are also observed with hypnotic agents that mainly inhibit excitatory neurotransmission. The link between the observations made using fMRI and the identified biochemical targets of hypnotic anesthetic agents still remains to be identified.

Modeling Radicalization Phenomena in Heterogeneous Populations.

PubMed

Galam, Serge; Javarone, Marco Alberto

2016-01-01

The phenomenon of radicalization is investigated within a mixed population composed of core and sensitive subpopulations. The latest includes first to third generation immigrants. Respective ways of life may be partially incompatible. In case of a conflict core agents behave as inflexible about the issue. In contrast, sensitive agents can decide either to live peacefully adjusting their way of life to the core one, or to oppose it with eventually joining violent activities. The interplay dynamics between peaceful and opponent sensitive agents is driven by pairwise interactions. These interactions occur both within the sensitive population and by mixing with core agents. The update process is monitored using a Lotka-Volterra-like Ordinary Differential Equation. Given an initial tiny minority of opponents that coexist with both inflexible and peaceful agents, we investigate implications on the emergence of radicalization. Opponents try to turn peaceful agents to opponents driving radicalization. However, inflexible core agents may step in to bring back opponents to a peaceful choice thus weakening the phenomenon. The required minimum individual core involvement to actually curb radicalization is calculated. It is found to be a function of both the majority or minority status of the sensitive subpopulation with respect to the core subpopulation and the degree of activeness of opponents. The results highlight the instrumental role core agents can have to hinder radicalization within the sensitive subpopulation. Some hints are outlined to favor novel public policies towards social integration.

Modeling Radicalization Phenomena in Heterogeneous Populations

PubMed Central

2016-01-01

The phenomenon of radicalization is investigated within a mixed population composed of core and sensitive subpopulations. The latest includes first to third generation immigrants. Respective ways of life may be partially incompatible. In case of a conflict core agents behave as inflexible about the issue. In contrast, sensitive agents can decide either to live peacefully adjusting their way of life to the core one, or to oppose it with eventually joining violent activities. The interplay dynamics between peaceful and opponent sensitive agents is driven by pairwise interactions. These interactions occur both within the sensitive population and by mixing with core agents. The update process is monitored using a Lotka-Volterra-like Ordinary Differential Equation. Given an initial tiny minority of opponents that coexist with both inflexible and peaceful agents, we investigate implications on the emergence of radicalization. Opponents try to turn peaceful agents to opponents driving radicalization. However, inflexible core agents may step in to bring back opponents to a peaceful choice thus weakening the phenomenon. The required minimum individual core involvement to actually curb radicalization is calculated. It is found to be a function of both the majority or minority status of the sensitive subpopulation with respect to the core subpopulation and the degree of activeness of opponents. The results highlight the instrumental role core agents can have to hinder radicalization within the sensitive subpopulation. Some hints are outlined to favor novel public policies towards social integration. PMID:27166677

Linking JNK Activity to the DNA Damage Response

PubMed Central

Picco, Vincent

2013-01-01

The activity of c-Jun N-terminal kinase (JNK) was initially described as ultraviolet- and oncogene-induced kinase activity on c-Jun. Shortly after this initial discovery, JNK activation was reported for a wider variety of DNA-damaging agents, including γ-irradiation and chemotherapeutic compounds. As the DNA damage response mechanisms were progressively uncovered, the mechanisms governing the activation of JNK upon genotoxic stresses became better understood. In particular, a recent set of papers links the physical breakage in DNA, the activation of the transcription factor NF-κB, the secretion of TNF-α, and an autocrine activation of the JNK pathway. In this review, we will focus on the pathway that is initiated by a physical break in the DNA helix, leading to JNK activation and the resultant cellular consequences. The implications of these findings will be discussed in the context of cancer therapy with DNA-damaging agents. PMID:24349633

Natural Organohalogens: A New Frontier for Medicinal Agents?

ERIC Educational Resources Information Center

Gribble, Gordon W.

2004-01-01

Newly discovered biogenic organo halogens with an emphasis on the biologically active examples from marine organisms, bacteria, terrestrial plants and higher life forms, including humans, are focused. Organohalogen compounds represent a valuable and expanding class of natural products, in many cases boasting exceptional biological activity.

Effect of glycation on α-crystallin structure and chaperone-like function

PubMed Central

Kumar, P. Anil; Kumar, M. Satish; Reddy, G. Bhanuprakash

2007-01-01

The chaperone-like activity of α-crystallin is considered to play an important role in the maintenance of the transparency of the eye lens. However, in the case of aging and in diabetes, the chaperone function of α-crystallin is compromized, resulting in cataract formation. Several post-translational modifications, including non-enzymatic glycation, have been shown to affect the chaperone function of α-crystallin in aging and in diabetes. A variety of agents have been identified as the predominant sources for the formation of AGEs (advanced glycation end-products) in various tissues, including the lens. Nevertheless, glycation of α-crystallin with various sugars has resulted in divergent results. In the present in vitro study, we have investigated the effect of glucose, fructose, G6P (glucose 6-phosphate) and MGO (methylglyoxal), which represent the major classes of glycating agents, on the structure and chaperone function of α-crystallin. Modification of α-crystallin with all four agents resulted in the formation of glycated protein, increased AGE fluorescence, protein cross-linking and HMM (high-molecular-mass) aggregation. Interestingly, these glycation-related profiles were found to vary with different glycating agents. For instance, CML [Nϵ-(carboxymethyl)lysine] was the predominant AGE formed upon glycation of α-crystallin with these agents. Although fructose and MGO caused significant conformational changes, there were no significant structural perturbations with glucose and G6P. With the exception of MGO modification, glycation with other sugars resulted in decreased chaperone activity in aggregation assays. However, modification with all four sugars led to the loss of chaperone activity as assessed using an enzyme inactivation assay. Glycation-induced loss of α-crystallin chaperone activity was associated with decreased hydrophobicity. Furthermore, α-crystallin isolated from glycated TSP (total lens soluble protein) had also increased AGE fluorescence, CML formation and diminished chaperone activity. These results indicate the susceptibility of α-crystallin to non-enzymatic glycation by various sugars and their derivatives, whose levels are elevated in diabetes. We also describes the effects of glycation on the structure and chaperone-like activity of α-crystallin. PMID:17696877

How to Join a Wave: Decision-Making Processes in Shimmering Behavior of Giant Honeybees (Apis dorsata)

PubMed Central

Kastberger, Gerald; Weihmann, Frank; Hoetzl, Thomas; Weiss, Sara E.; Maurer, Michael; Kranner, Ilse

2012-01-01

Shimmering is a collective defence behaviour in Giant honeybees (Apis dorsata) whereby individual bees flip their abdomen upwards, producing Mexican wave-like patterns on the nest surface. Bucket bridging has been used to explain the spread of information in a chain of members including three testable concepts: first, linearity assumes that individual “agent bees” that participate in the wave will be affected preferentially from the side of wave origin. The directed-trigger hypothesis addresses the coincidence of the individual property of trigger direction with the collective property of wave direction. Second, continuity describes the transfer of information without being stopped, delayed or re-routed. The active-neighbours hypothesis assumes coincidence between the direction of the majority of shimmering-active neighbours and the trigger direction of the agents. Third, the graduality hypothesis refers to the interaction between an agent and her active neighbours, assuming a proportional relationship in the strength of abdomen flipping of the agent and her previously active neighbours. Shimmering waves provoked by dummy wasps were recorded with high-resolution video cameras. Individual bees were identified by 3D-image analysis, and their strength of abdominal flipping was assessed by pixel-based luminance changes in sequential frames. For each agent, the directedness of wave propagation was based on wave direction, trigger direction, and the direction of the majority of shimmering-active neighbours. The data supported the bucket bridging hypothesis, but only for a small proportion of agents: linearity was confirmed for 2.5%, continuity for 11.3% and graduality for 0.4% of surface bees (but in 2.6% of those agents with high wave-strength levels). The complimentary part of 90% of surface bees did not conform to bucket bridging. This fuzziness is discussed in terms of self-organisation and evolutionary adaptedness in Giant honeybee colonies to respond to rapidly changing threats such as predatory wasps scanning in front of the nest. PMID:22662123

How to join a wave: decision-making processes in shimmering behavior of Giant honeybees (Apis dorsata).

PubMed

Kastberger, Gerald; Weihmann, Frank; Hoetzl, Thomas; Weiss, Sara E; Maurer, Michael; Kranner, Ilse

2012-01-01

Shimmering is a collective defence behaviour in Giant honeybees (Apis dorsata) whereby individual bees flip their abdomen upwards, producing Mexican wave-like patterns on the nest surface. Bucket bridging has been used to explain the spread of information in a chain of members including three testable concepts: first, linearity assumes that individual "agent bees" that participate in the wave will be affected preferentially from the side of wave origin. The directed-trigger hypothesis addresses the coincidence of the individual property of trigger direction with the collective property of wave direction. Second, continuity describes the transfer of information without being stopped, delayed or re-routed. The active-neighbours hypothesis assumes coincidence between the direction of the majority of shimmering-active neighbours and the trigger direction of the agents. Third, the graduality hypothesis refers to the interaction between an agent and her active neighbours, assuming a proportional relationship in the strength of abdomen flipping of the agent and her previously active neighbours. Shimmering waves provoked by dummy wasps were recorded with high-resolution video cameras. Individual bees were identified by 3D-image analysis, and their strength of abdominal flipping was assessed by pixel-based luminance changes in sequential frames. For each agent, the directedness of wave propagation was based on wave direction, trigger direction, and the direction of the majority of shimmering-active neighbours. The data supported the bucket bridging hypothesis, but only for a small proportion of agents: linearity was confirmed for 2.5%, continuity for 11.3% and graduality for 0.4% of surface bees (but in 2.6% of those agents with high wave-strength levels). The complimentary part of 90% of surface bees did not conform to bucket bridging. This fuzziness is discussed in terms of self-organisation and evolutionary adaptedness in Giant honeybee colonies to respond to rapidly changing threats such as predatory wasps scanning in front of the nest.

Fibrous Filter to Protect Building Environments from Polluting Agents: A Review

NASA Astrophysics Data System (ADS)

Chavhan, Md. Vaseem; Mukhopadhyay, Arunangshu

2016-04-01

This paper discusses the use of fibrous filter to protect the building environments from air born polluting agents and especially of concern chemical, biological and radiological agents. Air-filtration includes removal of particulate from air and toxic gases from air. In air filtration, particulate which are mostly biological and radioactive types of agents can be removed by using mechanical and electrostatic filters. Some biological agents, which cannot be removed by air filtration alone, special techniques like antimicrobial finish, UV germicides, coated filters etc. are required. Biocide agent can be added into the fibre itself by grafting reaction to impart antimicrobial activity. Chemical agents like toxic gases can be removed by integrating adsorbents and sorbents in filters or by fibre modifications. It is also possible to impart catalytic conversion properties into the fibre to remove volatile gasous. Radioactive agents can be removed by particulate filter if present in the form of aerosol or by gas cleaning by the use of specific fibre impregnate.

Processes for making dense, spherical active materials for lithium-ion cells

DOEpatents

Kang, Sun-Ho [Naperville, IL; Amine, Khalil [Downers Grove, IL

2011-11-22

Processes are provided for making dense, spherical mixed-metal carbonate or phosphate precursors that are particularly well suited for the production of active materials for electrochemical devices such as lithium ion secondary batteries. Exemplified methods include precipitating dense, spherical particles of metal carbonates or metal phosphates from a combined aqueous solution using a precipitating agent such as ammonium hydrogen carbonate, sodium hydrogen carbonate, or a mixture that includes sodium hydrogen carbonate. Other exemplified methods include precipitating dense, spherical particles of metal phosphates using a precipitating agent such as ammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, or a mixture of any two or more thereof. Further provided are compositions of and methods of making dense, spherical metal oxides and metal phosphates using the dense, spherical metal precursors. Still further provided are electrodes and batteries using the same.

Anti-ulcer agents: chemical aspect of solving the problem

NASA Astrophysics Data System (ADS)

Rogoza, L. N.; Salakhutdinov, N. F.

2015-01-01

The data on chemical structures and specific activities of compounds functioning as histamine H2-receptor antagonists, H+/K+-ATPase inhibitors at the exchange sites of hydrogen ions (proton pump inhibitors) and potassium ions (K+-competitive acid blockers) published from 1990 to 2013 are surveyed. The antisecretory agents with studied cytoprotective activity or with additional therapeutic properties compensating for disorders of internal defence mechanisms are presented. A separate section is devoted to the drugs that prevent or mitigate the NSAID-induced intestinal damage. All of the considered structures are classified according to the type of biological mechanism of action. Some aspects of the structure-activity relationships for such compounds are considered. The bibliography includes 83 references.

New Drugs and Novel Mechanisms of Action in Multiple Myeloma in 2013: A Report from the International Myeloma Working Group (IMWG)

PubMed Central

Ocio, EM; Richardson, PG; Rajkumar, SV; Palumbo, A; Mateos, MV; Orlowski, R; Kumar, S; Usmani, S; Roodman, D; Niesvizky, R; Einsele, H; Anderson, KC; Dimopoulos, MA; Avet-Loiseau, H; Mellqvist, UH; Turesson, I; Merlini, G; Schots, R; McCarthy, P; Bergsagel, L; Chim, J; Lahuerta, JJ; Shah, J; Reiman, A; Mikhael, J; Zweegman, S; Lonial, S; Comenzo, R; Chng, WJ; Moreau, P; Sonneveld, P; Ludwig, H; Durie, BGM; San Miguel, JF

2014-01-01

Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation- proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors. Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting. PMID:24253022

Emergency management of chemical weapons injuries.

PubMed

Anderson, Peter D

2012-02-01

The potential for chemical weapons to be used in terrorism is a real possibility. Classes of chemical weapons include nerve agents, vesicants (blister agents), choking agents, incapacitating agents, riot control agents, blood agents, and toxic industrial chemicals. The nerve agents work by blocking the actions of acetylcholinesterase leading to a cholinergic syndrome. Nerve agents include sarin, tabun, VX, cyclosarin, and soman. The vesicants include sulfur mustard and lewisite. The vesicants produce blisters and also damage the upper airways. Choking agents include phosgene and chlorine gas. Choking agents cause pulmonary edema. Incapacitating agents include fentanyl and its derivatives and adamsite. Riot control agents include Mace and pepper spray. Blood agents include cyanide. The mechanism of toxicity for cyanide is blocking oxidative phosphorylation. Toxic industrial chemicals include agents such as formaldehyde, hydrofluoric acid, and ammonia.

A primary-school-based study to reduce prevalence of childhood obesity in Catalunya (Spain)--EDAL-Educació en alimentació: study protocol for a randomised controlled trial.

PubMed

Giralt, Montse; Albaladejo, Rosa; Tarro, Lucia; Moriña, David; Arija, Victoria; Solà, Rosa

2011-02-27

The EdAL (Educació en Alimentació) study is a long-term, nutrition educational, primary-school-based program designed to prevent obesity by promoting a healthy lifestyle that includes dietary recommendations and physical activity.The aims are: 1) to evaluate the effects of a 3-year school-based life-style improvement program on the prevalence of obesity in an area of north-west Mediterranean 2) To design a health-promotion program to be implemented by health-promoter agents (university students) in primary schools. 1) The intervention study is a randomised, controlled, school-based program performed by university-student health-promoter agents. Initial pupil enrolment was in 2006 and continued for 3 years. We considered two clusters (designated as cluster A and cluster B) as the units for randomisation. The first cluster involved 24 schools from Reus and the second involved 14 schools from surrounding towns Cambrils, Salou and Vilaseca combined in order to obtain comparable groups. There are very good communications between schools in each town, and to avoid cross influence of the programs resulting from inter-school dialogue, the towns themselves were the unit for randomisation. Data collected included name, gender, date and place of birth at the start of the program and, subsequently, weight, height, body mass index (BMI) and waist circumference every year for 3 years. Questionnaires on eating and physical activity habits are filled-in by the parents at the start and end of the study and, providing that informed consent is given, the data are analysed on the intention-to-treat basis.The interventions are based on 8 nutritional and physical activity objectives. They are implemented by university students as part of the university curriculum in training health-promoter agents. These 8 objectives are developed in 4 educational activities/year for 3 years (a total of 12 activities; 1 h/activity) performed by the health-promoter agents in primary schools. Control pupils follow their usual activities.2) Courses on education and promotion of health, within in the curriculum of medicine and health sciences for university students, are designed to train health-promoter agents to administer these activities in primary schools. This controlled school-based intervention will test the possibility of preventing childhood obesity. ISRCTN: ISRCTN29247645.

Metformin targets multiple signaling pathways in cancer.

PubMed

Lei, Yong; Yi, Yanhua; Liu, Yang; Liu, Xia; Keller, Evan T; Qian, Chao-Nan; Zhang, Jian; Lu, Yi

2017-01-26

Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.

Activation of corn cellulose with alcohols to improve its dissolvability in fabricating ultrafine fibers via electrospinning.

PubMed

Chen, Haizhen; Ni, Jinping; Chen, Jing; Xue, Wenwen; Wang, Jinggang; Na, Haining; Zhu, Jin

2015-06-05

Water and four small molecular alcohols are respectively used to activate corn cellulose (CN cellulose) with the aim to improve the dissolvability in DMAc/LiCl. Among all these activated agents, monohydric alcohols are found to produce the optimal effect of activation in the whole process including of activating, dissolving, and electrospinning of CN cellulose. Meanwhile, well distributed fibers with the diameter of 500nm-2μm are fabricated in electrospinning. Understanding the activation effect of monohydric alcohols with water and polyhydric alcohols, the most effective activated agent is ascertained with the characteristics of small molecular size, low viscosity, and single functionality. This work is definitely initiated to understand the critical principle of CN cellulose in dissolving. Accordingly, a feasible methodology is also established to prepare ultrafine cellulose fibers with good morphology in electrospinning. Copyright © 2015 Elsevier Ltd. All rights reserved.

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development †

PubMed Central

Newman, David J.; Cragg, Gordon M.

2014-01-01

The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies. PMID:24424355

A Cationic Polymer That Shows High Antifungal Activity against Diverse Human Pathogens.

PubMed

Rank, Leslie A; Walsh, Naomi M; Liu, Runhui; Lim, Fang Yun; Bok, Jin Woo; Huang, Mingwei; Keller, Nancy P; Gellman, Samuel H; Hull, Christina M

2017-10-01

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus , reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus , including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies. Copyright © 2017 American Society for Microbiology.

Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms.

PubMed

Zhang, Yong; Kong, Weijia; Jiang, Jiandong

2017-06-01

Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression, and spread of cancer, in which proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and transcription factors, such as nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-κB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products (green tea catechins, andrographolide, curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation-related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future.

Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery

PubMed Central

2015-01-01

There is a need for new molecular-guided contrast agents to enhance surgical procedures such as tumor resection that require a high degree of precision. Cysteine cathepsins are highly up-regulated in a wide variety of cancers, both in tumor cells and in the tumor-supporting cells of the surrounding stroma. Therefore, tools that can be used to dynamically monitor their activity in vivo could be used as imaging contrast agents for intraoperative fluorescence image guided surgery (FGS). Although multiple classes of cathepsin-targeted substrate probes have been reported, most suffer from overall fast clearance from sites of protease activation, leading to reduced signal intensity and duration in vivo. Here we describe the design and synthesis of a series of near-infrared fluorogenic probes that exploit a latent cationic lysosomotropic effect (LLE) to promote cellular retention upon protease activation. These probes show tumor-specific retention, fast activation kinetics, and rapid systemic distribution. We demonstrate that they are suitable for detection of diverse cancer types including breast, colon and lung tumors. Most importantly, the agents are compatible with the existing, FDA approved, da Vinci surgical system for fluorescence guided tumor resection. Therefore, our data suggest that the probes reported here can be used with existing clinical instrumentation to detect tumors and potentially other types of inflammatory lesions to guide surgical decision making in real time. PMID:26039341

Triumph and tragedy: anemia management in chronic kidney disease.

PubMed

Novak, James E; Szczech, Lynda A

2008-11-01

Recent trial data have resulted in a reevaluation of the management of anemia in chronic kidney disease, including the use of erythropoiesis-stimulating agents, intravenous iron, and novel pharmaceuticals. In this review, we evaluate the latest research on anemia management in chronic kidney disease. Clinical trials of erythropoiesis-stimulating agents indicate that targeting the complete correction of anemia in patients with chronic kidney disease results in a greater risk of morbidity and mortality despite improved hemoglobin and quality of life. Conversely, intravenous iron has been found effective and relatively well tolerated in treating anemia in chronic kidney disease, even in patients with elevated ferritin. New agents to manage anemia, including long-acting erythropoietin derivatives, are also in active development. Erythropoiesis-stimulating agents should be used to target hemoglobin 11-12 g/dl in patients with chronic kidney disease. Intravenous iron may be beneficial for patients with hemoglobin less than 11 g/dl and transferrin saturation less than 25% despite elevated ferritin (500-1200 ng/ml). An upcoming placebo-controlled trial of darbepoetin should help to define the role of erythropoiesis-stimulating agents in chronic kidney disease.

Allergic reactions to indoor air pollutants.

PubMed Central

Karol, M H

1991-01-01

Inhalation of airborne chemicals can result in allergic sensitization with episodic pulmonary responses occurring on subsequent exposures. Responses may occur in the upper respiratory tract (rhinitis), the lower respiratory tract (wheeze, bronchospasm) or systemically, for example, a febrile response. The mechanisms underlying these responses are not always clear but include production of reaginic antibody, activation of T-lymphocyte subsets, and release of spasmogenic and inflammatory mediators from pulmonary cell populations. A variety of agents have been associated with elicitation of these reactions including chemical vapors, dusts and particulates, and microbial organisms. As a result of the widespread occurrence of allergy in indoor environments, conditions conducive to development of allergy have received close attention. Agent-related factors include the nature of the chemical, its concentration, and the frequency and length of exposure to the agent. Host-related factors include the sex, age, and race of the host, as well as the general physical well being. The interactive nature of the host's immune system with the environment is the ultimate determinant of allergic disease. PMID:1821377

Clinical Trials | Division of Cancer Prevention

Cancer.gov

Information about actively enrolling, ongoing, and completed clinical trials of cancer prevention, early detection, and supportive care, including phase I, II, and III agent and action trials and clinical trials management. |

Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity.

PubMed

Benavente-García, O; Castillo, J

2008-08-13

Significantly, much of the activity of Citrus flavonoids appears to impact blood and microvascular endothelial cells, and it is not surprising that the two main areas of research on the biological actions of Citrus flavonoids have been inflammation and cancer. Epidemiological and animal studies point to a possible protective effect of flavonoids against cardiovascular diseases and some types of cancer. Although flavonoids have been studied for about 50 years, the cellular mechanisms involved in their biological action are still not completely known. Many of the pharmacological properties of Citrus flavonoids can be linked to the abilities of these compounds to inhibit enzymes involved in cell activation. Attempts to control cancer involve a variety of means, including the use of suppressing, blocking, and transforming agents. Suppressing agents prevent the formation of new cancers from procarcinogens, and blocking agents prevent carcinogenic compounds from reaching critical initiation sites, while transformation agents act to facilitate the metabolism of carcinogenic components into less toxic materials or prevent their biological actions. Flavonoids can act as all three types of agent. Many epidemiological studies have shown that regular flavonoid intake is associated with a reduced risk of cardiovascular diseases. In coronary heart disease, the protective effects of flavonoids include mainly antithrombotic, anti-ischemic, anti-oxidant, and vasorelaxant. It is suggested that flavonoids decrease the risk of coronary heart disease by three major actions: improving coronary vasodilatation, decreasing the ability of platelets in the blood to clot, and preventing low-density lipoproteins (LDLs) from oxidizing. The anti-inflammatory properties of the Citrus flavonoids have also been studied. Several key studies have shown that the anti-inflammatory properties of Citrus flavonoids are due to its inhibition of the synthesis and biological activities of different pro-inflammatory mediators, mainly the arachidonic acid derivatives, prostaglandins E 2, F 2, and thromboxane A 2. The anti-oxidant and anti-inflammatory properties of Citrus flavonoids can play a key role in their activity against several degenerative diseases and particularly brain diseases. The most abundant Citrus flavonoids are flavanones, such as hesperidin, naringin, or neohesperidin. However, generally, the flavones, such as diosmin, apigenin, or luteolin, exhibit higher biological activity, even though they occur in much lower concentrations. Diosmin and rutin have a demonstrated activity as a venotonic agent and are present in several pharmaceutical products. Apigenin and their glucosides have been shown a good anti-inflammatory activity without the side effects of other anti-inflammatory products. In this paper, we discuss the relation between each structural factor of Citrus flavonoids and the anticancer, anti-inflammatory, and cardiovascular protection activity of Citrus flavonoids and their role in degenerative diseases.

Methods for improved selectivity in photo-activation and detection of molecular diagnostic agents

DOEpatents

Wachter, Eric A [Oak Ridge, TN; Fisher, Walter G [Knoxville, TN; Dees, H Craig [Knoxville, TN

2008-03-18

A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method comprises the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention also provides a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

D-Cateslytin: a new antifungal agent for the treatment of oral Candida albicans associated infections.

PubMed

Dartevelle, Pauline; Ehlinger, Claire; Zaet, Abdurraouf; Boehler, Christian; Rabineau, Morgane; Westermann, Benoit; Strub, Jean-Marc; Cianferani, Sarah; Haïkel, Youssef; Metz-Boutigue, Marie-Hélène; Marban, Céline

2018-06-18

The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (Ctl), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of Ctl, L-Ctl and D-Ctl against Candida albicans. Our results show that both D-Ctl and L-Ctl were potent and safe antifungal agents. However, in contrast to L-Ctl, D-Ctl was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video microscopy, we also demonstrated that D-Ctl can rapidly enter C. albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, we revealed that the antifungal activity of D-Ctl could be synergized by voriconazole, an antifungal of reference in the treatment of Candida albicans related infections. In conclusion, D-Ctl can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida albicans related diseases including oral candidosis.

Multiagent Work Practice Simulation: Progress and Challenges

NASA Technical Reports Server (NTRS)

Clancey, William J.; Sierhuis, Maarten; Shaffe, Michael G. (Technical Monitor)

2001-01-01

Modeling and simulating complex human-system interactions requires going beyond formal procedures and information flows to analyze how people interact with each other. Such work practices include conversations, modes of communication, informal assistance, impromptu meetings, workarounds, and so on. To make these social processes visible, we have developed a multiagent simulation tool, called Brahms, for modeling the activities of people belonging to multiple groups, situated in a physical environment (geographic regions, buildings, transport vehicles, etc.) consisting of tools, documents, and a computer system. We are finding many useful applications of Brahms for system requirements analysis, instruction, implementing software agents, and as a workbench for relating cognitive and social theories of human behavior. Many challenges remain for representing work practices, including modeling: memory over multiple days, scheduled activities combining physical objects, groups, and locations on a timeline (such as a Space Shuttle mission), habitat vehicles with trajectories (such as the Shuttle), agent movement in 3D space (e.g., inside the International Space Station), agent posture and line of sight, coupled movements (such as carrying objects), and learning (mimicry, forming habits, detecting repetition, etc.).

Multiagent Work Practice Simulation: Progress and Challenges

NASA Technical Reports Server (NTRS)

Clancey, William J.; Sierhuis, Maarten

2002-01-01

Modeling and simulating complex human-system interactions requires going beyond formal procedures and information flows to analyze how people interact with each other. Such work practices include conversations, modes of communication, informal assistance, impromptu meetings, workarounds, and so on. To make these social processes visible, we have developed a multiagent simulation tool, called Brahms, for modeling the activities of people belonging to multiple groups, situated in a physical environment (geographic regions, buildings, transport vehicles, etc.) consisting of tools, documents, and computer systems. We are finding many useful applications of Brahms for system requirements analysis, instruction, implementing software agents, and as a workbench for relating cognitive and social theories of human behavior. Many challenges remain for representing work practices, including modeling: memory over multiple days, scheduled activities combining physical objects, groups, and locations on a timeline (such as a Space Shuttle mission), habitat vehicles with trajectories (such as the Shuttle), agent movement in 3d space (e.g., inside the International Space Station), agent posture and line of sight, coupled movements (such as carrying objects), and learning (mimicry, forming habits, detecting repetition, etc.).

Ginseng saponins and the treatment of osteoporosis: mini literature review

PubMed Central

Siddiqi, Muhammad Hanif; Siddiqi, Muhammad Zubair; Ahn, Sungeun; Kang, Sera; Kim, Yeon-Ju; Sathishkumar, Natarajan; Yang, Dong-Uk; Yang, Deok-Chun

2013-01-01

The ginseng plant (Panax ginseng Meyer) has a large number of active ingredients including steroidal saponins with a dammarane skeleton as well as protopanaxadiol and protopanaxatriol, commonly known as ginsenosides, which have antioxidant, anticancer, antidiabetic, anti-adipocyte, and sexual enhancing effects. Though several discoveries have demonstrated that ginseng saponins (ginsenosides) as the most important therapeutic agent for the treatment of osteoporosis, yet the molecular mechanism of its active metabolites is unknown. In this review, we summarize the evidence supporting the therapeutic properties of ginsenosides both in vivo and in vitro, with an emphasis on the different molecular agents comprising receptor activator of nuclear factor kappa-B ligand, receptor activator of nuclear factor kappa-B, and matrix metallopeptidase-9, as well as the bone morphogenetic protein-2 and Smad signaling pathways. PMID:24198650

A Review on Antibacterial, Antiviral, and Antifungal Activity of Curcumin

PubMed Central

Zorofchian Moghadamtousi, Soheil; Abdul Kadir, Habsah; Hassandarvish, Pouya; Tajik, Hassan; Abubakar, Sazaly; Zandi, Keivan

2014-01-01

Curcuma longa L. (Zingiberaceae family) and its polyphenolic compound curcumin have been subjected to a variety of antimicrobial investigations due to extensive traditional uses and low side effects. Antimicrobial activities for curcumin and rhizome extract of C. longa against different bacteria, viruses, fungi, and parasites have been reported. The promising results for antimicrobial activity of curcumin made it a good candidate to enhance the inhibitory effect of existing antimicrobial agents through synergism. Indeed, different investigations have been done to increase the antimicrobial activity of curcumin, including synthesis of different chemical derivatives to increase its water solubility as well ass cell up take of curcumin. This review aims to summarize previous antimicrobial studies of curcumin towards its application in the future studies as a natural antimicrobial agent. PMID:24877064

Biodegradation of Organophosphate Chemical Warfare Agents by Activated Sludge

DTIC Science & Technology

2012-03-01

Holmstedt, B. (1963). Structure- activity relationships of the organophosphorus anticholinesterase agents. In: Koelle, G.B. (ed.), Handbuch...BIODEGRADATION OF ORGANOPHOSPHATE CHEMICAL WARFARE AGENTS BY ACTIVATED SLUDGE Steven J. Schuldt...AFIT/GES/ENV/12-M04 BIODEGRADATION OF ORGANOPHOSPHATE CHEMICAL WARFARE AGENTS BY ACTIVATED SLUDGE THESIS Presented to the

Antagonistic activity of Bacillus subtilis SB1 and its biocontrol effect on tomato bacterial wilt

USDA-ARS?s Scientific Manuscript database

A potential biocontrol agent of bacterial wilt, Bacillus subtilis SB1, isolated from tomato roots, showed a broad-spectrum of antimicrobial activity in in vitro experiments. It inhibited the growth of many plant pathogens, including Ralstonia solanacearum, Xanthomonas oryzae pv. oryzae, Fusarium ox...

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP

PubMed Central

Lev, Avital; Lulla, Amriti R.; Wagner, Jessica; Ralff, Marie D.; Kiehl, Joshua B.; Zhou, Yan; Benes, Cyril H.; Prabhu, Varun V.; Oster, Wolfgang; Astsaturov, Igor; Dicker, David T.; El-Deiry, Wafik S.

2017-01-01

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (N=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo. We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs. PMID:29137221

Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP.

PubMed

Lev, Avital; Lulla, Amriti R; Wagner, Jessica; Ralff, Marie D; Kiehl, Joshua B; Zhou, Yan; Benes, Cyril H; Prabhu, Varun V; Oster, Wolfgang; Astsaturov, Igor; Dicker, David T; El-Deiry, Wafik S

2017-10-10

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines ( N =16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo . We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.

A potential photocatalytic, antimicrobial and anticancer activity of chitosan-copper nanocomposite.

PubMed

Arjunan, Nithya; Singaravelu, Chandra Mohan; Kulanthaivel, Jeganathan; Kandasamy, Jothivenkatachalam

2017-11-01

In this study, chitosan-copper (CS-Cu) nanocomposite was synthesized without the aid of any external chemical reducing agents. The optical, structural, spectral, thermal and morphological analyses were carried out by several techniques. The prepared nanocomposite acts as a photocatalyst for the removal of Rhodamine B (RhB) and Conge red (CR) dyes under visible light irradiation. The pseudo first order kinetics was derived according to Langmuir-Hinshelwood (L-H) model. The nanocomposite also proved to be an excellent antimicrobial agent against Gram-positive and Gram-negative bacteria; and also show activity against fungus. The advanced material was used for the major research areas which include photocatalytic materials for waste water treatment; biological applications in the development of drug resistant antimicrobials and anticancer agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Hydrolysis of Synthetic Esters by the Antibacterial Agent in Serum

PubMed Central

Yotis, William W.

1966-01-01

Yotis, William W. (Loyola University, Chicago, Ill.). Hydrolysis of synthetic esters by the antibacterial agent in serum. J. Bacteriol. 91:488–493. 1966.—An antistaphylococcal serum agent was assayed colorimetrically, manometrically, and titrimetrically for esterase activity. p-Nitrophenol acetate, triacetin, l-lysine methyl and ethyl ester, and norleucine methyl ester were hydrolyzed by the antistaphylococcal agent. Acetylcholine and benzoylcholine esters, triolein, tristearin, and p-tosylarginine methyl ester were not attacked by this agent. With p-nitrophenol acetate as substrate, optimal activity occurred at pH 7.4. Incubation at 60 C for 30 min reduced drastically the esterase activity of the antistaphylococcal agent, and incubation at 75 C for 30 min abolished the esterase activity of this agent. Almost complete inhibition of esterase activity was observed with 0.001 m HgCl2, ZnSO4, and ethylenediaminetetraacetic acid (EDTA). EDTA inhibition could be reversed by the addition of CaCl2, but not MgCl2. Cysteine reversed the inhibition of HgCl2. NaF, atoxyl, diisopropyl fluorophosphate, quinine, and physostigmine did not influence the esterase activity of the antibacterial agent. The demonstration of esterase activity of both the antistaphylococcal agent and coagulase may shed further light on the reported ability of coagulase to neutralize the antistaphylococcal activity of this agent, or the prevention of absorption of the agent on the staphylococcal cell surface. In addition, the colorimetric procedure described in this report may be a convenient tool in assaying the potency of the antistaphylococcal agent. Images PMID:4956776

Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis.

PubMed

Raggi, D; Miceli, R; Sonpavde, G; Giannatempo, P; Mariani, L; Galsky, M D; Bellmunt, J; Necchi, A

2016-01-01

The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status ≥1 and hepatic metastases. Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Virocidal activity of Egyptian scorpion venoms against hepatitis C virus.

PubMed

El-Bitar, Alaa M H; Sarhan, Moustafa M H; Aoki, Chie; Takahara, Yusuke; Komoto, Mari; Deng, Lin; Moustafa, Mohsen A; Hotta, Hak

2015-03-24

Hepatitis C virus (HCV) is a major global health problem, causing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Development of well-tolerated regimens with high cure rates and fewer side effects is still much needed. Recently, natural antimicrobial peptides (AMPs) are attracting more attention as biological compounds and can be a good template to develop therapeutic agents, including antiviral agents against a variety of viruses. Various AMPs have been characterized from the venom of different venomous animals including scorpions. The possible antiviral activities of crude venoms obtained from five Egyptian scorpion species (Leiurus quinquestriatus, Androctonus amoreuxi, A. australis, A. bicolor and Scorpio maurus palmatus) were evaluated by a cell culture method using Huh7.5 cells and the J6/JFH1-P47 strain of HCV. Time-of-addition experiments and inactivation of enzymatic activities of the venoms were carried out to determine the characteristics of the anti-HCV activities. S. maurus palmatus and A. australis venoms showed anti-HCV activities, with 50% inhibitory concentrations (IC₅₀) being 6.3 ± 1.6 and 88.3 ± 5.8 μg/ml, respectively. S. maurus palmatus venom (30 μg/ml) impaired HCV infectivity in culture medium, but not inside the cells, through virocidal effect. The anti-HCV activity of this venom was not inhibited by a metalloprotease inhibitor or heating at 60°C. The antiviral activity was directed preferentially against HCV. S. maurus palmatus venom is considered as a good natural source for characterization and development of novel anti-HCV agents targeting the entry step. To our knowledge, this is the first report describing antiviral activities of Egyptian scorpion venoms against HCV, and may open a new approach towards discovering antiviral compounds derived from scorpion venoms.

Changing therapeutic paradigms in CMV retinitis in AIDS.

PubMed

Piper, H; Ciulla, T A; Danis, R P; Pratt, L M

2000-12-01

Cytomegalovirus (CMV) retinitis is a common ocular complication of immunosuppression. The management of CMV retinitis has been continuously evolving over the last decade. The mainstay of therapy remains ganciclovir and foscarnet. However, increasing resistance and ongoing toxicities to these agents remain a challenge. Additional frequently utilised agents include cidofovir and fomivirsen. The advent of highly active antiretroviral therapy (HAART) has allowed the restoration of immunocompetency to many patients previously challenged by CMV infection. In some circumstances, HAART has even eliminated the need for ongoing antiviral therapy. This paper reviews the current treatment modalities, including their toxicities and dosing recommendations.

Blood doping: risks to athletes' health and strategies for detection.

PubMed

Oliveira, Carolina Dizioli Rodrigues de; Bairros, André Valle de; Yonamine, Mauricio

2014-07-01

Blood doping has been defined as the misuse of substances or certain techniques to optimize oxygen delivery to muscles with the aim to increase performance in sports activities. It includes blood transfusion, administration of erythropoiesis-stimulating agents or blood substitutes, and gene manipulations. The main reasons for the widespread use of blood doping include: its availability for athletes (erythropoiesis-stimulating agents and blood transfusions), its efficiency in improving performance, and its difficult detection. This article reviews and discusses the blood doping substances and methods used for in sports, the adverse effects related to this practice, and current strategies for its detection.

Reduction of serum TARC levels in atopic dermatitis by topical anti-inflammatory treatments.

PubMed

Yasukochi, Yumi; Nakahara, Takeshi; Abe, Takeru; Kido-Nakahara, Makiko; Kohda, Futoshi; Takeuchi, Satoshi; Hagihara, Akihito; Furue, Masutaka

2014-09-01

Serum thymus and activation-regulated chemokine (TARC) levels are associated with the disease activity of patients with atopic dermatitis (AD) and sensitively reflect short-term changes in skin conditions. The main treatment for AD is topical agent application. This study investigated the relationship between serum TARC levels and the dosage of topical agents, including corticosteroids and/or tacrolimus, in patients with AD. The serum TARC levels of 56 AD patients and the amounts of topical agents prescribed to them were investigated retrospectively. The weekly reduction in serum TARC levels and weekly dosage of topical agents among AD patients were compared and their associations were evaluated. The dosage of topical agents was closely related to serum TARC levels. One gram of strong rank steroid or the equivalent amount of steroid/tacrolimus is required to reduce serum TARC levels by 9.94 pg/mL weekly in moderate to severe AD patients. Higher initial TARC levels require more topical agent, which results in a more rapid decrease in TARC levels. The serum TARC levels and eosinophil numbers in peripheral blood are significantly correlated. Serum TARC level improvement and topical agent dosage are strongly correlated. TARC and eosinophil numbers are significantly correlated, but the wider range of TARC levels seems to be clinically more useful for monitoring AD severity. The serum TARC level is a very sensitive biomarker for monitoring the severity and treatment response in AD.

Autonomous Mission Operations for Sensor Webs

NASA Astrophysics Data System (ADS)

Underbrink, A.; Witt, K.; Stanley, J.; Mandl, D.

2008-12-01

We present interim results of a 2005 ROSES AIST project entitled, "Using Intelligent Agents to Form a Sensor Web for Autonomous Mission Operations", or SWAMO. The goal of the SWAMO project is to shift the control of spacecraft missions from a ground-based, centrally controlled architecture to a collaborative, distributed set of intelligent agents. The network of intelligent agents intends to reduce management requirements by utilizing model-based system prediction and autonomic model/agent collaboration. SWAMO agents are distributed throughout the Sensor Web environment, which may include multiple spacecraft, aircraft, ground systems, and ocean systems, as well as manned operations centers. The agents monitor and manage sensor platforms, Earth sensing systems, and Earth sensing models and processes. The SWAMO agents form a Sensor Web of agents via peer-to-peer coordination. Some of the intelligent agents are mobile and able to traverse between on-orbit and ground-based systems. Other agents in the network are responsible for encapsulating system models to perform prediction of future behavior of the modeled subsystems and components to which they are assigned. The software agents use semantic web technologies to enable improved information sharing among the operational entities of the Sensor Web. The semantics include ontological conceptualizations of the Sensor Web environment, plus conceptualizations of the SWAMO agents themselves. By conceptualizations of the agents, we mean knowledge of their state, operational capabilities, current operational capacities, Web Service search and discovery results, agent collaboration rules, etc. The need for ontological conceptualizations over the agents is to enable autonomous and autonomic operations of the Sensor Web. The SWAMO ontology enables automated decision making and responses to the dynamic Sensor Web environment and to end user science requests. The current ontology is compatible with Open Geospatial Consortium (OGC) Sensor Web Enablement (SWE) Sensor Model Language (SensorML) concepts and structures. The agents are currently deployed on the U.S. Naval Academy MidSTAR-1 satellite and are actively managing the power subsystem on-orbit without the need for human intervention.

Emerging Drugs and Vaccines for Candidemia

PubMed Central

Moriyama, Brad; Gordon, Lori A.; McCarthy, Matthew; Henning, Stacey A.; Walsh, Thomas J.; Penzak, Scott R.

2014-01-01

Summary Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus, and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords “Candida” or “Candidemia” or “Candidiasis” and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarized. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161, and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. PMID:25294098

Are there any reasons to change our behavior in necrotizing fasciitis with the advent of new antibiotics?

PubMed

Menichetti, Francesco; Giuliano, Simone; Fortunato, Simona

2017-04-01

The treatment of necrotizing fasciitis requires a multifaceted approach, consisting of surgical source control with immediate surgical debridement along with life support, clinical monitoring, and antimicrobial therapy. Many drugs are now available for the treatment of this life-threatening infectious disease, and the purpose of this review is to provide the reader with an updated overview of the newest therapeutic options. Because most necrotizing soft tissue infections are polymicrobial, broad-spectrum coverage is advisable. Acceptable monotherapy regimens include piperacillin-tazobactam or a carbapenem. However, drugs such as ceftolozane-tazobactam, ceftazidime-avibactam in association with an antianaerobic agent (metronidazole or clindamycin) are currently available as valuable alternatives. The new cephalosporins active against methicillin-resistant Staphylococcus aureus (MRSA), ceftaroline, and ceftobiprole share similar antibacterial activity against Gram-positive cocci, and they might be considered as an alternative to nonbetalactam anti-MRSA agents for necrotizing fasciitis management. Two new long-acting lypoglycopeptides - oritavancin and dalbavancin - share the indications for acute bacterial skin and skin structure infections and had similar activity against Gram-positive cocci including MRSA and streptococci. Carbapenem-sparing agents are particularly suitable for antimicrobial stewardship strategy. The new long-acting lypoglycopeptides are very effective in treating necrotizing fasciitis and are uttermost attractive for patients requiring short hospital stays and early discharge.

Installation Restoration Program. Phase 1 - Records Search, Homestead AFB, Florida

DTIC Science & Technology

1983-08-01

con- ducted on a weekly basis. Since the early 1970’s, water and Aqueous . Film Forming Foam ( AFFF ) have been the main extinguishing agents used. Fuels...were occasionally disposed of at the site. Typically, water and AFFF were used as fire extinguishing agents. The site received a HARM score of 66. This...project activities include designs for Owens-Corning Fiberglas; 36,000 gpm neutralization facilities for FC Corporation; wastewater reclamation facilities

Current Approaches and New Developments in the Pharmacological Management of Tourette Syndrome.

PubMed

Quezada, Julio; Coffman, Keith A

2018-01-01

Tourette syndrome (TS) is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics. Once thought to be rare, TS affects 0.3-1% of the population. Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities. The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown. However, clinical experience gained from treating TS has helped us better understand its pathogenesis and, as a result, derive treatment options. The strongest data exist for the antipsychotic agents, both typical and atypical, although their use is often limited in children and adolescents due to their side-effect profiles. There are agents in a variety of other pharmacologic categories that have evidence for the treatment of TS and whose side-effect profiles are more tolerable than the antipsychotics; these include clonidine, guanfacine, baclofen, topiramate, botulinum toxin A, tetrabenazine, and deutetrabenazine. A number of new agents are being developed and tested as potential treatments for TS. These include valbenazine, delta-9-tetrahydrocannabidiol, and ecopipam. Additionally, there are agents with insufficient data for efficacy, as well as agents that have been shown to be ineffective. Those without sufficient data for efficacy include clonazepam, ningdong granule, 5-ling granule, omega-3 fatty acids, and n-acetylcysteine. The agents that have been shown to be ineffective include pramipexole and metoclopramide. We will review all of the established pharmacologic treatments, and discuss those presently in development.

Development of novel therapeutic drugs in humans from plant antimicrobial peptides.

PubMed

da Rocha Pitta, Maira Galdino; da Rocha Pitta, Marina Galdino; Galdino, Suely Lins

2010-05-01

All living organisms, ranging from microorganisms to plants and mammals, have evolved mechanisms to actively defend themselves against pathogen attack. A wide range of biological activities have been attributed to plant antimicrobial peptides (AMPs) including growth inhibitory effects on a broad range of fungi, Gram-positive and Gram-negative bacteria, viruses, neoplasic cells and parasitic protozoa. Classes of AMPs, their mechanisms of action, biological activity, and cytotoxicity towards host cells are discussed. A particular focus regards AMP candidates with potential for use in defense against biological warfare agents. This field is young, but provides additional stimulus to consideration of these molecules as a new class of therapeutic agents and promises to revolutionize treatment of many infectious diseases.

Antimicrobial activity of pyrrocidines from Acremonium zeae against endophytes and pathogens of maize.

PubMed

Wicklow, Donald T; Poling, Stephen M

2009-01-01

Acremonium zeae produces pyrrocidines A and B, which are polyketide-amino acid-derived antibiotics, and is recognized as a seedborne protective endophyte of maize which augments host defenses against microbial pathogens causing seedling blights and stalk rots. Pyrrocidine A displayed significant in vitro activity against Aspergillus flavus and Fusarium verticillioides in assays performed using conidia as inoculum, with pyrrocidine A being more active than B. In equivalent assays performed with conidia or hyphal cells as inoculum, pyrrocidine A revealed potent activity against major stalk and ear rot pathogens of maize, including F. graminearum, Nigrospora oryzae, Stenocarpella (Diplodia) maydis, and Rhizoctonia zeae. Pyrrocidine A displayed significant activity against seed-rotting saprophytes A. flavus and Eupenicillium ochrosalmoneum, as well as seed-infecting colonists of the phylloplane Alternaria alternata, Cladosporium cladosporioides, and Curvularia lunata, which produces a damaging leaf spot disease. Protective endophytes, including mycoparasites which grow asymptomatically within healthy maize tissues, show little sensitivity to pyrrocidines. Pyrrocidine A also exhibited potent activity against Clavibacter michiganense subsp. nebraskense, causal agent of Goss's bacterial wilt of maize, and Bacillus mojaviense and Pseudomonas fluorescens, maize endophytes applied as biocontrol agents, but were ineffective against the wilt-producing bacterium Pantoea stewartii.

Inhibitory Activities of Phenolic Compounds Isolated from Adina rubella Leaves Against 5α-Reductase Associated with Benign Prostatic Hypertrophy.

PubMed

Yin, Jun; Heo, Jun Hyeok; Hwang, Yoon Jeong; Le, Thi Tam; Lee, Min Won

2016-07-07

Adina rubella Hance (AR), a plant native to Korea, has been used as traditional medicine for dysentery, eczema, intoxication, and external hemorrhages. Previous phytochemical studies of AR have reported several components, including terpenoids, phenolics, and alkaloids. The current study evaluated the anti-oxidative and anti-inflammatory activities and 5α-reductase inhibition of isolated compounds of AR leaves to find a potential therapeutic agent for benign prostatic hypertrophy (BPH). Repeated chromatographic isolation of an 80% acetone extract of AR leaves yielded seven phenolic compounds: caffeic acid (1), chlorogenic acid (2), methyl chlorogenate (3), quercetin-3-rutinoside (4), kaempferol-3-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (5), hyperoside (6), and grandifloroside (7). Compound 7 is a novel compound in AR. Caffeoyl derivatives 1-3 and 7 showed good anti-oxidative activities. In particular, caffeic acid (1) and grandifloroside (7) showed potent anti-inflammatory activities, and 7 also exhibited potent inhibitory activity against TNF-α and 5α-reductase. Our results show that the extract and grandifloroside (7) from leaves of AR might be developed as a source of potent anti-oxidative and anti-inflammatory agents and therapeutic agent for BPH.

[Exposure to biological agents used in Polish enterprises: analysis of data derived from the National Register of Biological Agent].

PubMed

Kozajda, Anna; Szadkowska-Stańczyk, Irena

2011-01-01

The National Register of Biological Agents at Work and the National Information Centre for Biological Agents Present at Workplaces were established in the Nofer Institute of Occupational Medicine in 2005. The National Information Centre carries out consultation and education activities concerning occupational exposure and risk assessment, development and implementation of preventive programs and accurate registration of reliable information about the use of biological agents. Educational materials on biological exposure are published on the website. The National Register of Biological Agents (database) collects and periodically analyzes the information obtained from employers about the use of biological agents for research, diagnostic or industrial purposes. As of 10 December 2010 there were 240 notifications from companies, which use biological agents for the following purposes: research--69, industrial--30 and diagnostic--321. Near 75% of all notifications were obtained from different diagnostic laboratories (public and private). In total, 3226 workers, including 2967 (92%) women and 256 (8%) men were exposed to biological agents. In general, occupational exposure to 209 biological agents (186 of risk group 2 and 23 of risk group 3, of which 16 are additionally marked by 3**) were registered in the data base.

Characterization of chemical warfare G-agent hydrolysis products by surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Inscore, Frank E.; Gift, Alan D.; Maksymiuk, Paul; Farquharson, Stuart

2004-12-01

The United States and its allies have been increasingly challenged by terrorism, and since the September 11, 2001 attacks and the war in Afghanistan and Iraq, homeland security has become a national priority. The simplicity in manufacturing chemical warfare agents, the relatively low cost, and previous deployment raises public concern that they may also be used by terrorists or rogue nations. We have been investigating the ability of surface-enhanced Raman spectroscopy (SERS) to detect extremely low concentrations (e.g. part-per-billion) of chemical agents, as might be found in poisoned water. Since trace quantities of nerve agents can be hydrolyzed in the presence of water, we have expanded our studies to include such degradation products. Our SERS-active medium consists of silver or gold nanoparticles incorporated into a sol-gel matrix, which is immobilized in a glass capillary. The choice of sol-gel precursor allows controlling hydrophobicity, while the porous silica network offers a unique environment for stabilizing the SERS-active metals. Here we present the use of these metal-doped sol-gels to selectively enhance the Raman signal of the hydrolyzed products of the G-series nerve agents.

General Theories of Chemical Disinfection and Sterilization of Sludge--Part 3.

ERIC Educational Resources Information Center

Wang, Mu Hao; And Others

1978-01-01

A general discussion of sewage sterilization methods, including techniques using pH, Chlorine, Chlorine Dioxide, Ozone, Iodine and Bromine, metal ions, and cationic surface active agents is presented. (MDR)

29 CFR 553.211 - Law enforcement activities.

Code of Federal Regulations, 2011 CFR

2011-07-01

... subordinates who are empowered by State statute or local ordinance to enforce laws designed to maintain public... include, for example, fish and game wardens or criminal investigative agents assigned to the office of a...

29 CFR 553.211 - Law enforcement activities.

Code of Federal Regulations, 2013 CFR

2013-07-01

... subordinates who are empowered by State statute or local ordinance to enforce laws designed to maintain public... include, for example, fish and game wardens or criminal investigative agents assigned to the office of a...

29 CFR 553.211 - Law enforcement activities.

Code of Federal Regulations, 2012 CFR

2012-07-01

... subordinates who are empowered by State statute or local ordinance to enforce laws designed to maintain public... include, for example, fish and game wardens or criminal investigative agents assigned to the office of a...

29 CFR 553.211 - Law enforcement activities.

Code of Federal Regulations, 2014 CFR

2014-07-01

... subordinates who are empowered by State statute or local ordinance to enforce laws designed to maintain public... include, for example, fish and game wardens or criminal investigative agents assigned to the office of a...

Oxidative acylation using thioacids

NASA Technical Reports Server (NTRS)

Liu, R.; Orgel, L. E.

1997-01-01

Several important prebiotic reactions, including the coupling of amino acids into polypeptides by the formation of amide linkages, involve acylation. Theae reactions present a challenge to the understanding of prebiotic synthesis. Condensation reactions relying on dehydrating agents are either inefficient in aqueous solution or require strongly acidic conditions and high temperatures. Activated amino acids such as thioester derivatives have therefore been suggested as likely substrates for prebiotic peptide synthesis. Here we propose a closely related route to amide bond formation involving oxidative acylation by thioacids. We find that phenylalanine, leucine and phenylphosphate are acylated efficiently in aqueous solution by thioacetic acid and an oxidizing agent. From a prebiotic point of view, oxidative acylation has the advantage of proceeding efficiently in solution and under mild conditions. We anticipate that oxidative acylation should prove to be a general method for activating carboxylic acids, including amino acids.

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization.

PubMed

Sawyer, Andrew J; Kyriakides, Themis R

2016-02-01

Extracellular matrix is composed of a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell-matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

pH-Sensitive Microparticles with Matrix-Dispersed Active Agent

NASA Technical Reports Server (NTRS)

Calle, Luz M. (Inventor); Jolley, Scott T. (Inventor); Buhrow, Jerry W. (Inventor); Li, Wenyan (Inventor)

2014-01-01

Methods to produce pH-sensitive microparticles that have an active agent dispersed in a polymer matrix have certain advantages over microcapsules with an active agent encapsulated in an interior compartment/core inside of a polymer wall. The current invention relates to pH-sensitive microparticles that have a corrosion-detecting or corrosion-inhibiting active agent or active agents dispersed within a polymer matrix of the microparticles. The pH-sensitive microparticles can be used in various coating compositions on metal objects for corrosion detecting and/or inhibiting.

Nature of the Elimination of the Penicillinase Plasmid from Staphylococcus aureus by Surface-Active Agents

PubMed Central

Sonstein, Stephen A.; Baldwin, J. N.

1972-01-01

Growth of Stapylococcus aureus in various ionic surface-active agents resulted in loss of the ability to produce penicillinase, whereas growth in nonionic surface-active agents had no effect on penicillinase production. The curing effect of various alkyl sulfates was found to be dependent upon the chain length. Curing by surface-active agents could be inhibited by magnesium. Reciprocal transduction experiments showed that curing by a surface-active agent was a property of the plasmid, not of the bacterial strain in which the plasmic resides. PMID:4204903

Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents

PubMed Central

German-Ponciano, León Jesús; Rosas-Sánchez, Gilberto Uriel; Rivadeneyra-Domínguez, Eduardo

2018-01-01

Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, and γ-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans. PMID:29623232

Effects of Animal Venoms and Toxins on Hallmarks of Cancer

PubMed Central

Chaisakul, Janeyuth; Hodgson, Wayne C.; Kuruppu, Sanjaya; Prasongsook, Naiyarat

2016-01-01

Animal venoms are a cocktail of proteins and peptides, targeting vital physiological processes. Venoms have evolved to assist in the capture and digestion of prey. Key venom components often include neurotoxins, myotoxins, cardiotoxins, hematoxins and catalytic enzymes. The pharmacological activities of venom components have been investigated as a source of potential therapeutic agents. Interestingly, a number of animal toxins display profound anticancer effects. These include toxins purified from snake, bee and scorpion venoms effecting cancer cell proliferation, migration, invasion, apoptotic activity and neovascularization. Indeed, the mechanism behind the anticancer effect of certain toxins is similar to that of agents currently used in chemotherapy. For example, Lebein is a snake venom disintegrin which generates anti-angiogenic effects by inhibiting vascular endothelial growth factors (VEGF). In this review article, we highlight the biological activities of animal toxins on the multiple steps of tumour formation or hallmarks of cancer. We also discuss recent progress in the discovery of lead compounds for anticancer drug development from venom components. PMID:27471574

In vitro activities of dalbavancin and nine comparator agents against anaerobic gram-positive species and corynebacteria.

PubMed

Goldstein, Ellie J C; Citron, Diane M; Merriam, C Vreni; Warren, Yumi; Tyrrell, Kerin; Fernandez, Helen T

2003-06-01

Dalbavancin is a novel semisynthetic glycopeptide with enhanced activity against gram-positive species. Its comparative in vitro activities and those of nine comparator agents, including daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin, against 290 recent gram-positive clinical isolates strains, as determined by the NCCLS agar dilution method, were studied. The MICs of dalbavancin at which 90% of various isolates tested were inhibited were as follows: Actinomyces spp., 0.5 microg/ml; Clostridium clostridioforme, 8 microg/ml; C. difficile, 0.25 microg/ml; C. innocuum, 0.25 microg/ml; C. perfringens, 0.125 microg/ml; C. ramosum, 1 microg/ml; Eubacterium spp., 1 microg/ml; Lactobacillus spp., >32 microg/ml, Propionibacterium spp., 0.5 microg/ml; and Peptostreptococcus spp., 0.25 microg/ml. Dalbavancin was 1 to 3 dilutions more active than vancomycin against most strains. Dalbavancin exhibited excellent activity against gram-positive strains tested and warrants clinical evaluation.

Antioxidant, antibacterial and anti-aging activities of intracellular zinc polysaccharides from Grifola frondosa SH-05.

PubMed

Zhang, Chen; Gao, Zheng; Hu, Chunlong; Zhang, Jianjun; Sun, Xinyi; Rong, Chengbo; Jia, Le

2017-02-01

In present work, the strain of Grifola frondosa SH-05 was used as a vector of zinc biotransformation to produce the IZPS. The bioactivities including antioxidant and antibacterial activities in vitro and anti-aging properties in vivo of IZPS were investigated comparing with the IPS. The results which were in consistent with the results of histopathology assay demonstrated that the IZPS had superior antioxidant and anti-aging activities by scavenging the hydroxyl and DPPH radicals, increasing enzyme activities, decreasing the MDA contents and ameliorating the anile condition of mice. Besides, the IZPS also showed potential antibacterial activities. The IZPS with higher bioactivities was composed of were Rha, Ino and Glu with a molar ratio of 4.7:3.6:1. These conclusions indicated that the IZPS might be a potential source of natural antioxidant, antibacterial agent and anti-aging agent. Copyright © 2016 Elsevier B.V. All rights reserved.

Biological Control Potential of Bacillus amyloliquefaciens KB3 Isolated from the Feces of Allomyrina dichotoma Larvae

PubMed Central

Nam, Hyo-Song; Yang, Hyun-Ju; Oh, Byung Jun; Anderson, Anne J.; Kim, Young Cheol

2016-01-01

Most biocontrol agents for plant diseases have been isolated from sources such as soils and plants. As an alternative source, we examined the feces of tertiary larvae of the herbivorous rhino beetle, Allomyrina dichotoma for presence of biocontrol-active microbes. The initial screen was performed to detect antifungal activity against two common fungal plant pathogens. The strain with strongest antifungal activity was identified as Bacillus amyloliquefaciens KB3. The inhibitory activity of this strain correlated with lipopeptide productions, including iturin A and surfactin. Production of these surfactants in the KB3 isolate varied with the culture phase and growth medium used. In planta biocontrol activities of cell-free culture filtrates of KB3 were similar to those of the commercial biocontrol agent, B. subtilis QST-713. These results support the presence of microbes with the potential to inhibit fungal growth, such as plant pathogens, in diverse ecological niches. PMID:27298603

Chemical agents for the control of plaque and plaque microflora: an overview.

PubMed

Gaffar, A; Afflitto, J; Nabi, N

1997-10-01

This presentation provides an overview of the technologies available for the chemical control of plaque. It is generally accepted that the formation of dental plaque at the interfaces of tooth/gingiva is one of the major causes of gingival inflammation and dental caries. Several therapeutic approaches have been used to control dental plaque and supragingival infections. These include fluoride preparations such as stannous fluoride, oxygenating agents, anti-attachment agents, and cationic and non-cationic antibacterial agents. Among the fluoride preparations, stable stannous fluoride pastes and gels have been shown to reduce supragingival plaque, gingivitis, hypersensitivity and caries. The effect of the oxygenating agents on the supragingival plaque has been equivocal, but recent data indicate that a stable agent which provides sustained active oxygen release is effective in controlling plaque. A polymer, PVPA, which reduced attachment of bacteria to teeth was shown to significantly reduce plaque formation in humans. A new generation of antibacterials includes non-ionics such as triclosan, which in combination with a special polymer delivery system, has been shown to reduce plaque, gingivitis, supragingival calculus and dental caries in long-term studies conducted around the world. Unlike the first generation of agents, the triclosan/copolymer/sodium fluoride system is effective in long-term clinicals and does not cause staining of teeth, increase in calculus, or disturbance in the oral microbial ecology.

Alpha-hydroxyacid chemical peeling agents: case studies and rationale for safe and effective use.

PubMed

Briden, M Elizabeth

2004-02-01

Chemical peeling is an in-office procedure that involves the application of a chemical agent to the skin to induce controlled destruction or exfoliation of old skin and stimulation of new epidermal growth with more evenly distributed melanin. When peel agents reach the dermal layer, important wound-healing activities occur that cause skin remodeling and skin smoothing, both antiaging benefits. There are a number of key factors in selecting a peeling agent and procedure, and each is discussed. Variables to consider are the peeling agent and its formulation, the concentration of the agent, the patient's skin type, the site to be peeled, the skin preparation procedure prior to and immediately preceding the application of the agent, the application method, the duration of contact, and the patient's medical history and lifestyle. Various types of peels are discussed. Of particular interest are superficial chemical peels, which offer great flexibility over a range of skin types and conditions with minimal to no "downtime." Alpha-hydroxyacid (AHA) peels are superficial and can be combined with other cosmetic procedures in the office to maximize benefits. In addition, AHA peels work well when combined with supportive homecare products including AHAs or polyhydroxy acids (PHAs), topical retinoids, and antiacne/antirosacea treatments. Case studies are presented of patients using AHA peels for the treatment of acne and hyperpigmentation in a variety of skin types, including Asian skin.

Newer biological agents in rheumatoid arthritis: impact on health-related quality of life and productivity.

PubMed

Strand, Vibeke; Singh, Jasvinder A

2010-01-01

Health-related quality of life (HR-QOL) in patients with rheumatoid arthritis (RA) is significantly impaired as a result of pain, deficits in physical function and fatigue associated with this disease. Decrements in HR-QOL are also associated with an increased probability of no longer working, absence from work due to RA-associated sickness, and reduced productivity while at work or in the home, all of which have consequences for the patient as well as society. HR-QOL and productivity are thus important components in the assessment of outcomes in RA, and assessment of HR-QOL is now recommended in clinical trials that assess the efficacy of new treatments for RA. Measures to assess HR-QOL include the Medical Outcomes Study Short Form 36 (SF-36), EuroQol (EQ-5D) and the Health Utilities Index - Mark 3 (HUI3); these measures not only provide an indication of the clinical (i.e. statistical) efficacy of a treatment, but also provide information on whether this efficacy is truly 'meaningful' from a patient's perspective. These measures have been utilized in clinical trials of biological agents in patients with RA, including tumour necrosis factor inhibitors (etanercept, infliximab, adalimumab, certolizumab pegol and golimumab), the co-stimulatory inhibitor molecule abatacept, the B-cell depletion agent rituximab and the interleukin-6 receptor antagonist tocilizumab, and have demonstrated that these agents can significantly improve HR-QOL. Assessment of work productivity in patients with RA and the impact of treatment is a practical way to measure disability from RA from individual and societal perspectives. As RA affects women three times more frequently than men, there is also a critical need for productivity assessment within the home as well as participation in family/social/leisure activities. Data from recent trials of biological agents demonstrate that these agents can reverse disease-related decrements in productivity and limitations in participation in family, social and leisure activities in patients with active RA. However, despite this recognition, several challenges in the assessment of productivity remain, including standardization of instruments. Development of additional instruments to assess HR-QOL and productivity that are easier to use in daily practice may further improve our ability to monitor the effectiveness of therapies.

Apoptosis induction and anti-cancer activity of LeciPlex formulations.

PubMed

Dhawan, Vivek V; Joshi, Ganesh V; Jain, Ankitkumar S; Nikam, Yuvraj P; Gude, Rajiv P; Mulherkar, Rita; Nagarsenker, Mangal S

2014-10-01

Cationic agents have been reported to possess anti-neoplastic properties against various cancer cell types. However, their complexes with lipids appear to interact differently with different cancer cells. The purpose of this study was to (i) design and generate novel cationic lecithin nanoparticles, (ii) assess and understand the mechanism underlying their putative cytotoxicity and (iii) test their effect on cell cycle progression in various cancer-derived cell lines. In addition, we aimed to evaluate the in vivo potential of these newly developed nanoparticles in oral anti-cancer delivery. Cationic lecithin nanoparticles were generated using a single step nanoprecipitation method and they were characterized for particle size, zeta potential, stability and in vitro release. Their cytotoxic potential was assessed using a sulforhodamine B assay, and their effect on cell cycle progression was evaluated using flow cytometry. The nanoparticle systems were also tested in vivo for their anti-tumorigenic potential. In contrast to cationic agents alone, the newly developed nanoformulations showed a specific toxicity against cancer cells. The mechanism of toxic cell death included apoptosis, S and G2/M cell cycle phase arrest, depending on the type of cationic agent and the cancer-derived cell line used. Both blank and drug-loaded systems exhibited significant anti-cancer activity, suggesting a synergistic anti-tumorigenic effect of the drug and its delivery system. Both in vitro and in vivo data indicate that cationic agents themselves exhibit broad anti-neoplastic activities. Complex formation of the cationic agents with phospholipids was found to provide specificity to the anti-cancer activity. These formulations thus possess potential for the design of effective anti-cancer delivery systems.

Ginsenosides as Anticancer Agents: In vitro and in vivo Activities, Structure–Activity Relationships, and Molecular Mechanisms of Action

PubMed Central

Nag, Subhasree Ashok; Qin, Jiang-Jiang; Wang, Wei; Wang, Ming-Hai; Wang, Hui; Zhang, Ruiwen

2012-01-01

Conventional chemotherapeutic agents are often toxic not only to tumor cells but also to normal cells, limiting their therapeutic use in the clinic. Novel natural product anticancer compounds present an attractive alternative to synthetic compounds, based on their favorable safety and efficacy profiles. Several pre-clinical and clinical studies have demonstrated the anticancer potential of Panax ginseng, a widely used traditional Chinese medicine. The anti-tumor efficacy of ginseng is attributed mainly to the presence of saponins, known as ginsenosides. In this review, we focus on how ginsenosides exert their anticancer effects by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (c-myc, EGFR, and vascular endothelial growth factor), tumor suppressors (p53 and p21), oncogenes (MDM2), cell death mediators (Bcl-2, Bcl-xL, XIAP, caspases, and death receptors), inflammatory response molecules (NF-κB and COX-2), and protein kinases (JNK, Akt, and AMP-activated protein kinase). We also discuss the structure–activity relationship of various ginsenosides and their potentials in the treatment of various human cancers. In summary, recent advances in the discovery and evaluation of ginsenosides as cancer therapeutic agents support further pre-clinical and clinical development of these agents for the treatment of primary and metastatic tumors. PMID:22403544

New Antiresorptive Therapies for Postmenopausal Osteoporosis

PubMed Central

2015-01-01

Osteoporosis is a systemic skeletal disease whose risk increases with age and it is common among postmenopausal women. Currently, almost all pharmacological agents for osteoporosis target the bone resorption component of bone remodeling activity. Current antiresorptive agents are effective, but the effectiveness of some agents is limited by real or perceived intolerance, longterm adverse events (AEs), coexisting comorbidities, and inadequate long-term adherence. New antiresorptive therapies that may expand options for the prevention and treatment of osteoporosis include denosumab, combination of conjugated estrogen/bazedoxifene and cathepsin K inhibitors. However, the long-term efficacy and AEs of these antiresorptive therapies need to be confirmed in studies with a longer follow-up period. PMID:26046031

Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.

PubMed

Molhoek, E Margo; van Dijk, Albert; Veldhuizen, Edwin J A; Dijk-Knijnenburg, Helma; Mars-Groenendijk, Roos H; Boele, Linda C L; Kaman-van Zanten, Wendy E; Haagsman, Henk P; Bikker, Floris J

2010-09-01

Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia pestis that may potentially be used by bioterrorists. Substitution of single and multiple phenylalanine (Phe) residues to tryptophan (Trp) in C1-15 resulted in variants with improved antibacterial activity against B. anthracis and Y. pestis as well as decreased salt sensitivity. In addition, these peptides exhibited enhanced neutralisation of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). The antibacterial and LPS-neutralising activities of these C1-15-derived peptides are exerted at concentrations far below the concentrations that are toxic to human PBMCs. Taken together, we show that Phe-->Trp substitutions in C1-15 variants enhances the antibacterial and LPS-neutralising activities against pathogenic bacteria, including those that may potentially be used as biological warfare agents. Copyright (c) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

PubMed Central

Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

2014-01-01

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

Isolation, screening, and characterization of surface-active agent-producing, oil-degrading marine bacteria of Mumbai Harbor.

PubMed

Mohanram, Rajamani; Jagtap, Chandrakant; Kumar, Pradeep

2016-04-15

Diverse marine bacterial species predominantly found in oil-polluted seawater produce diverse surface-active agents. Surface-active agents produced by bacteria are classified into two groups based on their molecular weights, namely biosurfactants and bioemulsifiers. In this study, surface-active agent-producing, oil-degrading marine bacteria were isolated using a modified Bushnell-Haas medium with high-speed diesel as a carbon source from three oil-polluted sites of Mumbai Harbor. Surface-active agent-producing bacterial strains were screened using nine widely used methods. The nineteen bacterial strains showed positive results for more than four surface-active agent screening methods; further, these strains were characterized using biochemical and nucleic acid sequencing methods. Based on the results, the organisms belonged to the genera Acinetobacter, Alcanivorax, Bacillus, Comamonas, Chryseomicrobium, Halomonas, Marinobacter, Nesterenkonia, Pseudomonas, and Serratia. The present study confirmed the prevalence of surface-active agent-producing bacteria in the oil-polluted waters of Mumbai Harbor. Copyright © 2016 Elsevier Ltd. All rights reserved.

Contamination control by use of ethylene oxide

NASA Technical Reports Server (NTRS)

Stroud, R. H.; Lyle, R. G.

1972-01-01

The uses of ethylene oxide as a decontaminating agent for planetary quarantine related applications are reported. Aspects discussed include: applications and limitations, chemical and physical properties, germicidal activity, methods of applications, and effects on personnel.

General principles of antimicrobial therapy.

PubMed

Leekha, Surbhi; Terrell, Christine L; Edson, Randall S

2011-02-01

Antimicrobial agents are some of the most widely, and often injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community.

General Principles of Antimicrobial Therapy

PubMed Central

Leekha, Surbhi; Terrell, Christine L.; Edson, Randall S.

2011-01-01

Antimicrobial agents are some of the most widely, and often injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community. PMID:21282489

DNA-PK assay

DOEpatents

Anderson, Carl W.; Connelly, Margery A.

2004-10-12

The present invention provides a method for detecting DNA-activated protein kinase (DNA-PK) activity in a biological sample. The method includes contacting a biological sample with a detectably-labeled phosphate donor and a synthetic peptide substrate defined by the following features to provide specific recognition and phosphorylation by DNA-PK: (1) a phosphate-accepting amino acid pair which may include serine-glutamine (Ser-Gln) (SQ), threonine-glutamine (Thr-Gln) (TQ), glutamine-serine (Gln-Ser) (QS), or glutamine-threonine (Gln-Thr) (QT); (2) enhancer amino acids which may include glutamic acid or glutamine immediately adjacent at the amino- or carboxyl- side of the amino acid pair and forming an amino acid pair-enhancer unit; (3) a first spacer sequence at the amino terminus of the amino acid pair-enhancer unit; (4) a second spacer sequence at the carboxyl terminus of the amino acid pair-enhancer unit, which spacer sequences may include any combination of amino acids that does not provide a phosphorylation site consensus sequence motif; and, (5) a tag moiety, which may be an amino acid sequence or another chemical entity that permits separating the synthetic peptide from the phosphate donor. A compostion and a kit for the detection of DNA-PK activity are also provided. Methods for detecting DNA, protein phosphatases and substances that alter the activity of DNA-PK are also provided. The present invention also provides a method of monitoring protein kinase and DNA-PK activity in living cells. -A composition and a kit for monitoring protein kinase activity in vitro and a composition and a kit for monitoring DNA-PK activities in living cells are also provided. A method for identifying agents that alter protein kinase activity in vitro and a method for identifying agents that alter DNA-PK activity in living cells are also provided.

A primary-school-based study to reduce prevalence of childhood obesity in Catalunya (Spain) - EDAL-Educació en alimentació: study protocol for a randomised controlled trial

PubMed Central

2011-01-01

Background The EdAL (Educació en Alimentació) study is a long-term, nutrition educational, primary-school-based program designed to prevent obesity by promoting a healthy lifestyle that includes dietary recommendations and physical activity. The aims are: 1) to evaluate the effects of a 3-year school-based life-style improvement program on the prevalence of obesity in an area of north-west Mediterranean 2) To design a health-promotion program to be implemented by health-promoter agents (university students) in primary schools. Methods/Design 1) The intervention study is a randomised, controlled, school-based program performed by university-student health-promoter agents. Initial pupil enrolment was in 2006 and continued for 3 years. We considered two clusters (designated as cluster A and cluster B) as the units for randomisation. The first cluster involved 24 schools from Reus and the second involved 14 schools from surrounding towns Cambrils, Salou and Vilaseca combined in order to obtain comparable groups. There are very good communications between schools in each town, and to avoid cross influence of the programs resulting from inter-school dialogue, the towns themselves were the unit for randomisation. Data collected included name, gender, date and place of birth at the start of the program and, subsequently, weight, height, body mass index (BMI) and waist circumference every year for 3 years. Questionnaires on eating and physical activity habits are filled-in by the parents at the start and end of the study and, providing that informed consent is given, the data are analysed on the intention-to-treat basis. The interventions are based on 8 nutritional and physical activity objectives. They are implemented by university students as part of the university curriculum in training health-promoter agents. These 8 objectives are developed in 4 educational activities/year for 3 years (a total of 12 activities; 1 h/activity) performed by the health-promoter agents in primary schools. Control pupils follow their usual activities. 2) Courses on education and promotion of health, within in the curriculum of medicine and health sciences for university students, are designed to train health-promoter agents to administer these activities in primary schools. Discussion This controlled school-based intervention will test the possibility of preventing childhood obesity. Trial registration number ISRCTN: ISRCTN29247645 PMID:21352597

Optimization of the central linker of dicationic bis-benzimidazole anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-07-01

A series of bis-benzimidazole diamidine compounds containing different central linkers has been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Seven compounds have shown potent antibacterial activities. The anti-MRSA and anti-VRE activities of compound 1h were more potent than that of the lead compound 1a and vancomycin.

Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1

PubMed Central

Sagar, S.M.; Yance, D.; Wong, R.K.

2006-01-01

An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies. PMID:17576437

Agent independent task planning

NASA Technical Reports Server (NTRS)

Davis, William S.

1990-01-01

Agent-Independent Planning is a technique that allows the construction of activity plans without regard to the agent that will perform them. Once generated, a plan is then validated and translated into instructions for a particular agent, whether a robot, crewmember, or software-based control system. Because Space Station Freedom (SSF) is planned for orbital operations for approximately thirty years, it will almost certainly experience numerous enhancements and upgrades, including upgrades in robotic manipulators. Agent-Independent Planning provides the capability to construct plans for SSF operations, independent of specific robotic systems, by combining techniques of object oriented modeling, nonlinear planning and temporal logic. Since a plan is validated using the physical and functional models of a particular agent, new robotic systems can be developed and integrated with existing operations in a robust manner. This technique also provides the capability to generate plans for crewmembers with varying skill levels, and later apply these same plans to more sophisticated robotic manipulators made available by evolutions in technology.

An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents.

PubMed

Xu, Bing; Wu, Gao-Rong; Zhang, Xin-Yu; Yan, Meng-Meng; Zhao, Rui; Xue, Nan-Nan; Fang, Kang; Wang, Hui; Chen, Meng; Guo, Wen-Bo; Wang, Peng-Long; Lei, Hai-Min

2017-06-02

Glycyrrhetinic Acid ( GA ), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors.

PubMed

Hanski, Leena; Vuorela, Pia

2016-11-28

Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we describe the strategies that have been successfully applied for the identification of nonconventional antichlamydial agents, including target-based and ligand-based virtual screening, ethnopharmacological approach and pharmacophore-based design of antimicrobial peptide-mimicking compounds. Among the antichlamydial agents identified via these strategies, most translational work has been carried out with plant phenolics. Thus, currently available data on their properties as antichlamydial agents are described, highlighting their potential mechanisms of action. In this context, the role of mitogen-activated protein kinase activation in the intracellular growth and survival of C . pneumoniae is discussed. Owing to the complex and often complementary pathways applied by C. pneumoniae in the different stages of its life cycle, multitargeted therapy approaches are expected to provide better tools for antichlamydial therapy than agents with a single molecular target.

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

PubMed Central

Hanski, Leena; Vuorela, Pia

2016-01-01

Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we describe the strategies that have been successfully applied for the identification of nonconventional antichlamydial agents, including target-based and ligand-based virtual screening, ethnopharmacological approach and pharmacophore-based design of antimicrobial peptide-mimicking compounds. Among the antichlamydial agents identified via these strategies, most translational work has been carried out with plant phenolics. Thus, currently available data on their properties as antichlamydial agents are described, highlighting their potential mechanisms of action. In this context, the role of mitogen-activated protein kinase activation in the intracellular growth and survival of C. pneumoniae is discussed. Owing to the complex and often complementary pathways applied by C. pneumoniae in the different stages of its life cycle, multitargeted therapy approaches are expected to provide better tools for antichlamydial therapy than agents with a single molecular target. PMID:27916800

Nano/micromotors for security/defense applications. A review.

PubMed

Singh, Virendra V; Wang, Joseph

2015-12-14

The new capabilities of man-made micro/nanomotors open up considerable opportunities for diverse security and defense applications. This review highlights new micromotor-based strategies for enhanced security monitoring and detoxification of chemical and biological warfare agents (CBWA). The movement of receptor-functionalized nanomotors offers great potential for sensing and isolating target bio-threats from complex samples. New mobile reactive materials based on zeolite or activated carbon offer considerable promise for the accelerated removal of chemical warfare agents. A wide range of proof-of-concept motor-based approaches, including the detection and destruction of anthrax spores, 'on-off' nerve-agent detection or effective neutralization of chemical warfare agents have thus been demonstrated. The propulsion of micromotors and their corresponding bubble tails impart significant mixing that greatly accelerates such detoxification processes. These nanomotors will thus empower sensing and destruction where stirring large quantities of decontaminating reagents and controlled mechanical agitation are impossible or undesired. New technological breakthroughs and greater sophistication of micro/nanoscale machines will lead to rapid translation of the micromotor research activity into practical defense applications, addressing the escalating threat of CBWA.

Nano/micromotors for security/defense applications. A review

NASA Astrophysics Data System (ADS)

Singh, Virendra V.; Wang, Joseph

2015-11-01

The new capabilities of man-made micro/nanomotors open up considerable opportunities for diverse security and defense applications. This review highlights new micromotor-based strategies for enhanced security monitoring and detoxification of chemical and biological warfare agents (CBWA). The movement of receptor-functionalized nanomotors offers great potential for sensing and isolating target bio-threats from complex samples. New mobile reactive materials based on zeolite or activated carbon offer considerable promise for the accelerated removal of chemical warfare agents. A wide range of proof-of-concept motor-based approaches, including the detection and destruction of anthrax spores, `on-off' nerve-agent detection or effective neutralization of chemical warfare agents have thus been demonstrated. The propulsion of micromotors and their corresponding bubble tails impart significant mixing that greatly accelerates such detoxification processes. These nanomotors will thus empower sensing and destruction where stirring large quantities of decontaminating reagents and controlled mechanical agitation are impossible or undesired. New technological breakthroughs and greater sophistication of micro/nanoscale machines will lead to rapid translation of the micromotor research activity into practical defense applications, addressing the escalating threat of CBWA.

Reversed enantioselectivity of diisopropyl fluorophosphatase against organophosphorus nerve agents by rational design.

PubMed

Melzer, Marco; Chen, Julian C-H; Heidenreich, Anne; Gäb, Jürgen; Koller, Marianne; Kehe, Kai; Blum, Marc-Michael

2009-12-02

Diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris is an efficient and robust biocatalyst for the hydrolysis of a range of highly toxic organophosphorus compounds including the nerve agents sarin, soman, and cyclosarin. In contrast to the substrate diisopropyl fluorophosphate (DFP) the nerve agents possess an asymmetric phosphorus atom, which leads to pairs of enantiomers that display markedly different toxicities. Wild-type DFPase prefers the less toxic stereoisomers of the substrates which leads to slower detoxification despite rapid hydrolysis. Enzyme engineering efforts based on rational design yielded two quadruple enzyme mutants with reversed enantioselectivity and overall enhanced activity against tested nerve agents. The reversed stereochemical preference is explained through modeling studies and the crystal structures of the two mutants. Using the engineered mutants in combination with wild-type DFPase leads to significantly enhanced activity and detoxification, which is especially important for personal decontamination. Our findings may also be of relevance for the structurally related enzyme human paraoxonase (PON), which is of considerable interest as a potential catalytic in vivo scavenger in case of organophosphorus poisoning.

Vibrational spectroscopy standoff detection of threat chemicals

NASA Astrophysics Data System (ADS)

Ortiz-Rivera, William; Pacheco-Londoño, Leonardo C.; Castro-Suarez, John R.; Felix-Rivera, Hilsamar; Hernandez-Rivera, Samuel P.

2011-06-01

Spectroscopy based standoff detection systems: Raman and FTIR have been tested for detection of threat chemicals, including highly energetic materials, homemade explosives, explosives formulations and high explosives mixtures. Other threat chemicals studied included toxic industrial compounds (TIC) and chemical agent simulants. Microorganisms and biological threat agent simulants have also been detected at standoff distances. Open Path FTIR has been used to detect vapors and chemicals deposited on metal surfaces at μg/cm2 levels at distances as far as 30 m in active mode and 60 m in passive mode. In the case of Raman telescope, standoff distances for acetonitrile and ammonium nitrate were 140 m.

Method for photo-altering a biological system to improve biological effect

DOEpatents

Hill, Richard A.; Doiron, Daniel R.; Crean, David H.

2000-08-01

Photodynamic therapy is a new adjunctive therapy for filtration surgery that does not use chemotherapy agents or radiation, but uses pharmacologically-active sensitizing compounds to produce a titratable, localized, transient, post operative avascular conjunctiva. A photosensitizing agent in a biological system is selectively activated by delivering the photosensitive agent to the biological system and laser activating only a spatially selected portion of the delivered photosensitive agent. The activated portion of the photosensitive agent reacts with the biological system to obtain a predetermined biological effect. As a result, an improved spatial disposition and effectuation of the biological effect by the photosensitive agent in the biological system is achieved.

Sales of veterinary antibacterial agents in nine European countries during 2005-09: trends and patterns.

PubMed

Grave, Kari; Greko, Christina; Kvaale, Mari K; Torren-Edo, Jordi; Mackay, David; Muller, Arno; Moulin, Gerard

2012-12-01

To identify trends and patterns of sales of veterinary antimicrobial agents in nine European countries during 2005-09 in order to document the situation. Existing sales data, in tonnes of active ingredients, of veterinary antimicrobial agents by class were collected from nine European countries in a standardized manner for the years 2005-09 (one country for 2006-09). A population correction unit (PCU) is introduced as a proxy for the animal population potentially treated with antimicrobial agents. The sales data are expressed as mg of active substance/PCU. Data coverage was reported to be 98%-100% for the nine countries. Overall, sales of veterinary antimicrobials agents, in mg/PCU, declined during the reporting period in the nine countries. Substantial differences in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents, expressed as mg/PCU, between the nine countries are observed. The major classes sold were penicillins, sulphonamides and tetracyclines. The sales accounted for by the various veterinary antimicrobial agents have changed substantially for most countries. An increase in the sales of third- and fourth-generation cephalosporins and fluoroquinolones were observed for the majority of the countries. Through re-analysis of existing data by application of a harmonized approach, an overall picture of the trends in the sales of veterinary antimicrobial agents in the nine countries was obtained. Notable differences in trends in sales between the countries were observed. Further studies, preferably including data by animal species, are needed to understand the factors that explain these observations.

A brief review on activated carbon derived from agriculture by-product

NASA Astrophysics Data System (ADS)

Yahya, Mohd Adib; Mansor, Muhammad Humaidi; Zolkarnaini, Wan Amani Auji Wan; Rusli, Nurul Shahnim; Aminuddin, Anisah; Mohamad, Khalidah; Sabhan, Fatin Aina Mohamad; Atik, Arif Abdallah Aboubaker; Ozair, Lailatun Nazirah

2018-06-01

A brief review focusing on preparation of the activated carbon derived from agriculture by-products is presented. The physical and chemical activation of activated carbon were also reviewed. The effects of various parameters including types of activating agents, temperature, impregnation ratio, were also discussed. The applications of activated carbon from agricultural by products were briefly reviewed. It is provenly evident in this review, the relatively inexpensive and renewable resources of the agricultural waste were found to be effectively being converted into wealth materials.

PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

PubMed Central

Massacesi, Cristian; Di Tomaso, Emmanuelle; Urban, Patrick; Germa, Caroline; Quadt, Cornelia; Trandafir, Lucia; Aimone, Paola; Fretault, Nathalie; Dharan, Bharani; Tavorath, Ranjana; Hirawat, Samit

2016-01-01

The PI3K–AKT–mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described. PMID:26793003

Comparison of the anti-proliferation and apoptosis-induction activities of sulindac, celecoxib, curcumin, and nifedipine in mismatch repair-deficient cell lines.

PubMed

Wei, Shu-Chen; Lin, Young-Sun; Tsao, Po-Nien; Wu-Tsai, Jyy-Ji; Wu, C H Herbert; Wong, Jau-Min

2004-08-01

The adenomatous polyposis coli (APC) and mismatch repair (MMR) pathways are both involved in the tumorigenesis of hereditary colorectal cancers. Chemoprevention focuses on the APC pathway in the absence of information concerning MMR targets. This study compared the anticancer effects of sulindac, celecoxib, curcumin, and nifedipine in MMR-deficient cell lines, in order to determine the most appropriate chemopreventive agent for long-term use in patients with hereditary colorectal cancer. Five human colorectal cell lines (SW480, HCT116, LoVo, SW48, and HCT15) and an endometrial cancer cell line (HEC-1-A) were used for susceptibility testing. Tests included assays for growth inhibition, cell-cycle arrest, and apoptosis. Sulindac, celecoxib, curcumin, and nifedipine all displayed dose- and time-dependent anti-proliferation activities. Celecoxib was the most effective anti-proliferative agent, and increased the G0/G1 phase proportion in the cell cycle after treatment more significantly than the other agents in all cell lines. Curcumin displayed a more potent apoptosis-inducing activity than the other agents in treated cells. The tested drugs were effective against colorectal and endometrial cancer cell lines. Celecoxib is more potent with fewer side effects than sulindac. Nifedipine's observed chemopreventive efficacy may complement its known therapeutic application in patients with hypertension.

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer

PubMed Central

Budisan, Liviuta; Gulei, Diana; Zanoaga, Oana Mihaela; Irimie, Alexandra Iulia; Chira, Sergiu; Braicu, Cornelia; Gherman, Claudia Diana; Berindan-Neagoe, Ioana

2017-01-01

Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer. PMID:28587155

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer.

PubMed

Budisan, Liviuta; Gulei, Diana; Zanoaga, Oana Mihaela; Irimie, Alexandra Iulia; Sergiu, Chira; Braicu, Cornelia; Gherman, Claudia Diana; Berindan-Neagoe, Ioana

2017-06-01

Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer.

Screening complex hazardous wastes for mutagenic activity using a modified version of the TLC/Salmonella assay.

PubMed

Houk, V S; Claxton, L D

1986-03-01

10 complex hazardous wastes were tested for mutagenic activity using a modified version of the TLC/Salmonella assay developed by Bjørseth et al. (1982). This fractionation/bioassay scheme couples thin-layer chromatography (TLC) with the Salmonella/mammalian-microsome (Ames) assay for the detection of mutagenic constituents in complex mixtures. Crude (unadulterated) hazardous wastes and selected hazardous waste extracts were fractionated on commercially available cellulose TLC plates. Mutagenicity testing was performed in situ by applying a single overlay of minimal growth agar, tester strain TA98 or TA100, and the optional metabolic activation system directly onto the developed chromatogram. A mutagenic effect was indicated either by the appearance of localized clusters of revertant colonies or by an increase in total revertant growth vis-à-vis control plates. 7 of 10 hazardous wastes (including tars, emulsions, sludges, and spent acids and caustics) demonstrated mutagenic activity when tested by this method. To assess the sensitivity of the modified TLC/Salmonella assay, 14 Salmonella mutagens from a wide range of chemical classes and polarities were tested. Selected compounds included heterocyclics, aromatic amines, alkylating agents, antitumor agents, a nitrosamine and a nitroaromatic. 11 of the 14 mutagens were positive in this test system. The 3 compounds refractory to analysis included a polycyclic aromatic hydrocarbon and two volatiles.

Targeting the Regulatory Machinery of BIM for Cancer Therapy

PubMed Central

Harada, Hisashi; Grant, Steven

2013-01-01

BIM represents a BH3-only proapoptotic member of the BCL-2 family of apoptotic regulatory proteins. Recent evidence suggests that in addition to its involvement in normal homeostasis, BIM plays a critical role in tumor cell biology, including the regulation of tumorigenesis through activities as a tumor suppressor, tumor metastasis, and tumor cell survival. Consequently, BIM has become the focus of intense interest as a potential target for cancer chemotherapy. The control of BIM expression is complex, and involves multiple factors, including epigenetic events (i.e., promoter acetylation or methylation, miRNA), transcription factors, posttranscriptional regulation, and posttranslational modifications, most notably phosphorylation. Significantly, the expression of BIM by tumor cells has been shown to play an important role in determining the response of transformed cells to not only conventional cytotoxic agents, but also to a broad array of targeted agents that interrupt cell signaling and survival pathways. Furthermore, modifications in BIM expression may be exploited to improve the therapeutic activity and potentially the selectivity of such agents. It is likely that evolving insights into the factors that regulate BIM expression will ultimately lead to novel BIM-based therapeutic strategies in the future. PMID:22856430

United States Department of Agriculture-Agricultural Research Service research programs on microbes for management of plant-parasitic nematodes.

PubMed

Meyer, Susan L F

2003-01-01

Restrictions on the use of conventional nematicides have increased the need for new methods of managing plant-parasitic nematodes. Consequently, nematode-antagonistic microbes, and active compounds produced by such organisms, are being explored as potential additions to management practices. Programs in this area at the USDA Agricultural Research Service investigate applied biocontrol agents, naturally occurring beneficial soil microbes and natural compounds. Specific research topics include use of plant growth-promoting rhizobacteria and cultural practices for management of root-knot and ring nematodes, determination of management strategies that enhance activity of naturally occurring Pasteuria species (bacterial obligate parasites of nematodes), studies on interactions between biocontrol bacteria and bacterial-feeding nematodes, and screening of microbes for compounds active against plant-parasitic nematodes. Some studies involve biocontrol agents that are active against nematodes and soil-borne plant-pathogenic fungi, or combinations of beneficial bacteria and fungi, to manage a spectrum of plant diseases or to increase efficacy over a broader range of environmental conditions. Effective methods or agents identified in the research programs are investigated as additions to existing management systems for plant-parasitic nematodes.

Identification of poly(rC) binding protein 2 (PCBP2) as a target protein of immunosuppressive agent 15-deoxyspergualin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murahashi, Masataka; Simizu, Siro; Morioka, Masahiko

15-Deoxyspergualin (DSG) is an immunosuppressive agent being clinically used. Unlike tacrolimus and cyclosporine A, it does not inhibit the calcineurin pathway, and its mechanism of action and target molecule have not been elucidated. Therefore, we previously prepared biotinylated derivative of DSG (BDSG) to fish up the target protein. In the present research, we identified poly(rC) binding protein 2 (PCBP2) as a DSG-binding protein using this probe. DSG was confirmed to bind to PCBP2 by pull-down assay. Intracellular localization of PCBP2 was changed from the nucleus to the cytoplasm by DSG treatment. DSG inhibited the cell growth, and over-expression of PCBP2more » reduced the anti-proliferative activity of DSG. PCBP2 is known to regulate various proteins including STAT1/2. Thus, we found PCBP2 as the first target protein of DSG that can explain the immunosuppressive activity. -- Highlights: •Fifteen-deoxyspergualin (DSG) is an immunosuppressive agent clinically used. •We have identified PCBP2, an RNA-binding protein, as a molecular target of DSG. •Alteration of PCBP2 activity may explain the immunosuppressive activity of DSG.« less

76 FR 79697 - Withdrawal of Notices of Opportunity for a Hearing; Penicillin and Tetracycline Used in Animal Feed

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-22

... antibiotic or antibacterial agent in animal feed presents a hazard to human and animal health. (Refs. 1 and 6... ``antimicrobial'' refers broadly to drugs with activity against a variety of microorganisms including: Bacteria, viruses, fungi, and parasites. Antimicrobial drugs that have specific activity against bacteria are...

Methods of Antimicrobial Coating of Diverse Materials

NASA Technical Reports Server (NTRS)

Akse, James R.; Holtsnider, John T.; Kliestik, Helen

2011-01-01

Methods of coating diverse substrate materials with antimicrobial agents have been developed. Originally intended to reduce health risks to astronauts posed by pathogenic microorganisms that can grow on surfaces in spacecraft, these methods could also be used on Earth for example, to ensure sterility of surgical inserts and other medical equipment. The methods involve, generally, chemical preparation of substrate surfaces to enable attachment of antimicrobial molecules to the substrate surfaces via covalent bonds. Substrate materials that have been treated successfully include aluminum, glass, a corrosion-resistant nickel alloy, stainless steel, titanium, and poly(tetrafluoroethylene). Antimicrobial agents that have been successfully immobilized include antibiotics, enzymes, bacteriocins, bactericides, and fungicides. A variety of linkage chem istries were employed. Activity of antimicrobial coatings against gram-positive bacteria, gram-negative bacteria, and fungi was demonstrated. Results of investigations indicate that the most suitable combination of antimicrobial agent, substrate, and coating method depends upon the intended application.

A Mechanistic Review on Medicinal Plants Used for Diabetes Mellitus in Traditional Persian Medicine

PubMed Central

Farzaei, Fatemeh; Morovati, Mohammad Reza; Farjadmand, Fatemeh; Farzaei, Mohammad Hosein

2017-01-01

Diabetes mellitus is the most common endocrine disorder and a major cause of morbidity and mortality. Traditional medicines worldwide suggest a wide range of natural remedies for the prevention and treatment of chronic disorders, including diabetes mellitus. This mechanistic review aims to highlight the significance of medicinal plants traditionally used as dietary supplements in Persian medicine in adjunct with restricted conventional drugs for the prevention and treatment of diabetes mellitus. Mounting evidence suggests that these natural agents perform their protective and therapeutic effect on diabetes mellitus via several cellular mechanisms, including regeneration of pancreatic β cell, limitation of glycogen degradation and gluconeogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, antioxidative stress, as well as modulation of intracellular signaling transduction pathways. In conclusion, traditional medicinal plants used in Persian medicine can be considered as dietary supplements with therapeutic potential for diabetes mellitus and maybe potential sources of new orally active agent(s). PMID:29228789

Use of atypical antipsychotics for treatment-resistant major depressive disorder.

PubMed

Papakostas, George I; Shelton, Richard C

2008-12-01

Despite the progressive increase in the number of pharmacologic agents with potential antidepressant activity, many patients suffering from major depressive disorder (MDD) continue to be symptomatic. Clearly, an urgent need exists to develop safer, better tolerated, and more effective treatments for MDD. Use of atypical antipsychotic agents as adjunctive treatment for treatment-resistant MDD (TRD) represents one such effort toward novel pharmacotherapy development. Atypical antipsychotic agents have been hypothesized to be beneficial in treating mood disorders, including TRD, as a result of their complex mechanisms of action. After an initial series of positive case reports, series, and small clinical trials, subsequent larger-scale projects have yielded conflicting results. However, more recently, larger-scale clinical trials have supported the effectiveness of at least some of these medications. This review summarizes the existing data regarding the effectiveness of these medications in treating TRD, including biochemical rationale and clinical data.

Identification and evaluation of agents isolated from traditionally used herbs against Ophiophagus hannah venom.

PubMed

Salama, R; Sattayasai, J; Gande, A K; Sattayasai, N; Davis, M; Lattmann, E

2012-02-01

The aim of this study was firstly to identify active molecules in herbs, that are traditionally used for the treatment of snake bite, such as Curcuma antinaia, Curcuma contravenenum, Andrographis paniculata, and Tanacetum parthenium; secondly to test similar structurally related molecules and finally to prepare and evaluate an efficient formulation against Ophiophagus hannah venom intoxification. Three labdane based compounds, including labdane dialdehyde, labdane lactone, and labdane trialdehyde and two lactones including 14-deoxy-11,12-didehydroandrographolide and parthenolide were isolated by column chromatography and characterised. Using the isolated rat phrenic nerve-hemidiaphragm preparation, the antagonistic effect of crude extracts, isolated compounds and prepared formulations were measured in vitro on the inhibition of the neuromuscular transmission. Inhibition on muscle contraction, produced by the 5 μg/mL venom, was reversed by test agents in organ bath preparations. A labdane trialdehyde, isolated from C. contravenenum, was identified as the best antagonising agent in the low micromolar range. Tests on formulations of the most potent C. contravenenum extract showed, that the suppository with witepsol H15 was an effective medicine against O. hannah venom. This study elucidated the active compounds, accounting for the antivenin activity of traditionally used herbs and suggested the most suitable formulation, which may help to develop potent medicines for the treatment of snake bite in the future.

Compact Apparatus Grows Protein Crystals

NASA Technical Reports Server (NTRS)

Bugg, Charles E.; Delucas, Lawrence J.; Suddath, Fred L.; Snyder, Robert S.; Herren, Blair J.; Carter, Daniel C.; Yost, Vaughn H.

1989-01-01

Laboratory apparatus provides delicately balanced combination of materials and chemical conditions for growth of protein crystals. Apparatus and technique for growth based on hanging-drop method for crystallization of macromolecules. Includes pair of syringes with ganged plungers. One syringe contains protein solution; other contains precipitating-agent solution. Syringes intrude into cavity lined with porous reservoir material saturated with 1 mL or more of similar precipitating-agent solution. Prior to activation, ends of syringes plugged to prevent transport of water vapor among three solutions.

Marine products with anti-protozoal activity: a review.

PubMed

García, Marley; Monzote, Lianet

2014-01-01

The marine organisms are a rich source of varied natural products with unique functionality. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna for treatment and/or prevention of human diseases. The present review briefly illustrates current status of marine products as antiprotozoal agents. The in vitro and in vivo studies of marine algae, invertebrates and micro-organism against different protozoa parasites are included. The marine products studied, according to international criterions for selection of more promisory products in the different models reported, demonstrated their potentialities as antiprozoal agents. Herein, the interest of scientific community to search new alternatives from marine environment has been demonstrated.

Appropriate use of the carbapenems.

PubMed

Brink, A J; Feldman, C; Grolman, D C; Muckart, D; Pretorius, J; Richards, G A; Senekal, M; Sieling, W

2004-10-01

The carbapenems are a group of broad-spectrum beta-lactam antibiotic agents of which there are three parenteral preparations currently available in South Africa, namely imimpenem/cilastatin, meropenem and ertapenem. Owing to the fact that imipenem/cilastatin and meropenem have a broad spectrum of activity that includes Pseudomonas and Acinetobacter species, they are ideal antibiotics for treatment of severe nosocomial infections. In contrast, ertapenem has limited in vitro activity against the latter non-fermentative gram-negative bacteria and is therefore more suitable for the treatment of certain severe community-acquired infections. This statement arises out of concerns about the general abuse of antibiotics such as the carbapenems, with the primary intention of highlighting the appropriate use of these agents.

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

NASA Astrophysics Data System (ADS)

Shi, Changhong; Wu, Jason Boyang; Pan, Dongfeng

2016-05-01

A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.

In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents.

PubMed

Czyzewski, Ann M; Jenssen, Håvard; Fjell, Christopher D; Waldbrook, Matt; Chongsiriwatana, Nathaniel P; Yuen, Eddie; Hancock, Robert E W; Barron, Annelise E

2016-01-01

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents.

Comparative in vitro activities of dalbavancin and seven comparator agents against 41 Staphylococcus species cultured from osteomyelitis infections and 18 VISA and hVISA strains.

PubMed

Citron, Diane M; Tyrrell, Kerin L; Goldstein, Ellie J C

2014-08-01

Due to a high rate of relapse, osteomyelitis remains difficult to treat, requiring prolonged parenteral therapy. MICs for 41 consecutive Staphylococcus species recovered from patients with osteomyelitis were determined for dalbavancin, daptomycin, doxycycline, levofloxacin, linezolid, vancomycin, trimethoprim-sulfamethoxazole, rifampin, and vancomycin. Strains of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant VISA were included for additional comparison. Except for rifampin, dalbavancin was the most active agent tested. Dalbavancin is given once a week, making treatment of infections such as osteomyelitis potentially more convenient and thus could help reduce the rate of hospitalizations and outpatient costs. Copyright © 2014 Elsevier Inc. All rights reserved.

New and investigational antiretroviral drugs for HIV infection: mechanisms of action and early research findings.

PubMed

Saag, Michael S

2012-12-01

Numerous investigational antiretroviral agents are in clinical development. Among them are festinavir (BMS986001), a thymidine analogue similar to stavudine with reduced potential for toxicity; GS-7340, a prodrug of tenofovir that achieves greater intracellular concentrations; MK-1439, a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI-associated resistance mutations; and albuvirtide, a long-acting parenteral fusion inhibitor. Investigational integrase strand transfer inhibitors (InSTIs) include elvitegravir, recently approved by the US Food and Drug Administration (FDA) as part of a once-daily, single-tablet formulation with cobicistat/tenofovir/emtricitabine; dolutegravir, which maintains some activity against raltegravir- and elvitegravir-resistant mutants; and S/GSK1265744, which also maintains some activity against resistance mutations in the integrase gene and is being developed as a long-lasting parenteral agent. Novel 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs), agents that were originally thought to inhibit the interaction of integrase with its cofactor lens epithelium-derived growth factor p75 (LEDGF/p75), be active against InSTI-resistant mutants and to have additive activity when combined with InSTIs. This article summarizes a presentation by Michael S. Saag, MD, at the IAS-USA live Improving the Management of HCV Disease continuing medical education program held in New York in October 2012.

Synthesis and Bioactivity Evaluation of Novel 2-Salicyloylbenzofurans as Antibacterial Agents.

PubMed

Phan, Phuong-Thuy T; Nguyen, Thu-Trang T; Nguyen, Hong-Nhung T; Le, Bao-Khanh N; Vu, Thao T; Tran, Dong C; Pham, Tuan-Anh N

2017-04-25

In order to discover new antibacterial agents, series of 2-salicyloylbenzofuran derivatives were designed, synthesized and evaluated for their antibacterial activities against three Gram-(+) strains (methicillin-sensitive Staphylococcus aureus (MSSA) ATCC 29213, methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, and Streptococcus faecalis ( S. faecalis ) ATCC 29212) and one Gram-(-) strain ( Escherichia coli (E. coli) ATCC 25922). The 2-salicyloylbenzofuran heterocycles were generated by Rap-Stoermer condensation of salicylaldehydes with phenacyl bromides and then converted to diverse O -ether derivatives by Williamson synthesis. The targeted products were screened for in vitro qualitative (zone of inhibition) and quantitative (MIC) antibacterial activities by agar well diffusion assay and agar dilution method. Amongst the compounds, those bearing carboxylic acid functional group were found to exhibit reasonable activity against Gram-(+) bacterial strains including S. faecalis , MSSA and MRSA with the most potent antibacterial agent 8h (MICs = 0.06-0.12 mM). Besides, the 2-salicyloylbenzofurans partly displayed inhibitory activity against MRSA with the best MICs = 0.14 mM ( 8f ) and 0.12 mM ( 8h ). Finally, the antibacterial results preliminarily suggested that the substituent bearing carboxylic acid group at salicyloyl-C2 and the bromine atoms on the benzofuran moiety seem to be the functionality necessary for antibacterial activities.

Common and distinct neural mechanisms of the fundamental dimensions of social cognition.

PubMed

Han, Mengfei; Bi, Chongzeng; Ybarra, Oscar

2016-01-01

In the present study, we used a valence classification task to investigate the common and distinct neural basis of the two fundamental dimensions of social cognition (agency and communion) using functional magnetic resonance imaging (fMRI). The results showed that several brain areas associated with mentalizing, along with the inferior parietal gyrus in the mirror system, showed overlap in response to both agentic and communal words. These findings suggest that both content categories are related to the neural basis of social cognition; further, several areas in the default mode network (DMN) showed similar deactivations between agency and communion, reflecting task-induced deactivation (TID). In terms of distinct activations, the findings indicated greater deactivations for communal than agentic content in the ventral anterior cingulate (vACC) and medial orbitofrontal cortex (mOFC). Communion also showed greater activation in some visual areas compared to agentic content, including occipital gyrus, lingual gyrus, and fusiform gyrus. These activations may reflect greater allocation of attentional resources to visual areas when processing communal content, or inhibition of cognitive activity irrelevant to task performance. If so, this suggests greater attention and engagement with communion-related content. The present research thus suggests common and differential activations for agency- versus communion-related content.

Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species.

PubMed

Credito, Kim L; Appelbaum, Peter C

2004-11-01

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between

Nutritional agents with anti-inflammatory properties in chemoprevention of colorectal neoplasia.

PubMed

Hull, Mark A

2013-01-01

The strong link between inflammation and colorectal carcinogenesis provides the rationale for using anti-inflammatory agents for chemoprevention of colorectal cancer (CRC). Several naturally occurring substances with anti-inflammatory properties, used in a purified 'nutraceutical' form, including omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and polyphenols such as curcumin and resveratrol, have been demonstrated to have anti-CRC activity in preclinical models. As expected, these agents have an excellent safety and tolerability profile in Phase II clinical trials. Phase III randomized clinical trials of these naturally occurring substances are now beginning to be reported. The omega-3 polyunsaturated fatty acid EPA, in the free fatty acid (FFA) form, has been demonstrated to reduce adenomatous polyp number and size in patients with familial adenomatous polyposis (FAP), a finding which has prompted evaluation of this formulation of EPA for prevention of 'sporadic' colorectal neoplasia. Anti-inflammatory 'nutraceuticals' require further clinical evaluation in polyp prevention trials as they exhibit many of the characteristics of the ideal cancer chemoprevention agent, including safety, tolerability and patient acceptability.

Minimizing Hemodialysis Catheter Dysfunction: An Ounce of Prevention

PubMed Central

Lee, Timmy; Lok, Charmaine; Vazquez, Miguel; Moist, Louise; Maya, Ivan; Mokrzycki, Michele

2012-01-01

The maintenance of tunneled catheter (TC) patency is critical for the provision of adequate hemodialysis in patients who are TC-dependent. TC dysfunction results in the need for costly and inconvenient interventions, and reduced quality of life. Since the introduction of TCs in the late 1980s, heparin catheter lock has been the standard prophylactic regimen for the prevention of TC dysfunction. More recently, alternative catheter locking agents have emerged, and in some cases have shown to be superior to heparin lock with respect to improving TC patency and reducing TC-associated infections. These include citrate, tissue plasminogen activator, and a novel agent containing sodium citrate, methylene blue, methylparaben, and propylparaben. In addition, prophylaxis using oral anticoagulants/antiplatelet agents, including warfarin, aspirin, ticlodipine, as well as the use of modified heparin-coated catheters have also been studied for the prevention of TC dysfunction with variable results. The use of oral anticoagulants and/or antiplatelet agents as primary or secondary prevention of TC dysfunction must be weighed against their potential adverse effects, and should be individualized for each patient. PMID:22518310

Method for improved selectivity in photo-activation of molecular agents

DOEpatents

Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

2000-01-01

An apparatus for the treatment of a particular volume of plant or animal tissue by treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue.

78 FR 28190 - Foreign-Trade Zone (FTZ) 134-Chattanooga, Tennessee; Notification of Proposed Production Activity...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-14

... domestic sales, Komatsu would be able to choose the duty rates during customs entry procedures that apply... abroad include: cleaning agents; glues; adhesives; adhesive plates; O-rings; rubber bolts/rods; hoses...

Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

PubMed

Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

2015-09-01

The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage.

Antimicrobial activity of chemomechanical gingival retraction products.

PubMed

Hsu, Belinda; Lee, Stephanie; Schwass, Donald; Tompkins, Geoffrey

2017-07-01

Application of astringent hemostatic agents is the most widely used technique for gingival retraction, and a variety of products are offered commercially. However, these products may have additional unintended yet clinically beneficial properties. The authors assessed the antimicrobial activities of marketed retraction products against plaque-associated bacteria in both planktonic and biofilm assays, in vitro. The authors assessed hemostatic solutions, gels, pellets, retraction cords, pastes, and their listed active agents against a collection of microorganisms by means of conventional agar diffusion and minimum bacteriostatic and bactericidal concentration determinations. The authors then tested the most active products against monospecies biofilms grown on hydroxyapatite disks. All of the tested retraction products exhibited some antimicrobial activity. The results of the most active products were comparable with those of a marketed mouthwash. The listed retraction-active agents displayed relatively little activity when tested in pure form. At 10% dilution, some products evidenced inhibitory activity against most tested bacteria within 3 minutes of exposure, whereas others displayed variable effects after 10 minutes. The most active agents reduced, but did not completely prevent, the metabolic activity of a monospecies biofilm. Commercial gingival retraction products exhibit antimicrobial effects to various degrees in vitro. Some products display rapid bactericidal activity. The antimicrobial activity is not owing to the retraction-active agents. Biofilm bacteria are less sensitive to the antimicrobial effects of the agents. The rapidity of killing by some hemostatic agents suggests an antimicrobial effect that may be efficacious during clinical placement. The results of this in vitro study suggest that clinicians should be aware of the potential antimicrobial effects of some hemostatic agents, but more research is needed to confirm these observations in clinical use. Copyright © 2017 American Dental Association. Published by Elsevier Inc. All rights reserved.

Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics.

PubMed

Pariente, Roberto; Bejarano, Ignacio; Espino, Javier; Rodríguez, Ana B; Pariente, José A

2017-11-01

Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant actions. Therefore, melatonin may be useful in the treatment of tumors in association with chemotherapy drugs. This study was performed to study the role of melatonin receptors on the cytotoxicity and apoptosis induced by the chemotherapeutic agents cisplatin and 5-fluorouracil in two tumor cell lines, such as human colorectal cancer HT-29 cells and cervical cancer HeLa cells. We found that both melatonin and the two chemotherapeutic agents tested induced a decrease in HT-29 and HeLa cell viability. Furthermore, melatonin significantly increased the cytotoxic effect of chemotherapeutic agents, particularly, in 5-fluorouracil-challenged cells. Stimulation of cells with either of the two chemotherapeutic agents in the presence of melatonin further increased caspase-3 activation. Concomitant treatments with melatonin and chemotherapeutic agents augmented the population of apoptotic cells compared to the treatments with chemotherapeutics alone. Blockade of MT1 and/or MT2 receptors with luzindole or 4-P-PDOT was unable to reverse the enhancing effects of melatonin on both cytotoxicity, caspase-3 activation and the amount of apoptotic cells evoked by the chemotherapeutic agents, whereas when MT3 receptors were blocked with prazosin, the synergistic effect of melatonin with chemotherapy on cytotoxicity and apoptosis was reversed. Our findings provided evidence that in vitro melatonin strongly enhances chemotherapeutic-induced cytotoxicity and apoptosis in two tumor cell lines, namely HT-29 and HeLa cells and, this potentiating effect of melatonin is mediated by MT3 receptor stimulation.

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

USDA-ARS?s Scientific Manuscript database

Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs.

PubMed

O'Neill, Paul M; Ward, Stephen A; Berry, Neil G; Jeyadevan, J Prince; Biagini, Giancarlo A; Asadollaly, Egbaleh; Park, B Kevin; Bray, Patrick G

2006-01-01

A broad overview is presented describing the current knowledge and the ongoing research concerning the 4-aminoquinolines (4AQ) as chemotherapeutic antimalarial agents. Included are discussions of mechanism of action, structure activity relationships (SAR), chemistry, metabolism and toxicity and parasite resistance mechanisms. In discussions of SAR, particular emphasis has been given to activity versus chloroquine resistant strains of Plasmodium falciparum. Promising new lead compounds undergoing development are described and an overview of physicochemical properties of chloroquine and amodiaquine analogues is also included.

Compositions and methods for adoptive and active immunotherapy

DOEpatents

Fahmy, Tarek; Steenblock, Erin

2014-01-14

Modular aAPCs and methods of their manufacture and use are provided. The modular aAPCs are constructed from polymeric microparticles. The aAPCs include encapsulated cytokines and coupling agents which modularly couple functional elements including T cell receptor activators, co-stimulatory molecules and adhesion molecules to the particle. The ability of these aAPCs to release cytokines in a controlled manner, coupled with their modular nature and ease of ligand attachment, results in an ideal, tunable APC capable of stimulating and expanding primary T cells.

TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic.

PubMed

Cheng, Emily; Armstrong, Cheryl L; Galisteo, Rebeca; Winkles, Jeffrey A

2013-12-23

The TNF superfamily member TWEAK (TNFSF12) is a multifunctional cytokine implicated in physiological tissue regeneration and wound repair. TWEAK is initially synthesized as a membrane-anchored protein, but furin cleavage within the stalk region can generate a secreted TWEAK isoform. Both TWEAK isoforms bind to a small cell surface receptor named Fn14 (TNFRSF12A) and this interaction stimulates various cellular responses, including proliferation and migration. Fn14, like other members of the TNF receptor superfamily, is not a ligand-activated protein kinase. Instead, TWEAK:Fn14 engagement promotes Fn14 association with members of the TNFR associated factor family of adapter proteins, which triggers activation of various signaling pathways, including the classical and alternative NF-κB pathways. Numerous studies have revealed that Fn14 gene expression is significantly elevated in injured tissues and in most solid tumor types. Also, sustained Fn14 signaling has been implicated in the pathogenesis of cerebral ischemia, chronic inflammatory diseases, and cancer. Accordingly, several groups are developing TWEAK- or Fn14-targeted agents for possible therapeutic use in patients. These agents include monoclonal antibodies, fusion proteins, and immunotoxins. In this article, we provide an overview of some of the TWEAK/Fn14 axis-targeted agents currently in pre-clinical animal studies or in human clinical trials and discuss two other potential approaches to target this intriguing signaling node.

Method for improved selectivity in photo-activation of molecular agents

DOEpatents

Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

1998-01-01

A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

Method for improved selectivity in photo-activation of molecular agents

DOEpatents

Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

1999-01-01

A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

Method for improved selectivity in photo-activation of molecular agents

DOEpatents

Fisher, W.G.; Wachter, E.A.; Dees, H.C.

1998-11-03

A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material. 23 figs.

Negotiating on location, timing, duration, and participant in agent-mediated joint activity-travel scheduling

NASA Astrophysics Data System (ADS)

Ma, Huiye; Ronald, Nicole; Arentze, Theo A.; Timmermans, Harry J. P.

2013-10-01

Agent-based simulation has become an important modeling approach in activity-travel analysis. Social activities account for a large amount of travel and have an important effect on activity-travel scheduling. Participants in joint activities usually have various options regarding location, participants, and timing and take different approaches to make their decisions. In this context, joint activity participation requires negotiation among agents involved, so that conflicts among the agents can be addressed. Existing mechanisms do not fully provide a solution when utility functions of agents are nonlinear and non-monotonic. Considering activity-travel scheduling in time and space as an application, we propose a novel negotiation approach, which takes into account these properties, such as continuous and discrete issues, and nonlinear and non-monotonic utility functions, by defining a concession strategy and a search mechanism. The results of experiments show that agents having these properties can negotiate efficiently. Furthermore, the negotiation procedure affects individuals’ choices of location, timing, duration, and participants.

In vitro activities of 14 antibiotics against 100 human isolates of Yersinia pestis from a southern African plague focus.

PubMed Central

Frean, J A; Arntzen, L; Capper, T; Bryskier, A; Klugman, K P

1996-01-01

A limited repertoire of antimicrobial agents is currently in use for the treatment of plague. We investigated the in vitro activities of some newer antimicrobial agents against Yersinia pestis. Among the injectable agents tested, cefotaxime was the most active, and among the oral agents, both levofloxacin and ofloxacin were highly active, with MICs at which 90% of isolates are inhibited of < 0.03 microgram/ml. the susceptibilities to the ketolide RU004 and the penem faropenem warrant attention. The enhanced activities of quinolones against Y. pestis suggest that these agents should be further investigated for the treatment of human plague in the future. PMID:8913481

Agent Orange Exposure and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) in Human Milk.

PubMed

Scialli, Anthony R; Watkins, Deborah K; Ginevan, Michael E

2015-06-01

Agent Orange was sprayed in parts of southern Vietnam during the U.S.-Vietnam war and was a mixture of two chlorophenoxy herbicides. The mixture was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD and other dioxins and furans are measurable in the milk of Vietnamese women. We explored whether the TCDD in milk from these women was from Agent Orange and whether lactational exposure can be a mode of transgenerational effects of TCDD from Agent Orange. A review of the world's literature on milk concentrations of polychlorinated compounds showed the presence of TCDD and other dioxins and furans in all countries that have been assessed. The congener profile of these chemicals, that is, the proportion of different congeners in the sample, can be used to assess the source of milk contamination. Measurements in most countries, including contemporary measurements in Vietnam, are consistent with non-Agent Orange exposure sources, including industrial activities and incineration of waste. Models and supporting human data suggest that TCDD from breastfeeding does not persist in a child past adolescence and that the adult body burden of TCDD is independent of whether the individual was breast- or bottle-fed as a child. These findings suggest that exposure to Agent Orange in Vietnam did not result in persistent transgenerational exposure through human milk. © 2015 Wiley Periodicals, Inc.

Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence

PubMed Central

De Flora, Silvio; Ganchev, Gancho; Iltcheva, Marietta; La Maestra, Sebastiano; Micale, Rosanna T.; Steele, Vernon E.; Balansky, Roumen

2016-01-01

Many drugs in common use possess pleiotropic properties that make them capable of interfering with carcinogenesis mechanisms. We discuss here the ability of pharmacological agents to mitigate the pulmonary carcinogenicity of mainstream cigarette smoke. The evaluated agents included antiinflammatory drugs (budesonide, celecoxib, aspirin, naproxen, licofelone), antidiabetic drugs (metformin, pioglitazone), antineoplastic agents (lapatinib, bexarotene, vorinostat), and other drugs and supplements (phenethyl isothiocyanate, myo-inositol, N-acetylcysteine, ascorbic acid, berry extracts). The drugs have been evaluated in mouse models mimicking interventions either in current smokers or in ex-smokers or a prenatal chemoprevention. They displayed a broad spectrum of activities by attenuating either smoke-induced preneoplastic lesions or benign tumors and/or malignant tumors. Together with epidemiological data, these findings provide useful information to predict the potential effects of pharmacological agents in smokers. PMID:26726119

Situation Awareness of Onboard System Autonomy

NASA Technical Reports Server (NTRS)

Schreckenghost, Debra; Thronesbery, Carroll; Hudson, Mary Beth

2005-01-01

We have developed intelligent agent software for onboard system autonomy. Our approach is to provide control agents that automate crew and vehicle systems, and operations assistants that aid humans in working with these autonomous systems. We use the 3 Tier control architecture to develop the control agent software that automates system reconfiguration and routine fault management. We use the Distributed Collaboration and Interaction (DCI) System to develop the operations assistants that provide human services, including situation summarization, event notification, activity management, and support for manual commanding of autonomous system. In this paper we describe how the operations assistants aid situation awareness of the autonomous control agents. We also describe our evaluation of the DCI System to support control engineers during a ground test at Johnson Space Center (JSC) of the Post Processing System (PPS) for regenerative water recovery.

The development of macrolides: clarithromycin in perspective.

PubMed

Neu, H C

1991-02-01

Macrolide antibiotics have been available and used clinically since 1952. The class of drugs originated from a soil sample obtained from the City of Ilo-Ilo on the Island of Paray in the Philippines. Erythromycin has been the most widely used agent of this class called 'macrolides' because they possess the macrocyclic lactone nucleus. Many esters of erythromycin are well established as agents to treat a variety of respiratory and cutaneous infections, particularly in children. There has been a resurgence of interest in macrolides as a result of the recognition of pathogens such as Legionella, Chlamydia and Campylobacter spp. A number of new 14-membered macrolides have been synthesised in recent years with the goal of overcoming some of the problems of the older erythromycin agents. There has been variable activity of erythromycin against Haemophilus influenzae; there has been gastrointestinal irritation, particularly in adults; and the older agents are administered four times a day. Clarithromycin has increased activity against Legionella, and Branhamella spp., and Pasteurella multocida, and, with its 14-OH metabolite, inhibits Haemophilus spp. It is also more active against chlamydia and against anaerobic species while retaining excellent activity against streptococci including Streptococcus pneumoniae. It has increased plasma peak levels and a sufficiently long half-life for twice daily administration. Furthermore, it is well tolerated. Thus clarithromycin offers potential for use in those areas in which a safe, well tolerated macrolide will be used, namely respiratory, skin structure and selected diarrhoeal and genital infections.

1,10-phenanthroline inhibits the metallopeptidase secreted by Phialophora verrucosa and modulates its growth, morphology and differentiation.

PubMed

Granato, Marcela Queiroz; Massapust, Priscila de Araújo; Rozental, Sonia; Alviano, Celuta Sales; dos Santos, André Luis Souza; Kneipp, Lucimar Ferreira

2015-04-01

Phialophora verrucosa is one of the etiologic agents of chromoblastomycosis, a fungal infection that affects cutaneous and subcutaneous tissues. This disease is chronic, recurrent and difficult to treat. Several studies have shown that secreted peptidases by fungi are associated with important pathophysiological processes. Herein, we have identified and partially characterized the peptidase activity secreted by P. verrucosa conidial cells. Using human serum albumin as substrate, the best hydrolysis profile was detected at extreme acidic pH (3.0) and at 37 °C. The enzymatic activity was completely blocked by classical metallopeptidase inhibitors/chelating agents as 1,10-phenanthroline and EGTA. Zinc ions stimulated the metallo-type peptidase activity in a dose-dependent manner. Several proteinaceous substrates were cleaved, in different extension, by the P. verrucosa metallopeptidase activity, including immunoglobulin G, fibrinogen, collagen types I and IV, fibronectin, laminin and keratin; however, mucin and hemoglobin were not susceptible to proteolysis. As metallopeptidases participate in different cellular metabolic pathways in fungal cells, we also tested the influence of 1,10-phenanthroline and EGTA on P. verrucosa development. Contrarily to EGTA, 1,10-phenanthroline inhibited the fungal viability (MIC 0.8 µg/ml), showing fungistatic effect, and induced profound morphological alterations as visualized by transmission electron microscopy. In addition, 1,10-phenanthroline arrested the filamentation process in P. verrucosa. Our results corroborate the supposition that metallopeptidase inhibitors/chelating agents have potential to control crucial biological events in fungal agents of chromoblastomycosis.

Rational drug design for anti-cancer chemotherapy: multi-target QSAR models for the in silico discovery of anti-colorectal cancer agents.

PubMed

Speck-Planche, Alejandro; Kleandrova, Valeria V; Luan, Feng; Cordeiro, M Natália D S

2012-08-01

The discovery of new and more potent anti-cancer agents constitutes one of the most active fields of research in chemotherapy. Colorectal cancer (CRC) is one of the most studied cancers because of its high prevalence and number of deaths. In the current pharmaceutical design of more efficient anti-CRC drugs, the use of methodologies based on Chemoinformatics has played a decisive role, including Quantitative-Structure-Activity Relationship (QSAR) techniques. However, until now, there is no methodology able to predict anti-CRC activity of compounds against more than one CRC cell line, which should constitute the principal goal. In an attempt to overcome this problem we develop here the first multi-target (mt) approach for the virtual screening and rational in silico discovery of anti-CRC agents against ten cell lines. Here, two mt-QSAR classification models were constructed using a large and heterogeneous database of compounds. The first model was based on linear discriminant analysis (mt-QSAR-LDA) employing fragment-based descriptors while the second model was obtained using artificial neural networks (mt-QSAR-ANN) with global 2D descriptors. Both models correctly classified more than 90% of active and inactive compounds in training and prediction sets. Some fragments were extracted from the molecules and their contributions to anti-CRC activity were calculated using mt-QSAR-LDA model. Several fragments were identified as potential substructural features responsible for the anti-CRC activity and new molecules designed from those fragments with positive contributions were suggested and correctly predicted by the two models as possible potent and versatile anti-CRC agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

Sticking with the nice guy: trait warmth information impairs learning and modulates person perception brain network activity.

PubMed

Lee, Victoria K; Harris, Lasana T

2014-12-01

Social learning requires inferring social information about another person, as well as evaluating outcomes. Previous research shows that prior social information biases decision making and reduces reliance on striatal activity during learning (Delgado, Frank, & Phelps, Nature Neuroscience 8 (11): 1611-1618, 2005). A rich literature in social psychology on person perception demonstrates that people spontaneously infer social information when viewing another person (Fiske & Taylor, 2013) and engage a network of brain regions, including the medial prefrontal cortex, temporal parietal junction, superior temporal sulcus, and precuneus (Amodio & Frith, Nature Reviews Neuroscience, 7(4), 268-277, 2006; Haxby, Gobbini, & Montgomery, 2004; van Overwalle Human Brain Mapping, 30, 829-858, 2009). We investigate the role of these brain regions during social learning about well-established dimensions of person perception-trait warmth and trait competence. We test the hypothesis that activity in person perception brain regions interacts with learning structures during social learning. Participants play an investment game where they must choose an agent to invest on their behalf. This choice is guided by cues signaling trait warmth or trait competence based on framing of monetary returns. Trait warmth information impairs learning about human but not computer agents, while trait competence information produces similar learning rates for human and computer agents. We see increased activation to warmth information about human agents in person perception brain regions. Interestingly, activity in person perception brain regions during the decision phase negatively predicts activity in the striatum during feedback for trait competence inferences about humans. These results suggest that social learning may engage additional processing within person perception brain regions that hampers learning in economic contexts.

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

PubMed

McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

2015-06-01

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.

The antitumor activity of plant-derived non-psychoactive cannabinoids

PubMed Central

McAllister, Sean D.; Soroceanu, Liliana; Desprez, Pierre-Yves

2015-01-01

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer stem cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. PMID:25916739

Assessment of the risk of antiangiogenic agents before and after surgery.

PubMed

Bailey, Christina E; Parikh, Alexander A

2018-05-08

Angiogenesis plays a critical role in the growth, progression, and metastasis of numerous solid tumor types, and thus, antiangiogenic agents have been studied for many years as potential therapeutic agents. Many different antiangiogenic agents, including monoclonal antibodies and multi-targeted tyrosine kinase inhibitors (TKIs), have been approved for various oncology indications, and promising clinical activity has been demonstrated. However, some of these agents have also been associated with serious safety concerns. Because angiogenesis is an important step in the wound healing process, agents targeting the angiogenesis pathway may interfere with wound healing, thus increasing the risk of surgical wound complications, such as dehiscence, surgical site bleeding, and wound infection. Nevertheless, antiangiogenic agents can be safely used in the perioperative setting if oncologists and surgeons are educated on the biology and pharmacokinetics of these agents. This review discusses the available published literature regarding surgical complications associated with the use of antiangiogenic agents and provides updated clinical recommendations on the optimal timing between surgery and antiangiogenic therapy. Due to the paucity of data surrounding this topic, current and future clinical trials need to evaluate prospectively the potential risks for surgical complications associated with antiangiogenic therapies to establish specific guidelines for their safe and effective use within the surgical oncology community. Copyright © 2018 Elsevier Ltd. All rights reserved.

Treatment of ebola virus disease.

PubMed

Kilgore, Paul E; Grabenstein, John D; Salim, Abdulbaset M; Rybak, Michael

2015-01-01

In March 2014, the largest Ebola outbreak in history exploded across West Africa. As of November 14, 2014, the World Health Organization has reported a total of 21,296 Ebola virus disease (EVD) cases, including 13,427 laboratory-confirmed EVD cases reported from the three most affected countries (Guinea, Liberia, and Sierra Leone). As the outbreak of EVD has spread, clinical disease severity and national EVD case-fatality rates have remained high (21.2-60.8%). Prior to 2013, several EVD outbreaks were controlled by using routine public health interventions; however, the widespread nature of the current EVD outbreak as well as cultural practices in the affected countries have challenged even the most active case identification efforts. In addition, although treatment centers provide supportive care, no effective therapeutic agents are available for EVD-endemic countries. The ongoing EVD outbreak has stimulated investigation of several different therapeutic strategies that target specific viral structures and mechanisms of Ebola viruses. Six to eight putative pharmacotherapies or immunologically based treatments have demonstrated promising results in animal studies. In addition, agents composed of small interfering RNAs targeting specific proteins of Ebola viruses, traditional hyperimmune globulin isolated from Ebola animal models, monoclonal antibodies, and morpholino oligomers (small molecules used to block viral gene expression). A number of EVD therapeutic agents are now entering accelerated human trials in EVD-endemic countries. The goal of therapeutic agent development includes postexposure prevention and EVD cure. As knowledge of Ebola virus virology and pathogenesis grows, it is likely that new therapeutic tools will be developed. Deployment of novel Ebola therapies will require unprecedented cooperation as well as investment to ensure that therapeutic tools become available to populations at greatest risk for EVD and its complications. In this article, we review several agents and strategies that are now under active development. © 2015 Pharmacotherapy Publications, Inc.

In-vitro susceptibility of 1982 respiratory tract pathogens and 1921 urinary tract pathogens against 19 antimicrobial agents: a Canadian multicentre study. Canadian Antimicrobial Study Group.

PubMed

Blondeau, J M; Yaschuk, Y; Suter, M; Vaughan, D

1999-03-01

A total of 3903 pathogens from 48 Canadian medical centres were tested against 19 antimicrobial agents. Five agents showed activity against > or = 90% of all 1982 respiratory tract pathogens tested (ciprofloxacin, 90%; cefoperazone, 91%; ticarcillin/clavulanate, 92%; ceftazidime and imipenem, 93% each). Nine agents had > or = 90% activity against Enterobacteriaceae from respiratory tract infection (cefotaxime and ticarcillin/clavulanate, 90% each; aztreonam, ceftizoxime and ceftriaxone, 91% each; ceftazidime, 93%; ciprofloxacin, 97%; imipenem and netilmicin, 98% each). Similarly, five agents had activity against > or = 90% of all 1921 urinary tract pathogens tested (ciprofloxacin and ticarcillin/clavulanate, 90% each; cefoperazone and netilmicin, 91% each; imipenem, 99%). Nine agents had > or = 95% activity against Enterobacteriaceae from urinary tract infection (ciprofloxacin, 95%; cefotetan, 97%; aztreonam, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone and netilmicin, 98% each; imipenem, 99%). Seventeen agents had activity against > or = 95% of Staphylococcus aureus strains. Susceptibility of Pseudomonas aeruginosa isolates ranged from 2% to 91%.

Biological conversion system

DOEpatents

Scott, C.D.

A system for bioconversion of organic material comprises a primary bioreactor column wherein a biological active agent (zymomonas mobilis) converts the organic material (sugar) to a product (alcohol), a rejuvenator column wherein the biological activity of said biological active agent is enhanced, and means for circulating said biological active agent between said primary bioreactor column and said rejuvenator column.

Contrast enhanced spectroscopic optical coherence tomography

NASA Technical Reports Server (NTRS)

Xu, Chenyang (Inventor); Boppart, Stephen A. (Inventor)

2010-01-01

A method of forming an image of a sample includes performing SOCT on a sample. The sample may include a contrast agent, which may include an absorbing agent and/or a scattering agent. A method of forming an image of tissue may include selecting a contrast agent, delivering the contrast agent to the tissue, acquiring SOCT data from the tissue, and converting the SOCT data into an image. The contributions to the SOCT data of an absorbing agent and a scattering agent in a sample may be quantified separately.

Evaluating Endocrine Disruption Activity of Deposits on Firefighting Gear Using a Sensitive and High Throughput Screening Method.

PubMed

Stevenson, Max; Alexander, Barbara; Baxter, C Stuart; Leung, Yuet-Kin

2015-12-01

Adverse health outcomes related to exposure to endocrine disrupting chemicals, including increased incidences of coronary heart disease, prostate and testicular cancers, and congenital disabilities, have been reported in firefighters or their offspring. We, therefore, measured the estrogenic and antiestrogenic activity of extracts of used firefighter gear to assess exposure to these agents. Extracts and known chemical contaminants were examined for estrogenicity and antiestrogenicity in yeast cells expressing the estrogen receptor. Most extracts of used gear and phthalate diesters detectable on this gear displayed strong antiestrogenic effects. Notably, new glove and hood extracts showed significant estrogenic activity. Overall, our data suggest that firefighters are exposed to both estrogenic and antiestrogenic agents, possibly phthalates that may lead to health risks observed in this occupation as a result of perturbation of hormone homeostasis.

Exposure of Salmonella enterica Serovar Typhimurium to Three Humectants Used in the Food Industry Induces Different Osmoadaptation Systems.

PubMed

Finn, Sarah; Rogers, Lisa; Händler, Kristian; McClure, Peter; Amézquita, Alejandro; Hinton, Jay C D; Fanning, Séamus

2015-10-01

Common salt (NaCl) is frequently used by the food industry to add flavor and to act as a humectant in order to reduce the water content of a food product. The improved health awareness of consumers is leading to a demand for food products with reduced salt content; thus, manufacturers require alternative water activity-reducing agents which elicit the same general effects as NaCl. Two examples include KCl and glycerol. These agents lower the water activity of a food matrix and also contribute to limit the growth of the microbiota, including foodborne pathogens. Little is currently known about how foodborne pathogens respond to these water activity-lowering agents. Here we examined the response of Salmonella enterica serovar Typhimurium 4/74 to NaCl, KCl, and glycerol at three time points, using a constant water activity level, compared with the response of a control inoculum. All conditions induced the upregulation of gluconate metabolic genes after 6 h of exposure. Bacteria exposed to NaCl and KCl demonstrated the upregulation of the osmoprotective transporter mechanisms encoded by the proP, proU, and osmU (STM1491 to STM1494) genes. Glycerol exposure elicited the downregulation of these osmoadaptive mechanisms but stimulated an increase in lipopolysaccharide and membrane protein-associated genes after 1 h. The most extensive changes in gene expression occurred following exposure to KCl. Because many of these genes were of unknown function, further characterization may identify KCl-specific adaptive processes that are not stimulated by NaCl. This study shows that the response of S. Typhimurium to different humectants does not simply reflect reduced water activity and likely involves systems that are linked to specific humectants. Copyright © 2015 Finn et al.

Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy.

PubMed

Harris, Zoey; Donovan, Micah G; Branco, Gisele Morais; Limesand, Kirsten H; Burd, Randy

2016-01-01

Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase - a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes feasible a target for polyphenol-based therapies. For example, quercetin (3,3',4',5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review, we explore the potential of quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a "four-focus area strategy" to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to (i) modulate cellular bioreduction potential and associated signaling cascades, (ii) affect transcription of relevant genes, (iii) regulate epigenetic processes, and (iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

In-Vitro Induced Immunosuppression in a Rotary Cell Culture System

NASA Technical Reports Server (NTRS)

Grimm, Elizabeth A.

1998-01-01

The function of the innate immune system is to provide a first-line of defense against infectious organisms, via control of bacterial and viral growth using antigen nonspecific means. These nonspecific immune effectors include macrophages and Natural Killing (NK) cells, and certain cytokines elicited in response to "super antigens" on the infectious agents. This innate system usually keeps most infectious agents from rapidly growing while the adaptive immune system is generating a specific response complete with immunologic memory. Compelling evidence suggests that space flight results in various immunosuppressive effects, including reduced innate and adaptive immune responses. We were particularly concerned with reduced NK activity at landing, and have asked whether the microgravity component of space flight could be responsible for the previously observed NK defect. We have conclusively demonstrated that simulated microgravity as provided by the Synthecon bioreactors does not inhibit the NK function nor the IL-2 activation of lymphokine-activated killing (LAK). Interleukin-2 is the key cytokine responsible for activation of NK cells to express LAK, as well as to support differentiation of lymphocytes during adaptive immune responses. Therefore, we have disproved our original hypothesis based on poor NK in many of the astronauts upon landing.

Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action

PubMed Central

Griffin, Michael O.; Ceballos, Guillermo; Villarreal, Francisco

2010-01-01

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The firstt of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline’s multiple mechanisms of action as a means to understand their beneficial effects. PMID:20951211

6-Gingerol inhibits ROS and iNOS through the suppression of PKC-{alpha} and NF-{kappa}B pathways in lipopolysaccharide-stimulated mouse macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Tzung-Yan, E-mail: joyamen@mail.cgu.edu.tw; Lee, Ko-Chen; Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

2009-04-24

Inflammation is involved in numerous diseases, including chronic inflammatory diseases and the development of cancer. Many plants possess a variety of biological activities, including antifungal, antibacterial and anti-inflammatory activities. However, our understanding of the anti-inflammatory effects of 6-gingerol is very limited. We used lipopolysaccharide (LPS)-stimulated macrophages as a model of inflammation to investigate the anti-inflammatory effects of 6-gingerol, which contains phenolic structure. We found that 6-gingerol exhibited an anti-inflammatory effect. 6-Gingerol could decrease inducible nitric oxide synthase and TNF-{alpha} expression through suppression of I-{kappa}B{alpha} phosphorylation, NF-{kappa}B nuclear activation and PKC-{alpha} translocation, which in turn inhibits Ca{sup 2+} mobilization and disruptionmore » of mitochondrial membrane potential in LPS-stimulated macrophages. Here, we demonstrate that 6-gingerol acts as an anti-inflammatory agent by blocking NF-{kappa}B and PKC signaling, and may be developed as a useful agent for the chemoprevention of cancer or inflammatory diseases.« less

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

PubMed

Kamata, Shigeyuki; Kishimoto, Takashi; Kobayashi, Soichi; Miyazaki, Masaru; Ishikura, Hiroshi

2007-07-01

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Model-free learning on robot kinematic chains using a nested multi-agent topology

NASA Astrophysics Data System (ADS)

Karigiannis, John N.; Tzafestas, Costas S.

2016-11-01

This paper proposes a model-free learning scheme for the developmental acquisition of robot kinematic control and dexterous manipulation skills. The approach is based on a nested-hierarchical multi-agent architecture that intuitively encapsulates the topology of robot kinematic chains, where the activity of each independent degree-of-freedom (DOF) is finally mapped onto a distinct agent. Each one of those agents progressively evolves a local kinematic control strategy in a game-theoretic sense, that is, based on a partial (local) view of the whole system topology, which is incrementally updated through a recursive communication process according to the nested-hierarchical topology. Learning is thus approached not through demonstration and training but through an autonomous self-exploration process. A fuzzy reinforcement learning scheme is employed within each agent to enable efficient exploration in a continuous state-action domain. This paper constitutes in fact a proof of concept, demonstrating that global dexterous manipulation skills can indeed evolve through such a distributed iterative learning of local agent sensorimotor mappings. The main motivation behind the development of such an incremental multi-agent topology is to enhance system modularity, to facilitate extensibility to more complex problem domains and to improve robustness with respect to structural variations including unpredictable internal failures. These attributes of the proposed system are assessed in this paper through numerical experiments in different robot manipulation task scenarios, involving both single and multi-robot kinematic chains. The generalisation capacity of the learning scheme is experimentally assessed and robustness properties of the multi-agent system are also evaluated with respect to unpredictable variations in the kinematic topology. Furthermore, these numerical experiments demonstrate the scalability properties of the proposed nested-hierarchical architecture, where new agents can be recursively added in the hierarchy to encapsulate individual active DOFs. The results presented in this paper demonstrate the feasibility of such a distributed multi-agent control framework, showing that the solutions which emerge are plausible and near-optimal. Numerical efficiency and computational cost issues are also discussed.

Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species

PubMed Central

Credito, Kim L.; Appelbaum, Peter C.

2004-01-01

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially Clostridium spp. (85 strains tested, including 21 strains of C. difficile), with MICs ranging between ≤0.016 and 0.25 μg/ml. PMID:15504874

Marine-Natural-Product Development: First Discovery of Nortopsentin Alkaloids as Novel Antiviral, Anti-phytopathogenic-Fungus, and Insecticidal Agents.

PubMed

Ji, Xiaofei; Guo, Jincheng; Liu, Yuxiu; Lu, Aidang; Wang, Ziwen; Li, Yongqiang; Yang, Shaoxiang; Wang, Qingmin

2018-04-25

Nortopsentin alkaloids were found to have potent antiviral, anti-phytopathogenic-fungus, and insecticidal activities for the first time. Antiviral-activity tests revealed that these compounds were very sensitive to substituents, so a series of nortopsentin derivatives were designed, synthesized, and systematically evaluated for their antiviral activities against TMV, their fungicidal activities, and their insecticidal activities on the basis of a structural-diversity-derivation strategy. Compounds 2e (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 50, 59, and 56%, respectively, at 500 μg/mL) and 2k (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 60, 58, and 52%, respectively, at 500 μg/mL), with excellent antiviral activities and good physicochemical properties, emerged as new lead compounds for novel-antiviral-agent development. Further fungicidal-activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds 2f, 2h, and 2j emerged as new lead compounds for antifungal-activity research. Additionally, all the compounds displayed good insecticidal activities against five kinds of insects, including Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis, Plutella xylostella, and Culex pipiens pallens.

3-Acyl dihydroflavonols from poplar resins collected by honey bees are active against the bee pathogens Paenibacillus larvae and Ascosphaera apis.

PubMed

Wilson, Michael B; Pawlus, Alison D; Brinkman, Doug; Gardner, Gary; Hegeman, Adrian D; Spivak, Marla; Cohen, Jerry D

2017-06-01

Honey bees, Apis mellifera, collect antimicrobial plant resins from the environment and deposit them in their nests as propolis. This behavior is of practical concern to beekeepers since the presence of propolis in the hive has a variety of benefits, including the suppression of disease symptoms. To connect the benefits that bees derive from propolis with particular resinous plants, we determined the identity and botanical origin of propolis compounds active against bee pathogens using bioassay-guided fractionation against the bacterium Paenibacillus larvae, the causative agent of American foulbrood. Eleven dihydroflavonols were isolated from propolis collected in Fallon, NV, including pinobanksin-3-octanoate. This hitherto unknown derivative and five other 3-acyl-dihydroflavonols showed inhibitory activity against both P. larvae (IC 50  = 17-68 μM) and Ascosphaera apis (IC 50  = 8-23 μM), the fungal agent of chalkbrood. A structure-activity relationship between acyl group size and antimicrobial activity was found, with longer acyl groups increasing activity against P. larvae and shorter acyl groups increasing activity against A. apis. Finally, it was determined that the isolated 3-acyl-dihydroflavonols originated from Populus fremontii, and further analysis showed these compounds can also be found in other North American Populus spp. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

PubMed Central

Raghavendran, Krishnan; Pryhuber, Gloria S.; Chess, Patricia R.; Davidson, Bruce A.; Knight, Paul R.; Notter, Robert H.

2009-01-01

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article. PMID:18691048

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures.

PubMed

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R; Schreiber, Fred; Anderson, Kyle

2012-01-21

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures

PubMed Central

Kumar, Nagi; Crocker, Theresa; Smith, Tiffany; Connors, Shahnjayla; Pow-Sang, Julio; Spiess, Philippe E.; Egan, Kathleen; Quinn, Gwen; Schell, Michael; Sebti, Said; Kazi, Aslam; Chuang, Tian; Salup, Raoul; Helal, Mohamed; Zagaja, Gregory; Trabulsi, Edouard; McLarty, Jerry; Fazili, Tajammul; Williams, Christopher R.; Schreiber, Fred; Anderson, Kyle

2014-01-01

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention. PMID:24533253

Nonylphenolethoxylates as Malarial Chloroquine Resistance Reversal Agents

PubMed Central

Crandall, Ian; Charuk, Jeffrey; Kain, Kevin C.

2000-01-01

Malaria-associated morbidity and mortality are increasing because of widespread resistance to one of the safest and least expensive antimalarials, chloroquine. The availability of an inexpensive agent that is capable of reversing chloroquine resistance would have a major impact on malaria treatment worldwide. The interaction of nonylphenolethoxylates (NPEs, commercially available synthetic surfactants) with drug-resistant Plasmodium falciparum was examined to determine if NPEs inhibited the growth of the parasites and if NPEs could sensitize resistant parasites to chloroquine. NPEs inhibited the development of the parasite when present in the low- to mid-micromolar range (5 to 90 μM), indicating that they possess antimalarial activity. Further, the presence of <10 μM concentrations of NPEs caused the 50% inhibitory concentrations for chloroquine-resistant lines to drop to levels (≤12 nM) observed for sensitive lines and generally considered to be achievable with treatment courses of chloroquine. Long-chain (>30 ethoxylate units) NPEs were found to be most active in P. falciparum, which contrasts with previously observed maximal activity of short-chain (∼9 ethoxylate units) NPEs in multidrug-resistant mammalian cell lines. NPEs may be attractive chloroquine resistance reversal agents since they are inexpensive and may be selectively directed against P. falciparum without inhibiting mammalian tissue P glycoproteins. Antimalarial preparations that include these agents may prolong the effective life span of chloroquine and other antimalarials. PMID:10952591

Integrated effect of gamma radiation and biocontrol agent on quality parameters of apple fruit: An innovative commercial preservation method

NASA Astrophysics Data System (ADS)

Ahari Mostafavi, Hossein; Mahyar Mirmajlessi, Seyed; Fathollahi, Hadi; Shahbazi, Samira; Mohammad Mirjalili, Seyed

2013-10-01

Effects of gamma irradiation and biocontrol agent (Pseudomonas fluorescens) on the physico-chemical parameters (including moisture, total soluble solids, antioxidant activity, phenolic content and firmness) of cv. Golden Delicious apples were investigated for their ability to avoid the post-harvest blue mold caused by Penicillium expansum during cold storage. Freshly harvested apples were inoculated with P. expansum. Treated fruits were irradiated at doses of 0, 200, 400, 600 and 800 Gy and then inoculated with P. fluorescens suspension. Samples were evaluated at 3 month intervals. The results demonstrated a clear link between antioxidant activity and phenolic content, so that dose range of 200-400 Gy significantly increased phenolic content and antioxidant activity. Effect of P. fluorescens was similar to irradiation at 200 and 400 Gy that could prevent lesion diameter in pathogen-treated apples. As dose and storage time increased firmness decreased but, combination of P. fluorescens as well as irradiation (at 200-400 Gy) could decrease softening apple fruits during storage. In all parameters, P. fluorescens (as biocontrol agent) inhibited P. expansum similar to irradiation at 200-400 Gy. So, integrated treatment of irradiation and biocontrol agent explored the potential dual benefit of low doses (200 and 400 Gy) as a suitable method to sustain physico-chemical quality and conclusively reduce apple fruits losses during post-harvest preservation.

Isolation and identification of lipopeptide antibiotics from Paenibacillus elgii B69 with inhibitory activity against methicillin-resistant Staphylococcus aureus.

PubMed

Ding, Rui; Wu, Xue-Chang; Qian, Chao-Dong; Teng, Yi; Li, Ou; Zhan, Zha-Jun; Zhao, Yu-Hua

2011-12-01

Two lipopeptide antibiotics, pelgipeptins C and D, were isolated from Paenibacillus elgii B69 strain. The molecular masses of the two compounds were both determined to be 1,086 Da. Mass-spectrometry, amino acid analysis and NMR spectroscopy indicated that pelgipeptin C was the same compound as BMY-28160, while pelgipeptin D was identified as a new antibiotic of the polypeptin family. These two peptides were active against all the tested microorganisms, including antibiotic-resistant pathogenic bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA). Time-kill assays demonstrated that pelgipeptin D exhibited rapid and effective bactericidal action against MRSA at 4×MIC. Based on acute toxicity test, the intraperitoneal LD50 value of pelgipeptin D was slightly higher than that of the structurally related antimicrobial agent polymyxin B. Pelgipeptins are highly potent antibacterial and antifungal agents, particularly against MRSA, and warrant further investigation as possible therapeutic agents for bacteria infections resistant to currently available antibiotics.

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

PubMed Central

Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois

2016-01-01

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

Boron chemicals in diagnosis and therapeutics

PubMed Central

Das, Bhaskar C; Thapa, Pritam; Karki, Radha; Schinke, Caroline; Das, Sasmita; Kambhampati, Suman; Banerjee, Sushanta K; Van Veldhuizen, Peter; Verma, Amit; Weiss, Louis M; Evans, Todd

2013-01-01

Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade®), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin’s lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans. PMID:23617429

Molecular biology of breast cancer stem cells: potential clinical applications.

PubMed

Nguyen, Nam P; Almeida, Fabio S; Chi, Alex; Nguyen, Ly M; Cohen, Deirdre; Karlsson, Ulf; Vinh-Hung, Vincent

2010-10-01

Breast cancer stem cells (CSC) have been postulated recently as responsible for failure of breast cancer treatment. The purpose of this study is to review breast CSCs molecular biology with respect to their mechanism of resistance to conventional therapy, and to develop treatment strategies that may improve survival of breast cancer patients. A literature search has identified in vitro and in vivo studies of breast CSCs. Breast CSCs overexpress breast cancer resistance protein (BCRP) which allows cancer cells to transport actively chemotherapy agents out of the cells. Radioresistance is modulated through activation of Wnt signaling pathway and overexpression of genes coding for glutathione. Lapatinib can selectively target HER-2 positive breast CSCs and improves disease-free survival in these patients. Metformin may target basal type breast CSCs. Parthenolide and oncolytic viruses are promising targeting agents for breast CSCs. Future clinical trials for breast cancer should include anti-cancer stem cells targeting agents in addition to conventional chemotherapy. Hypofractionation radiotherapy may be indicated for residual disease post chemotherapy. 2010 Elsevier Ltd. All rights reserved.

Agent Architecture for Aviation Data Integration System

NASA Technical Reports Server (NTRS)

Kulkarni, Deepak; Wang, Yao; Windrem, May; Patel, Hemil; Wei, Mei

2004-01-01

This paper describes the proposed agent-based architecture of the Aviation Data Integration System (ADIS). ADIS is a software system that provides integrated heterogeneous data to support aviation problem-solving activities. Examples of aviation problem-solving activities include engineering troubleshooting, incident and accident investigation, routine flight operations monitoring, safety assessment, maintenance procedure debugging, and training assessment. A wide variety of information is typically referenced when engaging in these activities. Some of this information includes flight recorder data, Automatic Terminal Information Service (ATIS) reports, Jeppesen charts, weather data, air traffic control information, safety reports, and runway visual range data. Such wide-ranging information cannot be found in any single unified information source. Therefore, this information must be actively collected, assembled, and presented in a manner that supports the users problem-solving activities. This information integration task is non-trivial and presents a variety of technical challenges. ADIS has been developed to do this task and it permits integration of weather, RVR, radar data, and Jeppesen charts with flight data. ADIS has been implemented and used by several airlines FOQA teams. The initial feedback from airlines is that such a system is very useful in FOQA analysis. Based on the feedback from the initial deployment, we are developing a new version of the system that would make further progress in achieving following goals of our project.

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

PubMed

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

PubMed Central

Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

2011-01-01

Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

Infectious Agents in Atherosclerotic Cardiovascular Diseases through Oxidative Stress

PubMed Central

Di Pietro, Marisa; Filardo, Simone; Falasca, Francesca; Turriziani, Ombretta; Sessa, Rosa

2017-01-01

Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis-induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research. PMID:29156574

Infectious Agents in Atherosclerotic Cardiovascular Diseases through Oxidative Stress.

PubMed

Di Pietro, Marisa; Filardo, Simone; Falasca, Francesca; Turriziani, Ombretta; Sessa, Rosa

2017-11-18

Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis -induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research.

The efficacy of HI-6 DMS in a sustained infusion against percutaneous VX poisoning in the guinea-pig.

PubMed

Whitmore, C; Cook, A R; Mann, T; Price, M E; Emery, E; Roughley, N; Flint, D; Stubbs, S; Armstrong, S J; Rice, H; Tattersall, J E H

2018-09-01

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal. Copyright © 2017 Crown Copyright. Published by Elsevier B.V. All rights reserved.

Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

PubMed

Newman-Tancredi, A; Gavaudan, S; Conte, C; Chaput, C; Touzard, M; Verrièle, L; Audinot, V; Millan, M J

1998-08-21

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical' antipsychotic agents displayed antagonist properties at h5-HT1A sites with generally much lower affinity than at hD2 dopamine receptors. It is suggested that agonist activity at 5-HT1A receptors may be of utility for certain antipsychotic agents.

Marine-derived angiogenesis inhibitors for cancer therapy.

PubMed

Wang, Ying-Qing; Miao, Ze-Hong

2013-03-15

Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs.

Blow spinning of food-grade-gelatin nanofibers (abstract)

USDA-ARS?s Scientific Manuscript database

Nanofibers have been examined for many diverse applications, including catalysis, filtration, controlled release of drugs and active agents, sensor, and tissue engineering and as texturized food ingredients. The primary advantage of nanofibers over larger diameter fibers is the larger surface area t...

An Active Learning Exercise for Introducing Agent-Based Modeling

ERIC Educational Resources Information Center

Pinder, Jonathan P.

2013-01-01

Recent developments in agent-based modeling as a method of systems analysis and optimization indicate that students in business analytics need an introduction to the terminology, concepts, and framework of agent-based modeling. This article presents an active learning exercise for MBA students in business analytics that demonstrates agent-based…

Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

PubMed

Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

2013-03-01

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs. © 2012 Wiley Periodicals, Inc.

Design, enantiopure synthesis, and biological evaluation of novel iso-D-2',3'-dideoxy-3'-fluorothianucleoside derivatives as a bioisostere of lamivudine.

PubMed

Kim, Kyung Ran; Park, Ah-Young; Moon, Hyung Ryong; Chun, Moon Woo; Jeong, Lak Shin

2007-01-01

Novel iso D-2',3'-dideoxythianucleoside derivatives 1-3 were designed and asymmetrically synthesized to search for new anti-HIV agents. Final compounds 1-3 were evaluated against a variety of viruses including HIV-1 and 2. Only cytosine analog 3 showed a potent anti-VSV activity (EC(50) = 9.43 microg/mL). This result implies that iso 2',3'-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent.

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models.

PubMed

Bandyopadhyay, Abhik; Favours, Edward; Phelps, Doris A; Pozo, Vanessa Del; Ghilu, Samson; Kurmashev, Dias; Michalek, Joel; Trevino, Aron; Guttridge, Denis; London, Cheryl; Hirotani, Kenji; Zhang, Ling; Kurmasheva, Raushan T; Houghton, Peter J

2018-02-01

Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents. Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program. Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E. P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone. © 2017 Wiley Periodicals, Inc.

High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

PubMed Central

Zhang, Lixin; Yan, Kezhi; Zhang, Yu; Huang, Ren; Bian, Jiang; Zheng, Chuansen; Sun, Haixiang; Chen, Zhihui; Sun, Nuo; An, Rong; Min, Fangui; Zhao, Weibo; Zhuo, Ying; You, Jianlan; Song, Yongjie; Yu, Zhenyan; Liu, Zhiheng; Yang, Keqian; Gao, Hong; Dai, Huanqin; Zhang, Xiaoli; Wang, Jian; Fu, Chengzhang; Pei, Gang; Liu, Jintao; Zhang, Si; Goodfellow, Michael; Jiang, Yuanying; Kuai, Jun; Zhou, Guochun; Chen, Xiaoping

2007-01-01

The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of ≈20,000 microbial extracts, 12 hits were identified with broad-spectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy. PMID:17360571

Drugs acting on amino acid neurotransmitters.

PubMed

Meldrum, B S

1986-01-01

The most potent agents currently available for suppressing myoclonic activity in animals and humans act to enhance GABA-mediated inhibition and/or to diminish amino acid-induced excitation. Postsynaptic GABA-mediated inhibition plays an important role at the cortical level, diminishing the effect of augmented afferent activity and preventing pathologically enhanced output. Enhancement of GABAergic inhibition, principally at the cortical level but also at lower levels, by clonazepam and by valproate appears to be a predominant element in their antimyoclonic action. Studies in various animal models, including photically induced myoclonus in the baboon, P papio, indicate the value of other approaches to enhancing GABA-mediated inhibition. Among such approaches meriting evaluation in humans are inhibition of GABA-transaminase activity by gamma-vinyl GABA and action at some of the benzodiazepine receptors to enhance the action of GABA, as by the novel anticonvulsant beta-carbolines. Excitatory transmission mediated by dicarboxylic amino acids appears to play a role in myoclonus, especially at the spinal level, but also in the brainstem, cerebellum, basal ganglia, and cortex. Among various novel agents that act at the postsynaptic receptor site to antagonize such excitation, those specifically blocking excitation induced by aspartate and/or NMDA prevent myoclonic activity in a wide range of animal models. Further research is required before such agents can be evaluated in humans.

RNA Interference of Endochitinases in the Sugarcane Endophyte Trichoderma virens 223 Reduces Its Fitness as a Biocontrol Agent of Pineapple Disease

PubMed Central

Romão-Dumaresq, Aline S.; de Araújo, Welington Luiz; Talbot, Nicholas J.; Thornton, Christopher R.

2012-01-01

The sugarcane root endophyte Trichoderma virens 223 holds enormous potential as a sustainable alternative to chemical pesticides in the control of sugarcane diseases. Its efficacy as a biocontrol agent is thought to be associated with its production of chitinase enzymes, including N-acetyl-ß-D-glucosaminidases, chitobiosidases and endochitinases. We used targeted gene deletion and RNA-dependent gene silencing strategies to disrupt N-acetyl-ß-D-glucosaminidase and endochitinase activities of the fungus, and to determine their roles in the biocontrol of soil-borne plant pathogens. The loss of N-acetyl-ß-D-glucosaminidase activities was dispensable for biocontrol of the plurivorous damping-off pathogens Rhizoctonia solani and Sclerotinia sclerotiorum, and of the sugarcane pathogen Ceratocystis paradoxa, the causal agent of pineapple disease. Similarly, suppression of endochitinase activities had no effect on R. solani and S. sclerotiorum disease control, but had a pronounced effect on the ability of T. virens 223 to control pineapple disease. Our work demonstrates a critical requirement for T. virens 223 endochitinase activity in the biocontrol of C. paradoxa sugarcane disease, but not for general antagonism of other soil pathogens. This may reflect its lifestyle as a sugarcane root endophyte. PMID:23110120

A heterodimer comprised of two bovine lactoferrin antimicrobial peptides exhibits powerful bactericidal activity against Burkholderia pseudomallei.

PubMed

Puknun, Aekkalak; Bolscher, Jan G M; Nazmi, Kamran; Veerman, Enno C I; Tungpradabkul, Sumalee; Wongratanacheewin, Surasakdi; Kanthawong, Sakawrat; Taweechaisupapong, Suwimol

2013-07-01

Melioidosis is a severe infectious disease that is endemic in Southeast Asia and Northern Australia. Burkholderia pseudomallei, the causative agent of this disease, has developed resistance to an increasing list of antibiotics, demanding a search for novel agents. Lactoferricin and lactoferrampin are two antimicrobial domains of lactoferrin with a broad spectrum of antimicrobial activity. A hybrid peptide (LFchimera) containing lactoferrampin (LFampin265-284) and a part of lactoferricin (LFcin17-30) has strikingly higher antimicrobial activities compared to the individual peptides. In this study, the antimicrobial activities of this chimeric construct (LFchimera1), as well as of another one containing LFcin17-30 and LFampin268-284, a shorter fragment of LFampin265-284 (LFchimera2), and the constituent peptides were tested against 7 isolates of B. pseudomallei and compared to the preferential antibiotic ceftazidime (CAZ). All isolates including B. pseudomallei 979b shown to be resistant to CAZ, at a density of 10(5) CFU/ml, could be killed by 5-10 μM of LFchimera1 within 2 h, while the other peptides as well as the antibiotic CAZ only inhibited the B. pseudomallei strains resulting in an overgrowth in 24 h. These data indicate that LFchimera1 could be considered for development of therapeutic agents against B. pseudomallei.

Use of KW-2189, a DNA minor groove-binding agent, in patients with hepatocellular carcinoma: a north central cancer treatment group (NCCTG) phase II clinical trial.

PubMed

Alberts, Steven R; Suman, Vera J; Pitot, Henry C; Camoriano, John K; Rubin, Joseph

2007-01-01

Hepatocellular carcinoma (HCC) is a common cancer in certain portions of the world. Currently no effective therapies exist for patients with advanced or metastatic HCC. KW-2189, a DNA minor groove-binding agent, has shown promising activity against HCC in preclinical evaluations. A phase II study was conducted to evaluate the activity of KW-2189 in patients with histologic or cytologic confirmed advanced or metastatic HCC who had no prior systemic therapy. Patients received KW-2189 at a dose of 0.5 mg/m2 administered on day 1 of a 6-week cycle. The primary endpoint of the trial was objective regression. Other endpoints included toxicity, disease-free survival, and overall survival. Due to hematologic toxicity the dose of KW-2189 was reduced to 0.375 mg/m2 after 11 patients had been enrolled into the trial. Due to continued significant hematologic toxicity in the next five patients enrolled at the lower dose the trial was closed to accrual. Two responses were seen in patients enrolled at the higher dose, including one sustained CR. KW-2189 showed evidence of anti-tumor activity in HCC. However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Further exploration of DNA minor groove-binding agents in the treatment of HCC appears warranted.

Regulation of Glucose Homeostasis by GLP-1

PubMed Central

Nadkarni, Prashant; Chepurny, Oleg G.; Holz, George G.

2014-01-01

Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics. PMID:24373234

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC).

PubMed

Atkins, Michael B; Philips, George K

2016-09-01

Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015. Current efforts with anti-PD1-based therapy include combinations with ipilimumab and with VEGF pathway blockers in the hopes on building on the activity of single agent therapy. We describe our current understanding of tumor immunology including the basis of the tumor-specific immune response and the adaptive mechanisms used by the tumor for immune escape. We describe the mechanisms of action as well as the therapeutic application of the antibodies, ipilimumab, nivolumab and atezolizumab in patients with RCC. We identify key areas of active research in biomarker development and combination therapies. Clinical trials and the field of RCC therapeutics are expected to move in the direction of combination therapies using immune checkpoint inhibitors, extending overall survival as a benchmark for new drug approvals, and biomarker validation for improved selection of patients for specific therapies.

NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

PubMed Central

Harkcom, William T.; Ghosh, Ananda K.; Sung, Matthew S.; Matov, Alexandre; Brown, Kevin D.; Giannakakou, Paraskevi; Jaffrey, Samie R.

2014-01-01

Nicotinamide adenine dinucleotide (NAD+) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD+-regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD+. Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD+ levels. We find that these effects of NAD+ are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD+ on microtubule polymers. Taken together, these data demonstrate that NAD+ and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents. PMID:24889606

The role of oxidative stress in organophosphate and nerve agent toxicity

PubMed Central

Pearson, Jennifer N.; Patel, Manisha

2016-01-01

Organophosphate nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent organophosphate toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to organophosphate agents. Key findings of these studies include alterations in mitochondrial function and increased free radical–mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in organophosphate neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of organophosphate-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures. PMID:27371936

G2 and G5 carboxyl-terminated polyamidoamine dendrimers interact differently with 1-palmitoyl-2-oleoyl phosphocholine bilayers **1

USDA-ARS?s Scientific Manuscript database

Limits on non-target tissue exposure and avoidance of metabolic changes to active agents make topical application/delivery of skin active agents highly desirable. Individually, phospholipid liposomes and polyamidoamine dendrimers are effective delivery systems of various active agents. Potentially...

Study of 2219 aluminum alloy using direct current A-TIG welding

NASA Astrophysics Data System (ADS)

Li, Hui; Zou, Jiasheng

2017-07-01

Direct current A-TIG (DCEN A-TIG) welding using special active agent had eliminated the pores and the oxidation of 2219 high-strength aluminum alloy in welding. Addition of AlF3-25% LiF active agent to DCEN A-TIG welding and arc morphology showed a trailing phenomenon. However, the change in arc morphology was not remarkable when AlF3-75% LiF active agent was added. Addition of AlF3-75% LiF active agent can refine the grain size of DCEN A-TIG joint. The mechanical properties of the weld were optimal at 10% AlF3-75% LiF active agent. Compared with AC TIG and AC A-TIG welding, DCEN A-TIG welding yielded better results for 2219 Al alloy.

Quantitative Agent Based Model of User Behavior in an Internet Discussion Forum

PubMed Central

Sobkowicz, Pawel

2013-01-01

The paper presents an agent based simulation of opinion evolution, based on a nonlinear emotion/information/opinion (E/I/O) individual dynamics, to an actual Internet discussion forum. The goal is to reproduce the results of two-year long observations and analyses of the user communication behavior and of the expressed opinions and emotions, via simulations using an agent based model. The model allowed to derive various characteristics of the forum, including the distribution of user activity and popularity (outdegree and indegree), the distribution of length of dialogs between the participants, their political sympathies and the emotional content and purpose of the comments. The parameters used in the model have intuitive meanings, and can be translated into psychological observables. PMID:24324606

Mesoporous TiO2 implants for loading high dosage of antibacterial agent

NASA Astrophysics Data System (ADS)

Park, Se Woong; Lee, Donghyun; Choi, Yong Suk; Jeon, Hoon Bong; Lee, Chang-Hoon; Moon, Ji-Hoi; Kwon, Il Keun

2014-06-01

We have fabricated mesoporous thin films composed of TiO2 nanoparticles on anodized titanium implant surfaces for loading drugs at high doses. Surface anodization followed by treatment with TiO2 paste leads to the formation of mechanically stable mesoporous thin films with controllable thickness. A series of antibacterial agents (silver nanoparticles, cephalothin, minocycline, and amoxicillin) were loaded into the mesoporous thin films and their antibacterial activities were evaluated against five bacterial species including three oral pathogens. Additionally, two agents (silver nanoparticles and minocycline) were loaded together on the thin film and tested for antibacterial effectiveness. The combination of silver nanoparticles and minocycline was found to display a wide range of effectiveness against all tested bacteria.

The reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent does not influence the effect of a second TNF blocking agent in patients with rheumatoid arthritis.

PubMed

Blom, Marlies; Kievit, Wietske; Fransen, Jaap; Kuper, Ina H; den Broeder, Alfons A; De Gendt, Carla M A; Jansen, Tim L; Brus, Herman L M; van de Laar, Mart A F J; van Riel, Piet L C M

2009-10-01

To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent. Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking agents. Patients were divided into 3 groups based on reason for discontinuation of the first: nonresponse, loss of response, or adverse events. The primary outcome was the change from baseline of the disease activity (by DAS28) at 6 months, corrected for the baseline DAS28 score. Secondary outcomes were the change from baseline at 3 months, EULAR response rates, and the percentages of patients who reached a DAS28 score < or = 3.2 at 3 and at 6 months. In total, 49 patients who failed due to nonresponse, 75 due to loss of response, and 73 due to adverse events were included. At 6 months, the change of DAS28 score from baseline did not differ significantly between the groups (-0.6 to -1.3; p > or = 0.173) and similar good and moderate response rates were found (12% to 18%, p > or = 0.523, and 34% to 55%, p > or = 0.078, respectively). The secondary outcomes were also comparable between the 3 groups. The results of our observational study suggest that a second TNF blocking agent may be effective after failure of the first, regardless of the reason for discontinuation of the first TNF blocking agent.

Effect of Two Cancer Chemotherapeutic Agents on the Antibacterial Activity of Three Antimicrobial Agents

PubMed Central

Moody, Marcia R.; Morris, Maureen J.; Young, Viola Mae; Moyé, Lemuel A.; Schimpff, Stephen C.; Wiernik, Peter H.

1978-01-01

Cancer chemotherapeutic agents and antibacterial antibiotics are often given concomitantly. Daunorubicin, cytosine arabinoside, and three antibiotics (gentamicin, amikacin, and ticarcillin) were tested individually and in combinations to determine their antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. These cytotoxic agents are commonly employed in the therapy of acute nonlymphocytic leukemia for remission induction therapy, and these antimicrobial agents are used in infection therapy. The maximum concentrations of the two cytotoxic drugs were chosen to be twice the known peak plasma levels of commonly employed dosage schedules. Neither of the cancer chemotherapeutic agents, alone or in combination, demonstrated bactericidal activity at the levels tested. However, in the presence of these agents, the antimicrobial activity of gentamicin and amikacin, although not that of ticarcillin, was depressed for 11 of 15 K. pneumoniae strains and 8 of 15 P. aeruginosa strains, but for none of the strains of E. coli. This level of decreased activity occasionally resulted in a minimal inhibitory concentration of the tested aminoglycoside well above the standard serum levels. Daunorubicin was more likely to antagonize gentamicin than was cytosine arabinoside. PMID:103494

Identification of a novel inhibitor of isocitrate lyase as a potent antitubercular agent against both active and non-replicating Mycobacterium tuberculosis.

PubMed

Liu, Yishuang; Zhou, Shuang; Deng, Qi; Li, Xinghua; Meng, Jianzhou; Guan, Yan; Li, Chuanyou; Xiao, Chunling

2016-03-01

Screen and identify novel inhibitors of isocitrate lyase (ICL) as potent antitubercular agents against Mycobacterium tuberculosis and determine their inhibitory characteristics, antitubercular activities and mechanisms of action. Recombinant ICL of M. tuberculosis was expressed and purified, which was used for high-throughput screening (HTS) and the following experiments. A total of 71,765 compounds were screened to identify ICL inhibitors which were then evaluated for their roles as potent antitubercular agents. To determine the inhibitory characteristics of the agents against latent M. tuberculosis in persistent infections, a macrophage model (mouse J774A.1 cell) infected with Mycobacterium marinum BAA-535 strain was built and assessed. The potent antitubercular agents were identified using the macrophage model. Then, the inhibitory intensity and mode of the agents that exhibit on ICL protein of M. tuberculosis were analyzed, and the interaction mechanisms were preliminarily clarified according to the parameters of enzyme kinetics, circular dichroism experiments, fluorescence quenching assay, and molecular docking. The previously established ICL inhibitor screening model was evaluated to be suitable for HTS assay. Of the 71,765 compounds, 13 of them were identified to inhibit ICL effectively and stably. IMBI-3 demonstrated the most significant inhibitory activity with IC50 of 30.9 μmol/L. Its minimum inhibitory concentration (MIC) for M. tuberculosis, including extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB), were determined in the range of 0.25-1 μg/mL. When IMBI-3 is used in combination with isoniazid, the colony-forming units (CFU) counting of latent M. tuberculosis in J774A.1 macrophage cells decreased significantly as IMBI-3 concentration increased. The inhibition mode of IMBI-3 on ICL was probably competitive inhibition with an inhibition constant (Ki) of approximate 1.85 μmol/L. The interaction between IMBI-3 and ICL of M. tuberculosis was also confirmed by circular dichroism experiments and fluorescence quenching assay. And seven possible active amino acids of ICL of M. tuberculosis were identified in the active site through molecular docking. IMBI-3, a novel potent antitubercular agent targeting ICL of M. tuberculosis, was identified and evaluated. It inhibited both log-phase M. tuberculosis in vitro and dormant M. tuberculosis in macrophages. It was the first representative compound of this family with the ICL enzyme inhibition and antimycobacterial activities. Copyright © 2016 Elsevier Ltd. All rights reserved.

The most novel of the novel agents for acute myeloid leukemia.

PubMed

Perl, Alexander E

2018-03-01

Precious few drugs were successfully developed for acute myeloid leukemia (AML) over the past decades, despite a dramatic expansion of our understanding of its molecular underpinnings during this time. Then in 2017, a wave of new drugs suddenly became approved. This review serves to introduce the newly available drugs, discuss their impact upon therapy, and highlight additional novel agents that are waiting in the wings. Newly approved agents in AML include a tyrosine kinase inhibitor for patients with FMS-like tyrosine kinase 3 (FLT3) mutations, an inhibitor of mutant isocitrate dehydrogenase (IDH2), and two novel agents using antibody-delivered or liposome-delivered cytotoxics. All of these new agents have demonstrable activity in AML and several have improved survival in randomized studies. In addition to these agents, promising data from other inhibitors of FLT3, IDH1, and B-cell lymphoma 2 (BCL2) will be discussed. Response, survival, and symptom burden of AML therapy are all improving through novel agents. As many of the newly approved drugs benefit-specific genetic subsets, a new priority has emerged to increase the speed of diagnostic genomic studies as a means to guide frontline therapy. This will ensure patients are optimally categorized and treated with to the most rational agents.

Comparative Efficacy and Acceptability of Anti-Diabetic Agents for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Network Meta-analysis.

PubMed

Cao, Bing; Rosenblat, Joshua D; Brietzke, Elisa; Park, Caroline; Lee, Yena; Musial, Natalie; Pan, Zihang; Mansur, Rodrigo B; McIntyre, Roger S

2018-05-23

The current meta-analysis compares the efficacy (i.e., pro-cognitive effects) and acceptability of anti-diabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials (RCTs) comparing anti-diabetic agents with placebo and/or another active anti-diabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4,855) evaluating the effects of six different anti-diabetic drugs (i.e., intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with anti-diabetic agents compared to placebo. Pioglitazone 15-30 mg demonstrated the greatest efficacy compared to placebo in network meta-analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro-cognitive class effect of anti-diabetic agents in AD/MCI. Other anti-diabetic agents should also be investigated in future studies. This study is registered with PROSPERO (CRD42018085967). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy.

PubMed

Diamond, E; Molina, A M; Carbonaro, M; Akhtar, N H; Giannakakou, P; Tagawa, S T; Nanus, D M

2015-12-01

Renal cell carcinoma (RCC) is a heterogeneous disease with regards to histology, progression, and response to treatment. Cytotoxic chemotherapy has been extensively studied in metastatic RCC (mRCC). Responses in most studies are modest and the mechanisms of resistance remain poorly understood. Targeted therapies have significantly improved outcomes in mRCC; however, most patients eventually relapse and die of their disease. Early clinical data suggest that combinations of chemotherapy and targeted agents are clinically active and are well tolerated. We reviewed the available literature for published clinical trials incorporating traditional chemotherapeutic agents in the treatment of mRCC. These papers were identified through a Medline search and were included if they employed at least one chemotherapeutic agent in the treatment of mRCC. The literature was also reviewed for information regarding mechanisms of chemotherapy resistance. The data regarding the use of cytotoxic chemotherapy in mRCC consist of small, non-randomized phase I and II studies. The major response proportions with single agent chemotherapies are low but combination regimens either with other cytotoxic agents, cytokines, or targeted agents have demonstrated moderate activity. Disparate trial designs and lack of head to head clinical trials make it difficult to compare the efficacy of chemotherapy with that of immunotherapy or targeted agents. Chemotherapy is particularly useful in patients with collecting duct histology and predominantly sarcomatoid differentiation. Chemotherapy resistance may be mediated by overexpression of p-glycoprotein efflux pumps and the dysregulation of the microtubule-hypoxia inducible factor signaling axis. The role of cytotoxic chemotherapy in the treatment for clear cell RCC remains poorly defined. Cytotoxic chemotherapy is considered a standard of care in patients with mRCC with predominantly sarcomatoid differentiation and collecting duct RCC variants (Motzer et al., 2014). Early trials combining chemotherapy with targeted therapies are generally well tolerated and show clinical activity. A better understanding of the biology of aggressive subsets of RCC and mechanisms of resistance will help elucidate the role of cytotoxic agents in the current treatment paradigm of RCC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Quantum-chemical Calculations in the Study of Antitumour Compounds

NASA Astrophysics Data System (ADS)

Luzhkov, V. B.; Bogdanov, G. N.

1986-01-01

The results of quantum-chemical calculations on antitumour preparations concerning the mechanism of their action at the electronic and molecular levels and structure-activity correlations are discussed in this review. Preparations whose action involves alkylating and free-radial mechanisms, complex-forming agents, and antimetabolites are considered. Modern quantum-chemical methods for calculations on biologically active substances are described. The bibliography includes 106 references.

The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain.

PubMed

Ehrhardt, Katharina; Davioud-Charvet, Elisabeth; Ke, Hangjun; Vaidya, Akhil B; Lanzer, Michael; Deponte, Marcel

2013-05-01

Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are "subversive substrates." These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.

Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action.

PubMed

Mohamed, Shimaa Ibrahim Abdelmonym; Jantan, Ibrahim; Haque, Md Areeful

2017-09-01

Natural products with immunomodulatory activity are widely used in treatment of many diseases including autoimmune diseases, inflammatory disorders in addition to cancer. They gained a great interest in the last decades as therapeutic agents since they provide inexpensive and less toxic products than the synthetic chemotherapeutic agents. Immunomodulators are the agents that have the ability to boost or suppress the host defense response that can be used as a prophylaxis as well as in combination with other therapeutic modalities. The anticancer activity of these immunomodulators is due to their anti-inflammatory, antioxidant, and induction of apoptosis, anti-angiogenesis, and anti-metastasis effect. These natural immunomodulators such as genistein, curcumin, and resveratrol can be used as prophylaxis against the initiation of cancer besides the inhibition of tumor growth and proliferation. Whereas, immunostimulants can elicit and activate humoral and cell-mediated immune responses against the tumor that facilitate the recognition and destruction of the already existing tumor. This review represents the recent studies on various natural immunomodulators with antitumor effects. We have focused on the relationship between their anticancer activity and immunomodulatory mechanisms. The mechanisms of action of various immunomodulators such as polyphenolic compounds, flavonoids, organosulfur compounds, capsaicin, vinca alkaloids, bromelain, betulinic acid and zerumbone, the affected cancerous cell lines in addition to the targeted molecules and transcriptional pathways have been review and critically analyzed. Copyright © 2017 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Wu; Canfield, Nathan L.; Zhang, Ji-Guang

Methods for making composite anodes, such as macroporous composite anodes, are disclosed. Embodiments of the methods may include forming a tape from a slurry including a substrate metal precursor, an anode active material, a pore-forming agent, a binder, and a solvent. A laminated structure may be prepared from the tape and sintered to produce a porous structure, such as a macroporous structure. The macroporous structure may be heated to reduce a substrate metal precursor and/or anode active material. Macroporous composite anodes formed by some embodiments of the disclosed methods comprise a porous metal and an anode active material, wherein themore » anode active material is both externally and internally incorporated throughout and on the surface of the macroporous structure.« less

In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents

PubMed Central

Fjell, Christopher D.; Waldbrook, Matt; Chongsiriwatana, Nathaniel P.; Yuen, Eddie; Hancock, Robert E. W.; Barron, Annelise E.

2016-01-01

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one of the best candidate peptoids at 4 mg/kg significantly reduces with a two-log order the bacterial counts compared with saline-treated controls. Taken together, our results demonstrate the promising therapeutic potential of peptoids as antimicrobial agents. PMID:26849681

Development and Sequential Analysis of a New Multi-Agent, Anti-Acne Formulation Based on Plant-Derived Antimicrobial and Anti-Inflammatory Compounds.

PubMed

Saviuc, Crina; Ciubucă, Bianca; Dincă, Gabriela; Bleotu, Coralia; Drumea, Veronica; Chifiriuc, Mariana-Carmen; Popa, Marcela; Gradisteanu Pircalabioru, Gratiela; Marutescu, Luminita; Lazăr, Veronica

2017-01-17

The antibacterial and anti-inflammatory potential of natural, plant-derived compounds has been reported in many studies. Emerging evidence indicates that plant-derived essential oils and/or their major compounds may represent a plausible alternative treatment for acne, a prevalent skin disorder in both adolescent and adult populations. Therefore, the purpose of this study was to develop and subsequently analyze the antimicrobial activity of a new multi-agent, synergic formulation based on plant-derived antimicrobial compounds (i.e., eugenol, β-pinene, eucalyptol, and limonene) and anti-inflammatory agents for potential use in the topical treatment of acne and other skin infections. The optimal antimicrobial combinations selected in this study were eugenol/β-pinene/salicylic acid and eugenol/β-pinene/2-phenoxyethanol/potassium sorbate. The possible mechanisms of action revealed by flow cytometry were cellular permeabilization and inhibition of efflux pumps activity induced by concentrations corresponding to sub-minimal inhibitory (sub-MIC) values. The most active antimicrobial combination represented by salycilic acid/eugenol/β-pinene/2-phenoxyethanol/potassium sorbate was included in a cream base, which demonstrated thermodynamic stability and optimum microbiological characteristics.

Promising new developments in cancer chemotherapy.

PubMed

Ferrante, K; Winograd, B; Canetta, R

1999-01-01

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active compounds with improved therapeutic indices. In addition, new insights into the pathways of human tumorigenesis have led to novel approaches aimed at specific mechanism-based targets. The taxane class, of which paclitaxel was the first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apoptotic cell death. Paclitaxel provides treatment benefit in a broad range of solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic target. Taxane analogues with improved preclinical efficacy have been identified and are entering clinical trials. The enthusiasm for oral anticancer agents and the therapeutic importance of platinum compounds has led to the development of JM216 (satraplatin), a novel platinum IV coordination complex with oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE, a chemopotentiator that enhances the in vivo antitumor effects of cytotoxic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a dual topoisomerase I and II inhibitor with preclinical efficacy in a broad spectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination strategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines utilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably at tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for intervention in several aspects of tumor progression. Local production of MMPs with subsequent degradation of the extracellular matrix is implicated in supporting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will likely require chronic administration in conjunction with other therapies. Oncogenes and tumor suppressor genes are appealing targets for therapy since they are thought to be responsible for a significant number of cancers. Mutations in the Ras oncogene occur with great frequency in a number of human cancers including lung, pancreas, and colon cancer. Clinical development of potent and selective inhibitors of farnesyltransferase, the Ras-processing enzyme, is ongoing. These compounds uncouple Ras activity, affect tumor growth, and have demonstrated significant antitumor activity against experimental models of human cancer. The exciting compounds and novel therapeutic approaches currently under investigation by Bristol-Myers Squibb Pharmaceutical Research Institute offer great potential as effective cancer chemotherapy agents for the near future.

From Each According to Her Ability

ERIC Educational Resources Information Center

Baumrind, Diana

1972-01-01

Examines possible sources of instrumental incompetence in women including their views of themselves as victims rather than as active agents responsible for their own destiny. Reviews research finding in socialization practices and their effects upon children. Women should value instrumental competence rather than being content with expressive…

DAPG-producing Pseudomonas fluorescens: beneficial agents for suppression of plant-parasitic nematodes?

USDA-ARS?s Scientific Manuscript database

Some beneficial strains of the bacterium Pseudomonas fluorescens produce the antibiotic 2, 4-diacetylphloroglucinol (DAPG). DAPG is active against a number of organisms, including viruses, bacteria, fungi and plants, and DAPG-producing P. fluorescens can also induce plant resistance against pathogen...

Rosemary, the beneficial chemistry of a garden herb.

PubMed

Hanson, James R

2016-01-01

The major natural products that are present in the garden herb, rosemary (Rosmarinus officinalis) including the mono di- and triterpenoid, flavonoid and phenolic constituents together with their biological activity as anti-microbial, anti-oxidant, anti-inflammatory, memory-enhancing and tumour-inhibitory agents, are reviewed.

77 FR 23462 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-19

... this law allocates the Aleutian Islands (AI) directed pollock fishery to the Aleut Corporation for... agents for activities necessary for conducting the AI directed pollock fishery. Management provisions for the AI directed pollock fishery include: restrictions on the harvest specifications for the AI...

[Mass spectrometry in medicine and biotechnology].

PubMed

Polunina, T A; Kireev, M N; Khramchenkova, T A; Spitsyn, A N; Grigor'eva, G V

2013-01-01

History of development and improvement of tandem mass spectrometry, possibilities of its application at the contemporary stage in various fields of medicine and biotechnology including production of novel medicinal preparations, identification of biologically active substances, pathogenic microorganisms and causative agents of especially dangerous infections is given.

Decontamination formulation with sorbent additive

DOEpatents

Tucker; Mark D. , Comstock; Robert H.

2007-10-16

A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

Antifungal resistance in mucorales.

PubMed

Dannaoui, E

2017-11-01

The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Synthesis and antibacterial activity of Schiff bases and amines derived from alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates.

PubMed

Goszczyńska, Agata; Kwiecień, Halina; Fijałkowski, Karol

A series of novel Schiff bases and secondary amines were obtained in good yields, as a result of the reductive amination of alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates with both aniline and 4-methoxyaniline under established mild reaction conditions. Sodium triacetoxyborohydride as well as hydrogen in the presence of palladium on carbon were used as efficient reducing agents of the Schiff bases, in both direct and stepwise reductive amination processes. The Schiff bases, amines, and amine hydrochlorides were designed as potential antibacterial agents, and structure-activity relationship could be established following in vitro assays against Gram-positive and Gram-negative bacteria. The minimal inhibitory concentration and zone of inhibition were also determined. In these tests, some of Schiff bases and secondary amine hydrochlorides showed moderate-to-good activity against Gram-positive bacteria, including S. aureus , M. luteus , and S. mutans .

Recent advancement of molecular mechanisms of liver fibrosis.

PubMed

Seki, Ekihiro; Brenner, David A

2015-07-01

Liver fibrosis occurs in response to any etiology of chronic liver injury including hepatitis B and C, alcohol consumption, fatty liver disease, cholestasis, and autoimmune hepatitis. Hepatic stellate cells (HSCs) are the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in the liver. Various inflammatory and fibrogenic pathways contribute to the activation of HSCs. Recent studies also discovered that liver fibrosis is reversible and activated HSCs can revert to quiescent HSCs when causative agents are removed. Although the basic research for liver fibrosis has progressed remarkably, sensitive and specific biomarkers as non-invasive diagnostic tools, and effective anti-fibrotic agents have not been developed yet. This review highlights the recent advances in cellular and molecular mechanisms of liver fibrosis, especially focusing on origin of myofibroblasts, inflammatory signaling, autophagy, cellular senescence, HSC inactivation, angiogenesis, and reversibility of liver fibrosis. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Commonly used disinfectants fail to eradicate Salmonella enterica biofilms from food contact surface materials.

PubMed

Corcoran, M; Morris, D; De Lappe, N; O'Connor, J; Lalor, P; Dockery, P; Cormican, M

2014-02-01

Salmonellosis is the second most common cause of food-borne illness worldwide. Contamination of surfaces in food processing environments may result in biofilm formation with a risk of food contamination. Effective decontamination of biofilm-contaminated surfaces is challenging. Using the CDC biofilm reactor, the activities of sodium hypochlorite, sodium hydroxide, and benzalkonium chloride were examined against an early (48-h) and relatively mature (168-h) Salmonella biofilm. All 3 agents result in reduction in viable counts of Salmonella; however, only sodium hydroxide resulted in eradication of the early biofilm. None of the agents achieved eradication of mature biofilm, even at the 90-min contact time. Studies of activity of chemical disinfection against biofilm should include assessment of activity against mature biofilm. The difficulty of eradication of established Salmonella biofilm serves to emphasize the priority of preventing access of Salmonella to postcook areas of food production facilities.

CDK1 promotes nascent DNA synthesis and induces resistance of cancer cells to DNA-damaging therapeutic agents

PubMed Central

Liao, Hongwei; Ji, Fang; Geng, Xinwei; Xing, Meichun; Li, Wen; Chen, Zhihua; Shen, Huahao; Ying, Songmin

2017-01-01

Cyclin dependent kinase 1 (CDK1) is essential for cell viability and plays a vital role in many biological events including cell cycle control, DNA damage repair, and checkpoint activation. Here, we identify an unanticipated role for CDK1 in promoting nascent DNA synthesis during S-phase. We report that a short duration of CDK1 inhibition, which does not perturb cell cycle progression, triggers a replication-associated DNA damage response (DDR). This DDR is associated with a disruption of replication fork progression and leads to genome instability. Moreover, we show that compromised CDK1 activity dramatically increases the efficacy of chemotherapeutic agents that kill cancer cells through perturbing DNA replication, including Olaparib, an FDA approved PARP inhibitor. Our study has revealed an important role for CDK1 in the DNA replication program, and suggests that the therapeutic targeting CDK1 may be a novel approach for combination chemotherapy. PMID:29207595

Synthesis, characterization, bioactivity and potential application of phenolic acid grafted chitosan: A review.

PubMed

Liu, Jun; Pu, Huimin; Liu, Shuang; Kan, Juan; Jin, Changhai

2017-10-15

In recent years, increasing attention has been paid to the grafting of phenolic acid onto chitosan in order to enhance the bioactivity and widen the application of chitosan. Here, we present a comprehensive overview on the recent advances of phenolic acid grafted chitosan (phenolic acid-g-chitosan) in many aspects, including the synthetic method, structural characterization, biological activity, physicochemical property and potential application. In general, four kinds of techniques including carbodiimide based coupling, enzyme catalyzed grafting, free radical mediated grafting and electrochemical methods are frequently used for the synthesis of phenolic acid-g-chitosan. The structural characterization of phenolic acid-g-chitosan can be determined by several instrumental methods. The physicochemical properties of chitosan are greatly altered after grafting. As compared with chitosan, phenolic acid-g-chitosan exhibits enhanced antioxidant, antimicrobial, antitumor, anti-allergic, anti-inflammatory, anti-diabetic and acetylcholinesterase inhibitory activities. Notably, phenolic acid-g-chitosan shows potential applications in many fields as coating agent, packing material, encapsulation agent and bioadsorbent. Copyright © 2017 Elsevier Ltd. All rights reserved.

Current and future management of infections due to methicillin-resistant staphylococci infections: the role of quinupristin/dalfopristin.

PubMed

Péchère, J C

1999-09-01

The rise in the number of multidrug-resistant gram-positive bacteria that has occurred in recent years has resulted in the development of infections that are difficult to treat, and also in severely restricted treatment options. In particular, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) has increased, with strains shown to cause up to 21% of skin infections and 59.6% of nosocomial pneumonia. Recently, strains of S. aureus with reduced susceptibility to vancomycin (glycopeptide-intermediate S. aureus or GISA) are causing great concern, particularly as vancomycin has been the agent of choice in the treatment of infection caused by MRSA. GISA has been identified in Japan, the USA and Europe. New agents that have anti-MRSA activity are now being investigated. These include the novel streptogramin, quinupristin/dalfopristin. This report examines the activity of quinupristin/dalfopristin against strains of S. aureus and coagulase-negative staphylococci, including multidrug-resistant MRSA and GISA.

Antibacterial Effects of Glycyrrhetinic Acid and Its Derivatives on Staphylococcus aureus

PubMed Central

Oyama, Kentaro; Kawada-Matsuo, Miki; Oogai, Yuichi; Hayashi, Tetsuya; Nakamura, Norifumi; Komatsuzawa, Hitoshi

2016-01-01

Staphylococcus aureus is a major pathogen in humans and causes serious problems due to antibiotic resistance. We investigated the antimicrobial effect of glycyrrhetinic acid (GRA) and its derivatives against 50 clinical S. aureus strains, including 18 methicillin-resistant strains. The minimum inhibitory concentrations (MICs) of GRA, dipotassium glycyrrhizate, disodium succinoyl glycyrrhetinate (GR-SU), stearyl glycyrrhetinate and glycyrrhetinyl stearate were evaluated against various S. aureus strains. Additionally, we investigated the bactericidal effects of GRA and GR-SU against two specific S. aureus strains. DNA microarray analysis was also performed to clarify the mechanism underlying the antibacterial activity of GR-SU. We detected the antimicrobial activities of five agents against S. aureus strains. GRA and GR-SU showed strong antibacterial activities compared to the other three agents tested. At a higher concentration (above 2x MIC), GRA and GR-SU showed bactericidal activity, whereas at a concentration of 1x MIC, they showed a bacteriostatic effect. Additionally, GRA and GR-SU exhibited a synergistic effect with gentamicin. The expression of a large number of genes (including transporters) and metabolic factors (carbohydrates and amino acids) was altered by the addition of GR-SU, suggesting that the inhibition of these metabolic processes may influence the degree of the requirement for carbohydrates or amino acids. In fact, the requirement for carbohydrates or amino acids was increased in the presence of either GRA or GR-SU. GRA and GR-SU exhibited strong antibacterial activity against several S. aureus strains, including MRSA. This activity may be partly due to the inhibition of several pathways involved in carbohydrate and amino acid metabolism. PMID:27820854

Copper and Quaternary Ammonium Cations Exert Synergistic Bactericidal and Antibiofilm Activity against Pseudomonas aeruginosa▿

PubMed Central

Harrison, Joe J.; Turner, Raymond J.; Joo, Daniel A.; Stan, Michelle A.; Chan, Catherine S.; Allan, Nick D.; Vrionis, Helen A.; Olson, Merle E.; Ceri, Howard

2008-01-01

Biofilms are slimy aggregates of microbes that are likely responsible for many chronic infections as well as for contamination of clinical and industrial environments. Pseudomonas aeruginosa is a prevalent hospital pathogen that is well known for its ability to form biofilms that are recalcitrant to many different antimicrobial treatments. We have devised a high-throughput method for testing combinations of antimicrobials for synergistic activity against biofilms, including those formed by P. aeruginosa. This approach was used to look for changes in biofilm susceptibility to various biocides when these agents were combined with metal ions. This process identified that Cu2+ works synergistically with quaternary ammonium compounds (QACs; specifically benzalkonium chloride, cetalkonium chloride, cetylpyridinium chloride, myristalkonium chloride, and Polycide) to kill P. aeruginosa biofilms. In some cases, adding Cu2+ to QACs resulted in a 128-fold decrease in the biofilm minimum bactericidal concentration compared to that for single-agent treatments. In combination, these agents retained broad-spectrum antimicrobial activity that also eradicated biofilms of Escherichia coli, Staphylococcus aureus, Salmonella enterica serovar Cholerasuis, and Pseudomonas fluorescens. To investigate the mechanism of action, isothermal titration calorimetry was used to show that Cu2+ and QACs do not interact in aqueous solutions, suggesting that each agent exerts microbiological toxicity through independent biochemical routes. Additionally, Cu2+ and QACs, both alone and in combination, reduced the activity of nitrate reductases, which are enzymes that are important for normal biofilm growth. Collectively, the results of this study indicate that Cu2+ and QACs are effective combinations of antimicrobials that may be used to kill bacterial biofilms. PMID:18519726

Topical Microbicides and HIV Prevention in the Female Genital Tract

PubMed Central

Cottrell, Mackenzie L; Kashuba, Angela D. M.

2014-01-01

Worldwide, HIV disproportionately affects women who are often unable to negotiate traditional HIV preventive strategies such as condoms. In the absence of an effective vaccine or cure, chemoprophylaxis may be a valuable self-initiated alternative. Topical microbicides have been investigated as one such option. The first generation topical microbicides were non-specific, broad-spectrum antimicrobial agents, including surfactants, polyanions, and acid buffering gels, that generally exhibited contraceptive properties. After extensive clinical study, none prevented HIV infection, and their development was abandoned. Second generation topical microbicides include agents with selective mechanisms of antiviral activity. Most are currently being used for, or have previously been explored as, drugs for treatment of HIV. The most advanced of these is tenofovir 1% gel: the first topical agent shown to significantly reduce HIV infection by 39% compared to placebo. This review summarizes the evolution of topical microbicides for HIV chemoprophylaxis, highlights important concepts learned, and offers current and future considerations for this area of research. PMID:24664786

Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model.

PubMed

Kelner, Michael J; McMorris, Trevor C; Rojas, Rafael J; Estes, Leita A; Suthipinijtham, Pharnuk

2008-12-01

Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.

Systemic therapy after first-line docetaxel in metastatic castration-resistant prostate cancer.

PubMed

Beardsley, Emma K; Chi, Kim N

2008-09-01

There is an urgent need for systemic treatment options for patients with castration-resistant prostate cancer who have progressed after receiving first-line docetaxel chemotherapy. The purpose of this article is to review recent developments in this area. Retreatment with docetaxel has been employed with evidence of activity in selected populations. Mitoxantrone, the previous first-line standard based on its palliative effect, has also been used with clinical responses observed; however, the symptom benefit in this setting has not been established. Several classes of cytotoxic agents have been tested including platinum agents (satraplatin), epothilones (ixabepilone and patupilone) and taxanes (XRP-6258). A number of targeted therapies have also been clinically evaluated including inhibitors of cytoprotective chaperones (OGX-011) and the vascular endothelial growth factor receptor (sorafenib, sunitinib, and cediranib). An area generating great interest has been the development of agents that target the androgen receptor axis more effectively (MDV3100 and abiraterone) with encouraging early phase trial results. There is no accepted standard systemic treatment for patients with castration resistant prostate cancer and progressive disease after docetaxel. Novel agents are in phase II and III clinical testing in this setting.

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

USDA-ARS?s Scientific Manuscript database

Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.

PubMed

Lin, Jie; Sampath, Deepak; Nannini, Michelle A; Lee, Brian B; Degtyarev, Michael; Oeh, Jason; Savage, Heidi; Guan, Zhengyu; Hong, Rebecca; Kassees, Robert; Lee, Leslie B; Risom, Tyler; Gross, Stefan; Liederer, Bianca M; Koeppen, Hartmut; Skelton, Nicholas J; Wallin, Jeffrey J; Belvin, Marcia; Punnoose, Elizabeth; Friedman, Lori S; Lin, Kui

2013-04-01

We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers. The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents. GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents. GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling. ©2012 AACR.

Recently disclosed chemical entities as potential candidates for management of tuberculosis.

PubMed

Stec, Jozef; Abourashed, Ehab A

2015-01-01

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide. The drug discovery process of novel, safe and effective agents to combat TB involves identification of new molecular targets and novel chemical scaffolds. The current anti-TB drug pipeline includes several small molecules with more to follow as new candidates are disclosed. This review highlights the most significant findings described in 78 international, European and US patents for chemically diverse compounds as prospective anti-TB medications. Main points of emphasis include chemical classification, in vitro and in vivo activity, ADME/Tox profile and mycobacterial target as described in each patent. The collective mass of compounds disclosed in the reviewed patents introduces new candidates as potential therapeutic agents for TB infections.

Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration.

PubMed

Hussain, Rehan M; Ciulla, Thomas A

2017-09-01

Evolving anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) include long acting agents, combination strategies involving new pathways, topical agents, sustained-release, and genetic therapy strategies. Areas covered: Brolucizumab and abicipar pegol have smaller molecular size, facilitating higher concentrations and potentially longer duration than current anti-VEGF agents. Agents being combined with anti-VEGFs include OPT-302 (to inhibit VEGF-C and VEGF-D); pegpleranib and rinucumab (to inhibit platelet derived growth factor, PDGF - but both failed to show consistently improved visual outcomes compared to anti-VEGF monotherapy); and RG7716, ARP-1536 and nesvacumab (to activate the Tie-2 tyrosine kinase receptor, which reduces permeability). X-82 is an oral anti-VEGF and anti-PDGF being tested in phase 2 studies. Topical anti-VEGF ± anti-PDGF drugs under study include pazopanib, PAN-90806, squalamine lactate, regorafinib, and LHA510. Sustained-release anti-VEGF delivery treatments, such as the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305 aim to reduce the burden of frequent injections. Gene therapies with new viral vectors hold the potential to induce sustained expression of anti-angiogenic proteins via the retina's cellular apparatus, and include AVA-101/201, ADVM-202/302, AAV2-sFLT01, RGX314, and Retinostat. Expert opinion: There are many emerging anti-VEGF treatments that aim to improve visual outcomes and reduce the treatment burden of nAMD.

Biological therapy of hematologic malignancies: toward a chemotherapy-free era.

PubMed

Klener, Pavel; Etrych, Tomas; Klener, Pavel

2017-10-06

Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs. Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but also might fundamental change treatment paradigms of certain types of hematologic malignancies in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A combination of silver nanoparticles and visible blue light enhances the antibacterial efficacy of ineffective antibiotics against methicillin-resistant Staphylococcus aureus (MRSA).

PubMed

Akram, Fatma Elzahraa; El-Tayeb, Tarek; Abou-Aisha, Khaled; El-Azizi, Mohamed

2016-08-17

Silver nanoparticles (AgNPs) are potential antimicrobials agents, which can be considered as an alternative to antibiotics for the treatment of infections caused by multi-drug resistant bacteria. The antimicrobial effects of double and triple combinations of AgNPs, visible blue light, and the conventional antibiotics amoxicillin, azithromycin, clarithromycin, linezolid, and vancomycin, against ten clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) were investigated. The antimicrobial activity of AgNPs, applied in combination with blue light, against selected isolates of MRSA was investigated at 1/2-1/128 of its minimal inhibitory concentration (MIC) in 24-well plates. The wells were exposed to blue light source at 460 nm and 250 mW for 1 h using a photon emitting diode. Samples were taken at different time intervals, and viable bacterial counts were determined. The double combinations of AgNPs and each of the antibiotics were assessed by the checkerboard method. The killing assay was used to test possible synergistic effects when blue light was further combined to AgNPs and each antibiotic at a time against selected isolates of MRSA. The bactericidal activity of AgNPs, at sub-MIC, and blue light was significantly (p < 0.001) enhanced when both agents were applied in combination compared to each agent alone. Similarly, synergistic interactions were observed when AgNPs were combined with amoxicillin, azithromycin, clarithromycin or linezolid in 30-40 % of the double combinations with no observed antagonistic interaction against the tested isolates. Combination of the AgNPs with vancomycin did not result in enhanced killing against all isolates tested. The antimicrobial activity against MRSA isolates was significantly enhanced in triple combinations of AgNPs, blue light and antibiotic, compared to treatments involving one or two agents. The bactericidal activities were highest when azithromycin or clarithromycin was included in the triple therapy compared to the other antibiotics tested. A new strategy can be used to combat serious infections caused by MRSA by combining AgNPs, blue light, and antibiotics. This triple therapy may include antibiotics, which have been proven to be ineffective against MRSA. The suggested approach would be useful to face the fast-growing drug-resistance with the slow development of new antimicrobial agents, and to preserve last resort antibiotics such as vancomycin.

The incorporation of activities to control dengue by community health agents

PubMed Central

Cazola, Luiza Helena de Oliveira; Tamaki, Edson Mamoru; Pontes, Elenir Rose Jardim Cury; de Andrade, Sonia Maria Oliveira

2014-01-01

OBJECTIVE To evaluate the performance of Community Health Agents when dengue control activities were added to their tasks. METHODS Performance was measured comparing the evolution of selected indicators from the Brazilian National Dengue Control Program and the Family Health Strategy for 2002 to 2008 in the municipality of Sao Gabriel do Oeste, MS, Central Western Brazil, with those of Rio Verde de Mato Grosso, neighboring municipality with demographic, socioeconomic and health services similarities. Data were collected from municipal databases of the Information System for Yellow Fever and Dengue and the Information System for Primary Healthcare of the Mato Grosso do Sul State Health Office. The variables selected for the family health strategy activities were: monthly home visits, pregnant women whose antenatal care began in the first trimester, children under one with up-to-date vaccinations and hypertensive patients. Those selected for the Brazilian National Dengue Control Program were: properties inspected with Aedes aegypti and properties not inspected. RESULTS The two municipalities maintained a similar trend in dengue control indicators in the period studied. With regard to the Family Health Strategy, in 2002 Sao Gabriel do Oeste was better off in three of the four indicators studied, however, this situation was reversed at the end of the period when the county was overtaken by Rio Verde de Mato Grosso in three of the four indicators analyzed, including, the monthly average community health worker visits per registered family, the main activity of a Family Health Strategy agent. CONCLUSIONS: Incorporating the National Dengue Control Program into the Family Health Strategy is viable and developed without prejudice to dengue control activities, however, the same did not occur with the activities of family health in Sao Gabriel do Oeste. The additional workload of the community health workers is the most likely hypothesis for the declining performance of these agents in the Family Health Strategy activities. PMID:24789644

Learning comunication strategies for distributed artificial intelligence

NASA Astrophysics Data System (ADS)

Kinney, Michael; Tsatsoulis, Costas

1992-08-01

We present a methodology that allows collections of intelligent system to automatically learn communication strategies, so that they can exchange information and coordinate their problem solving activity. In our methodology communication between agents is determined by the agents themselves, which consider the progress of their individual problem solving activities compared to the communication needs of their surrounding agents. Through learning, communication lines between agents might be established or disconnected, communication frequencies modified, and the system can also react to dynamic changes in the environment that might force agents to cease to exist or to be added. We have established dynamic, quantitative measures of the usefulness of a fact, the cost of a fact, the work load of an agent, and the selfishness of an agent (a measure indicating an agent's preference between transmitting information versus performing individual problem solving), and use these values to adapt the communication between intelligent agents. In this paper we present the theoretical foundations of our work together with experimental results and performance statistics of networks of agents involved in cooperative problem solving activities.

Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent.

PubMed

Ugurel, Selma; Paschen, Annette; Becker, Jürgen C

2013-02-01

Chemotherapeutic drugs are clinically used to treat cancer because of their cytotoxic activities against tumor cells. Recently, however, evidence is accumulating-including the report of Hervieu et al. (2012) in the current issue of The Journal of Investigative Dermatology-indicating that at least some of these drugs have broader activities and that they should also be considered immunomodulatory agents. Indeed, Hervieu demonstrates that dacarbazine (DTIC) exerts immunostimulatory effects by inducing local activation of natural killer (NK) and T cells, suggesting that upon treatment with DTIC, the tumor participates in the initiation of an immune response: (i) DTIC treatment elicits the expression of ligands of the immunoreceptor NKG2D on melanoma cells; (ii) engagement of the ligands by NKG2D on NK cells leads to their activation, allowing enhanced tumor-cell killing and the release of IFN-γ; and (iii) IFN-γ in turn upregulates major histocompatibility complex class I expression on tumor cells, which favors their recognition by cytotoxic CD8+ T lymphocytes (CTLs).

Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin

PubMed Central

Zhang, Li; Wang, Handong

2015-01-01

Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma (PPARγ). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX. PMID:26184238

Activation of cGAS-dependent antiviral responses by DNA intercalating agents

PubMed Central

Pépin, Geneviève; Nejad, Charlotte; Thomas, Belinda J.; Ferrand, Jonathan; McArthur, Kate; Bardin, Philip G.; Williams, Bryan R.G.; Gantier, Michael P.

2017-01-01

Acridine dyes, including proflavine and acriflavine, were commonly used as antiseptics before the advent of penicillins in the mid-1940s. While their mode of action on pathogens was originally attributed to their DNA intercalating activity, work in the early 1970s suggested involvement of the host immune responses, characterized by induction of interferon (IFN)-like activities through an unknown mechanism. We demonstrate here that sub-toxic concentrations of a mixture of acriflavine and proflavine instigate a cyclic-GMP-AMP (cGAMP) synthase (cGAS)-dependent type-I IFN antiviral response. This pertains to the capacity of these compounds to induce low level DNA damage and cytoplasmic DNA leakage, resulting in cGAS-dependent cGAMP-like activity. Critically, acriflavine:proflavine pre-treatment of human primary bronchial epithelial cells significantly reduced rhinovirus infection. Collectively, our findings constitute the first evidence that non-toxic DNA binding agents have the capacity to act as indirect agonists of cGAS, to exert potent antiviral effects in mammalian cells. PMID:27694309

Polyether ionophores-promising bioactive molecules for cancer therapy.

PubMed

Huczyński, Adam

2012-12-01

The natural polyether ionophore antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the polyether ionophores undergoing pre-clinical evaluation are reviewed. Most of polyether ionophores have shown potent activity against the proliferation of various cancer cells, including those that display multidrug resistance (MDR) and cancer stem cells (CSC). The mechanism underlying the anticancer activity of ionophore agents can be related to their ability to form complexes with metal cations and transport them across cellular and subcellular membranes. Increasing evidence shows that the anticancer activity of polyether ionophores may be a consequence of the induction of apoptosis leading to apoptotic cell death, arresting cell cycle progression, induction of the cell oxidative stress, loss of mitochondrial membrane potential, reversion of MDR, synergistic anticancer effect with other anticancer drugs, etc. Continued investigation of the mechanisms of action and development of new polyether ionophores and their derivatives may provide more effective therapeutic drugs for cancer treatments. Copyright © 2012 Elsevier Ltd. All rights reserved.

From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump.

PubMed

Sabatini, Stefano; Kaatz, Glenn W; Rossolini, Gian Maria; Brandini, David; Fravolini, Arnaldo

2008-07-24

Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.

Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286).

PubMed

Zask, Arie; Birnberg, Gary; Cheung, Katherine; Kaplan, Joshua; Niu, Chuan; Norton, Emily; Suayan, Ronald; Yamashita, Ayako; Cole, Derek; Tang, Zhilian; Krishnamurthy, Girija; Williamson, Robert; Khafizova, Gulnaz; Musto, Sylvia; Hernandez, Richard; Annable, Tami; Yang, Xiaoran; Discafani, Carolyn; Beyer, Carl; Greenberger, Lee M; Loganzo, Frank; Ayral-Kaloustian, Semiramis

2004-09-09

Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.

Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

PubMed

Taupin, Philippe

2009-05-01

The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

Biosensor Based on Self-Assembling Acetylcholinesterase on Carbon Nanotubes for Flow injection/Amperometric Detection of Organophosphate Pesticides and Nerve Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Guodong; Lin, Yuehe

A highly sensitive flow-injection amperometric biosensor for organophosphate pesticides and nerve agents based on self-assembly of acetylcholinesterase (AChE) on carbon nanotube (CNT)-modified glassy carbon (GC) electrode is described. AChE is immobilized on the negatively-charged CNT surface by alternatively assembling a cationic polydiallyldimethylammonium chloride (PDDA) layer and an AChE layer. Transmission electron microscopy images confirm the formation of layer-by-layer nanostructures on carboxyl functionalized CNTs. The unique sandwich-like structure (PDDA/AChE/PDDA) on the CNT surface formed by self-assembly provides a favorable microenvironment to keep the bioactivity of AChE and to prevent enzyme molecule leakage. The electrocatalytic activity of CNT leads to a greatlymore » improved electrochemical detection of the enzymatically generated thiocholine product, including a low oxidation overvoltage (+150 mV), higher sensitivity, and stability. The developed PDDA/AChE/PDDA/CNT/GC biosensor integrated into a flow injection system was used to monitor organophosphate pesticides and nerve agents, such as paraoxon. The sensor performance, including inhibition time and regeneration conditions, was optimized with respect to operating conditions. Under the optimal conditions, the biosensor was used to measure as low as 0.4 pM paraoxon with a 6-min inhibition time. The biosensor had excellent operational lifetime stability with no decrease in the activity of enzymes for more than 20 repeated measurements over a 1-week period. The developed biosensor system is an ideal tool for online monitoring of organophosphate pesticides and nerve agents.« less

Chemoprevention of esophageal squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoner, Gary D.; Wang Lishu; Chen Tong

2007-11-01

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, andmore » to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.« less

Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections

PubMed Central

Goodlet, Kellie J; Nicolau, David P; Nailor, Michael D

2016-01-01

Complicated intra-abdominal infections (cIAI) represent a large proportion of all hospital admissions and are a major cause of morbidity and mortality in the intensive care unit. Rising rates of multidrug resistant organisms (MDRO), including extended-spectrum β-lactamase producing Enterobacteriaceae and carbapenem-nonsusceptible Pseudomonas spp., for which there are few remaining active antimicrobial agents, pose an increased challenge to clinicians. Patients with frequent exposures to the health care system or multiple recurrent IAIs are at increased risk for MDRO; however, treatment options have traditionally been limited, in some cases necessitating the utilization of last-line agents with unfavorable side-effect profiles. Ceftolozane/tazobactam and ceftazidime/avibactam are two new cephalosporin and β-lactamase inhibitor combinations with recent US Food and Drug Administration approvals for the treatment of cIAI in combination with metronidazole. Ceftolozane/tazobactam has demonstrated excellent in vitro activity against MDR and extensively drug-resistant Pseudomonas spp., including carbapenem-nonsusceptible strains, while ceftazidime/avibactam effectively inhibits a broad range of β-lactamases, making it an excellent option for the treatment of carbapenem-resistant Enterobacteriaceae. Both agents were shown to be noninferior to meropenem for treatment of cIAI in Phase III trials; however, reduced responses in patients with renal impairment at baseline highlight the importance of routine serum creatinine monitoring and ongoing dose adjustments. This review highlights in vitro and in vivo data of these two agents and suggests their proper place in cIAI treatment to ensure adequate therapy in our most at-risk patients while sparing unnecessary use in patients without MDRO risk factors. PMID:27942218

Burnout among Extension Agents in the Ohio Cooperative Extension Service.

ERIC Educational Resources Information Center

Igodan, O. Chris; Newcomb, L. H.

A study examined the extent and causes of burnout among extension agents in Ohio. From the 241 extension agents working in the 88 counties of Ohio, researchers selected a random sample of 101 agents. Included in the sample were 34 agriculture agents, 33 home economics agents. Included in the sample agents were asked to complete a survey…

Antimicrobial Activity of Chitosan Film Forming Solution Enriched with Essential Oils; an in Vitro Assay

PubMed Central

Raphaël, Kana Jean; Meimandipour, Amir

2017-01-01

Background: The resistance of the bacteria and fungi to the innumerous antimicrobial agents is a major challenge in the treatment of the infections demands to the necessity for searching and finding new sources of substances with antimicrobial properties. The incorporation of the essential oils (EOs) in chitosan film forming solution may enhance antimicrobial properties. However, its use as the feeding additive in the poultry nutrition needs to clarify the product’s activity against both pathogen and the useful microbes in the gastrointestinal tract. Objectives: In the present study, we carried out an in vitro investigation and evaluated the antimicrobial activity of chitosan film forming solution incorporated with essential oils (CFs+EOs) against microbial strains including Staphylococcus aureus, Escherichia coli, Enterococcus faecium, Lactobacillus rahmnosus, Aspergillus niger and Alternaria alternate. Material and Methods: In three replicates, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of different treatments including: 1- essential oils (EOs), 2- chitosan film solution (CFs), and 3-chitosan film solution enriched with EOs (CFs+EOs) were determined against above mentioned microbes. Results: The results indicated that the chitosan solution enriched with essential oils (CFs+EOs) is capable of inhibiting the bacterial and fungal growth even at the lowest concentrations. The MIC and MBC for all the antimicrobial agents against Escherichia coli and Staphylococcus aureus were very low compared to the concentrations needed to inhibit the growth of useful bacteria, Lactobacillus rahmnosu and Enterococcus faecium. The antifungal activity of chitosan was enhanced as the concentration of EOs increased in the film solution. Conclusion: Chitosan-EOs complexes are the promising candidate for novel contact antimicrobial agents that can be used in animal feeds. PMID:29845058

Antimicrobial Activity of Chitosan Film Forming Solution Enriched with Essential Oils; an in Vitro Assay.

PubMed

Raphaël, Kana Jean; Meimandipour, Amir

2017-01-01

Background: The resistance of the bacteria and fungi to the innumerous antimicrobial agents is a major challenge in the treatment of the infections demands to the necessity for searching and finding new sources of substances with antimicrobial properties. The incorporation of the essential oils (EOs) in chitosan film forming solution may enhance antimicrobial properties. However, its use as the feeding additive in the poultry nutrition needs to clarify the product's activity against both pathogen and the useful microbes in the gastrointestinal tract. Objectives: In the present study, we carried out an in vitro investigation and evaluated the antimicrobial activity of chitosan film forming solution incorporated with essential oils (CFs+EOs) against microbial strains including Staphylococcus aureus, Escherichia coli, Enterococcus faecium, Lactobacillus rahmnosus, Aspergillus niger and Alternaria alternate . Material and Methods: In three replicates, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of different treatments including: 1- essential oils (EOs), 2- chitosan film solution (CFs), and 3-chitosan film solution enriched with EOs (CFs+EOs) were determined against above mentioned microbes. Results: The results indicated that the chitosan solution enriched with essential oils (CFs+EOs) is capable of inhibiting the bacterial and fungal growth even at the lowest concentrations. The MIC and MBC for all the antimicrobial agents against Escherichia coli and Staphylococcus aureus were very low compared to the concentrations needed to inhibit the growth of useful bacteria, Lactobacillus rahmnosu and Enterococcus faecium . The antifungal activity of chitosan was enhanced as the concentration of EOs increased in the film solution. Conclusion: Chitosan-EOs complexes are the promising candidate for novel contact antimicrobial agents that can be used in animal feeds.

Comparative in vitro activity of CGP 31608, a new penem antibiotic.

PubMed Central

Eliopoulos, G M; Wennersten, C; Reiszner, E; Moellering, R C

1987-01-01

The in vitro activity of a new penem antimicrobial agent, CGP 31608, was compared with those of imipenem, SCH 34343, and several other antimicrobial agents against approximately 600 bacterial isolates. CGP 31608 was active against gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MIC for 90% of the isolates [MIC90], 0.25 microgram/ml) and penicillin-susceptible streptococci (MIC90s, less than or equal to 2 micrograms/ml). Penicillin-resistant streptococci (including enterococci) and methicillin-resistant S. aureus were more resistant to the penem. Activities of CGP 31608 against members of the family Enterobacteriaceae were remarkably uniform, with MIC90s of 8 to 16 micrograms/ml. CGP 31608 was at least as active as imipenem and ceftazidime and more active than piperacillin against Pseudomonas aeruginosa. Drug activity was not influenced by the presence of any of 10 plasmid-mediated beta-lactamases. Against strains of Serratia marcescens, Enterobacter cloacae, and P. aeruginosa with derepressible chromosomally mediated beta-lactamases, the presence of cefoxitin did not induce increased resistance to CGP 31608. The new drug was also active against anaerobes (MIC90s, 0.25 to 8 micrograms/ml), Haemophilus influenzae (MIC90s, 0.5 to 1.0 micrograms/ml), and Legionella spp. (MIC90, 2 micrograms/ml). CGP 31608 showed an antibacterial spectrum similar to those of imipenem and SCH 34343 (except that the latter is not active against P. aeruginosa) but was generally less potent than these drugs. However, CGP 31608 demonstrated more activity (MIC90) than imipenem against P. aeruginosa, Pseudomonas cepacia, and methicillin-resistant Staphylococcus epidermidis and S. aureus. PMID:3498437

Improving the Army’s Next Effort in Technology Forecasting

DTIC Science & Technology

2010-09-01

Health Maintenance— ability to make the robotic system more robust and to provide maintenance capabilities for self -monitoring, diagnostics, and...exhibit a verity of responses, including self -sensing and self - healing activities.43 A team of chemists and materials scientists led by the Moore...ultimately lead to i) applications in vehicles, including self -repairing armor, rubber , and coatings resistant to chemical agents, ii) aerospace

Effect of capping agents: Structural, optical and biological properties of ZnO nanoparticles

NASA Astrophysics Data System (ADS)

Javed, Rabia; Usman, Muhammad; Tabassum, Saira; Zia, Muhammad

2016-11-01

Different biological activities of capped and uncapped ZnO nanoparticles were investigated, and the effects of potential capping agents on these biological activities were studied. ZnO nanoparticles were synthesized and capped by polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) using a simple chemical method of co-precipitation. Characterization by X-ray diffraction (XRD), Fourier transform Infrared spectroscopy (FTIR) and UV-vis spectroscopy confirmed the crystallinity, size, functional group, and band gap of synthesized nanoparticles. Reduction in size occurred from 34 nm to 26 nm due to surfactant. Results of all biological activities indicated significantly higher values in capped as compared to uncapped nanoparticles. Antibacterial activity against Staphylococcus aureus (ATCC 6538), Bacillus subtilis (ATCC 6633), Escherichia coli (ATCC15224), and Acetobacter was obtained. This activity was more prominent against Gram-positive bacteria, and ZnO-PVP nanoparticles elucidated highest antibacterial activity (zone of inhibition 17 mm) against Gram-positive, Bacillus subtilis species. Antioxidant activities including total flavonoid content, total phenolic content, total antioxidant capacity, total reducing power and %age inhibition of DPPH, and antidiabetic activity against α-amylase enzyme found to be exhibited highest by ZnO-PEG nanoparticles.

Aqueous lithium air batteries

DOEpatents

Visco, Steven J.; Nimon, Yevgeniy S.; De Jonghe, Lutgard C.; Petrov, Alexei; Goncharenko, Nikolay

2017-05-23

Aqueous Li/Air secondary battery cells are configurable to achieve high energy density and prolonged cycle life. The cells include a protected a lithium metal or alloy anode and an aqueous catholyte in a cathode compartment. The aqueous catholyte comprises an evaporative-loss resistant and/or polyprotic active compound or active agent that partakes in the discharge reaction and effectuates cathode capacity for discharge in the acidic region. This leads to improved performance including one or more of increased specific energy, improved stability on open circuit, and prolonged cycle life, as well as various methods, including a method of operating an aqueous Li/Air cell to simultaneously achieve improved energy density and prolonged cycle life.

Bacillus subtilis extracytoplasmic function (ECF) sigma factors and defense of the cell envelope

PubMed Central

Helmann, John D.

2016-01-01

Summary Bacillus subtilis provides a model for investigation of the bacterial cell envelope, the first line of defense against environmental threats. Extracytoplasmic function (ECF) sigma factors activate genes that confer resistance to agents that threaten the integrity of the envelope. Although their individual regulons overlap, σW is most closely associated with membrane-active agents, σX with cationic antimicrobial peptide resistance, and σV with resistance to lysozyme. Here, I highlight the role of the σM regulon, which is strongly induced by conditions that impair peptidoglycan synthesis and includes the core pathways of envelope synthesis and cell division, as well as stress-inducible alternative enzymes. Studies of these cell envelope stress responses provide insights into how bacteria acclimate to the presence of antibiotics. PMID:26901131

Exercise, character strengths, well-being, and learning climate in the prediction of performance over a 6-month period at a call center.

PubMed

Moradi, Saleh; Nima, Ali A; Rapp Ricciardi, Max; Archer, Trevor; Garcia, Danilo

2014-01-01

Performance monitoring might have an adverse influence on call center agents' well-being. We investigate how performance, over a 6-month period, is related to agents' perceptions of their learning climate, character strengths, well-being (subjective and psychological), and physical activity. Agents (N = 135) self-reported perception of the learning climate (Learning Climate Questionnaire), character strengths (Values In Action Inventory Short Version), well-being (Positive Affect, Negative Affect Schedule, Satisfaction With Life Scale, Psychological Well-Being Scales Short Version), and how often/intensively they engaged in physical activity. Performance, "time on the phone," was monitored for 6 consecutive months by the same system handling the calls. Performance was positively related to having opportunities to develop, the character strengths clusters of Wisdom and Knowledge (e.g., curiosity for learning, perspective) and Temperance (e.g., having self-control, being prudent, humble, and modest), and exercise frequency. Performance was negatively related to the sense of autonomy and responsibility, contentedness, the character strengths clusters of Humanity and Love (e.g., helping others, cooperation) and Justice (e.g., affiliation, fairness, leadership), positive affect, life satisfaction and exercise Intensity. Call centers may need to create opportunities to develop to increase agents' performance and focus on individual differences in the recruitment and selection of agents to prevent future shortcomings or worker dissatisfaction. Nevertheless, performance measurement in call centers may need to include other aspects that are more attuned with different character strengths. After all, allowing individuals to put their strengths at work should empower the individual and at the end the organization itself. Finally, physical activity enhancement programs might offer considerable positive work outcomes.

Exercise, character strengths, well-being, and learning climate in the prediction of performance over a 6-month period at a call center

PubMed Central

Moradi, Saleh; Nima, Ali A.; Rapp Ricciardi, Max; Archer, Trevor; Garcia, Danilo

2014-01-01

Background: Performance monitoring might have an adverse influence on call center agents' well-being. We investigate how performance, over a 6-month period, is related to agents' perceptions of their learning climate, character strengths, well-being (subjective and psychological), and physical activity. Method: Agents (N = 135) self-reported perception of the learning climate (Learning Climate Questionnaire), character strengths (Values In Action Inventory Short Version), well-being (Positive Affect, Negative Affect Schedule, Satisfaction With Life Scale, Psychological Well-Being Scales Short Version), and how often/intensively they engaged in physical activity. Performance, “time on the phone,” was monitored for 6 consecutive months by the same system handling the calls. Results: Performance was positively related to having opportunities to develop, the character strengths clusters of Wisdom and Knowledge (e.g., curiosity for learning, perspective) and Temperance (e.g., having self-control, being prudent, humble, and modest), and exercise frequency. Performance was negatively related to the sense of autonomy and responsibility, contentedness, the character strengths clusters of Humanity and Love (e.g., helping others, cooperation) and Justice (e.g., affiliation, fairness, leadership), positive affect, life satisfaction and exercise Intensity. Conclusion: Call centers may need to create opportunities to develop to increase agents' performance and focus on individual differences in the recruitment and selection of agents to prevent future shortcomings or worker dissatisfaction. Nevertheless, performance measurement in call centers may need to include other aspects that are more attuned with different character strengths. After all, allowing individuals to put their strengths at work should empower the individual and at the end the organization itself. Finally, physical activity enhancement programs might offer considerable positive work outcomes. PMID:25002853

HURON (HUman and Robotic Optimization Network) Multi-Agent Temporal Activity Planner/Scheduler

NASA Technical Reports Server (NTRS)

Hua, Hook; Mrozinski, Joseph J.; Elfes, Alberto; Adumitroaie, Virgil; Shelton, Kacie E.; Smith, Jeffrey H.; Lincoln, William P.; Weisbin, Charles R.

2012-01-01

HURON solves the problem of how to optimize a plan and schedule for assigning multiple agents to a temporal sequence of actions (e.g., science tasks). Developed as a generic planning and scheduling tool, HURON has been used to optimize space mission surface operations. The tool has also been used to analyze lunar architectures for a variety of surface operational scenarios in order to maximize return on investment and productivity. These scenarios include numerous science activities performed by a diverse set of agents: humans, teleoperated rovers, and autonomous rovers. Once given a set of agents, activities, resources, resource constraints, temporal constraints, and de pendencies, HURON computes an optimal schedule that meets a specified goal (e.g., maximum productivity or minimum time), subject to the constraints. HURON performs planning and scheduling optimization as a graph search in state-space with forward progression. Each node in the graph contains a state instance. Starting with the initial node, a graph is automatically constructed with new successive nodes of each new state to explore. The optimization uses a set of pre-conditions and post-conditions to create the children states. The Python language was adopted to not only enable more agile development, but to also allow the domain experts to easily define their optimization models. A graphical user interface was also developed to facilitate real-time search information feedback and interaction by the operator in the search optimization process. The HURON package has many potential uses in the fields of Operations Research and Management Science where this technology applies to many commercial domains requiring optimization to reduce costs. For example, optimizing a fleet of transportation truck routes, aircraft flight scheduling, and other route-planning scenarios involving multiple agent task optimization would all benefit by using HURON.

Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

PubMed Central

Calderon, Leonardo A.; Sobrinho, Juliana C.; Zaqueo, Kayena D.; de Moura, Andrea A.; Grabner, Amy N.; Mazzi, Maurício V.; Marcussi, Silvana; Fernandes, Carla F. C.; Zuliani, Juliana P.; Carvalho, Bruna M. A.; da Silva, Saulo L.; Stábeli, Rodrigo G.; Soares, Andreimar M.

2014-01-01

For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP), disintegrins, L-amino acid oxidases (LAAOs), C-type lectins, and phospholipases A2 (PLA2s). Their mechanisms of action include direct toxic action (PLA2s), free radical generation (LAAOs), apoptosis induction (PLA2s, MP, and LAAOs), and antiangiogenesis (disintegrins and lectins). Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development. PMID:24683541

Synthesis and structure-activity relationship of dicationic diaryl ethers as novel potent anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-08-15

A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of 0.06 microg/mL and enhanced antimicrobial selectivity.

Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX.

PubMed

Carmany, Dan; Walz, Andrew J; Hsu, Fu-Lian; Benton, Bernard; Burnett, David; Gibbons, Jennifer; Noort, Daan; Glaros, Trevor; Sekowski, Jennifer W

2017-04-17

Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.

[In vitro activity of voriconazole and three other antifungal agents against dermatophytes].

PubMed

Serrano-Martino, María del Carmen; Chávez-Caballero, Mónica; Valverde-Conde, Anastasio; Claro, Rosa María; Pemán, Javier; Martín-Mazuelos, Estrella

2003-11-01

The increase in infections due to dermatophytes in recent years led us to study the effectiveness of new antifungal formulations against these microorganisms. The in vitro activity of a new antifungal agent, voriconazole, was compared with three other antifungal agents, itraconazole, fluconazole and terbinafine, against 120 dermatophytes belonging to four species (61 Trichophyton mentagrophytes, 34 Microsporum canis, 13 M. gypseum and 12 T. rubrum). A broth microdilution method was used following the recommendations of the NCCLS document M38-P with some modifications. Terbinafine was the most active agent against the dermatophytes studied (MIC90 < or = 0.03 mg/ml), followed by voriconazole (MIC90, 0.25 micro g/ml) and itraconazole (MIC90, 0.5 micro g/ml). Fluconazole was the least active antifungal agent. The most susceptible species was M. canis. Voriconazole was found to have effective activity against dermatophytes.

Biosynthesis of gold and silver chloride nanoparticles mediated by Crataegus pinnatifida fruit extract: in vitro study of anti-inflammatory activities.

PubMed

Kang, Jong Pyo; Kim, Yeon Ju; Singh, Priyanka; Huo, Yue; Soshnikova, Veronika; Markus, Josua; Ahn, Sungeun; Chokkalingam, Mohan; Lee, Hyun A; Yang, Deok Chun

2017-09-18

This research article investigates the one-pot synthesis of gold and silver chloride nanoparticles functionalized by fruit extract of Crataegus pinnatifida as reducing and stabilizing agents and their possible roles as novel anti-inflammatory agents. Hawthorn (C. pinnatifida) fruits are increasingly popular as raw materials for functional foods and anti-inflammatory potential agents because of abundant flavonoids. The reduction of auric chloride and silver nitrate by the aqueous fruit extract led to the formation of gold and silver chloride nanoparticles. The nanoparticles were further characterized by field emission transmission electron microscopy indicated that CP-AuNps and CP-AgClNps were hexagonal and cubic shape, respectively. According to X-ray diffraction results, the average crystallite sizes of CP-AuNps and CP-AgClNps were 14.20 nm and 24.80 nm. The biosynthesized CP-AgClNps served as efficient antimicrobial agents against Escherichia coli and Staphylococcus aureus. Furthermore, CP-AuNps and CP-AgClNps enhanced the DPPH radical scavenging activity of the fruit extract. Lastly, MTT assay of nanoparticles demonstrated low toxicity in murine macrophage (RAW264.7). Biosynthesized nanoparticles also reduced the production of the inflammatory cytokines including nitric oxide and prostaglandin E2 in lipopolysaccharide-induced RAW264.7 cells. Altogether, these findings suggest that CP-AuNps and CP-AgClNps can be used as novel drug carriers or biosensors with intrinsic anti-inflammatory activity.

Activeness as a key to counter democratic balance

NASA Astrophysics Data System (ADS)

Qian, Shen; Liu, Yijun; Galam, Serge

2015-08-01

According to the classic Galam model of opinion dynamics, each agent participates at each update of an opinion interaction. While the scheme gives everyone the same chance to influence others, in reality, social activity and influence vary considerably from one agent to another. To account for such a feature, we introduce a new individual attribute-"activeness"-which makes some agents more inclined than others at engaging in local discussions. To enhance the corresponding effect, opinion updates are shifted from all-out agent interaction cycles to few agent interaction cycles. Using dynamic analysis and simulations the resulting model is found to exhibit a "Minority Counteroffensive" phenomenon, which under some initial conditions makes the minority to win the opinion competition despite a threshold tipping point at fifty percent. The associated probabilistic phenomenon persists in the case "activeness" is held equal for all agents. The effect of "opinion leaders" is also investigated. Indeed, a leader is an inflexible agent, i.e., an agent who does not change opinion. The results reveal that two opinion leaders with moderate social influence may have a stronger effect than one opinion leader with a strong social influence. The model may shed a new light to the understanding of opinion formation and public voting.

Anti-herpesvirus agents: a patent and literature review (2003 to present).

PubMed

Skoreński, Marcin; Sieńczyk, Marcin

2014-08-01

The standard therapy used to treat herpesvirus infections is based on the application of DNA polymerase inhibitors such as ganciclovir or aciclovir. Unfortunately, all of these compounds exhibit relatively high toxicity and the mutation of herpesviruses results in the appearance of new drug-resistant strains. Consequently, there is a great need for the development of new, effective and safe anti-herpesvirus agents that employ different patterns of therapeutic action at various stages of the virus life cycle. Patents and patent applications concerning the development of anti-herpesvirus agents displaying different mechanisms of action that have been published since 2003 are reviewed. In addition, major discoveries in this field that have been published in academic papers have also been included. Among all the anti-herpesvirus agents described in this article, the inhibitors of viral serine protease seem to present one of the most effective/promising therapeutics. Unfortunately, the practical application of these antiviral agents has not yet been proven in any clinical trials. Nevertheless, the dynamic and extensive work on this subject gives hope that a new class of anti-herpesvirus agents aimed at the enzymatic activity of herpesvirus serine protease may be developed.

Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression

PubMed Central

Zhao, Yane; Zhang, Jin; Shi, Xiaoyu; Li, Jing; Wang, Rui; Song, Ruiwen; Wei, Qun; Cai, Huaibin; Luo, Jing

2016-01-01

Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor. It is desirable to develop alternative immunosuppressive agents. To this end, we first tested the interactions between CN and the LxVP-type substrates, including endogenous regulators of calcineurin (RCAN1) and NFAT. Interestingly, we found that quercetin, the primary dietary flavonol, can inhibit the activity of CN and significantly disrupt the associations between CN and its LxVP-type substrates. We then validated the inhibitory effects of quercetin on the CN-NFAT interactions in cell-based assays. Further, quercetin also shows dose-dependent suppression of cytokine gene expression in mouse spleen cells. These data raise the possibility that the interactions of CN with its LxVP-type substrates are potential targets for immunosuppressive agents. PMID:27109380

Benzothiazole Derivatives as Potential Anti-Infective Agents.

PubMed

Sharma, Prabodh Chander; Bansal, Kushal Kumar; Deep, Aakash; Pathak, Meenakshi

2017-01-01

Severity of microbial infections and escalating resistance towards antibiotics has created a deep necessity for discovery of novel anti-infective agents. Heterocyclic chemistry of benzothiazole has become one of the most prolific areas in the field of drug discovery and development that has attracted great attention in recent time due to its increasing importance in the field of pharmaceuticals. The importance of benzothiazole and derivatives as potential antimicrobial agents has been well established and a large number of papers have been published in this regard. The present communication is an earnest attempt to review the chemistry, synthetic aspects including click chemistry and antimicrobial activities of benzothiazole derivatives reported in recent scientific literature. The scientific information of this manuscript may be worthwhile in encouraging the prospective researchers working on this heterocyclic scaffold.

Activity of Polish unifloral honeys against pathogenic bacteria and its correlation with colour, phenolic content, antioxidant capacity and other parameters.

PubMed

Kuś, P M; Szweda, P; Jerković, I; Tuberoso, C I G

2016-03-01

The use of honey as an antimicrobial agent gains importance due to often ineffectiveness of conventional treatment. However, activity of honey depends mainly on its botanical and geographical origin. To date, antimicrobial potential of Polish honeys has not yet been entirely investigated. In this study, 37 unifloral samples of 14 honey types (including rare varieties) from Poland were analysed and compared with manuka honey. The most active were cornflower, thyme and buckwheat honeys. Their MICs ranged from 3·12 to 25·00%, (depending on tested micro-organism) and often were lower than for manuka honey. Additionally, colour, antioxidant activity, total phenols, pH and conductivity were assessed and significant correlations (P < 0·05) of MICs with several parameters were found. The most active were darker honeys, with strong yellow colour component, rich in phenolics, with high conductivity and water content. The honey antibacterial properties depended mainly on peroxide mechanism and were vulnerable to excessive heating, but quite stable during storage in cold. A number of honey samples showed potential as effective antimicrobial agents. The observed correlations of MICs and physical-chemical parameters help to understand better the factors impacting the antibacterial activity. Honey is a promising agent in the treatment of non-healing infected wounds. Thirty-seven unifloral samples of 14 honey varieties from Poland were analysed for their antimicrobial activity and compared with manuka honey. Several honey types exert even higher antimicrobial potential and could be introduced to wound therapy. Additionally, positive correlations of the antimicrobial activity were found, especially with yellow colour and could be important in the search and screening of the honey active against Escherichia coli. © 2015 The Society for Applied Microbiology.

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PubMed

Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside.

PubMed

Shabbir, Munira; Stuart, Robert

2010-03-01

Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population. An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade. The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent. Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.

Antibiosis and bmyB Gene Presence As Prevalent Traits for the Selection of Efficient Bacillus Biocontrol Agents against Crown Gall Disease.

PubMed

Frikha-Gargouri, Olfa; Ben Abdallah, Dorra; Bhar, Ilhem; Tounsi, Slim

2017-01-01

This study aimed to improve the screening method for the selection of Bacillus biocontrol agents against crown gall disease. The relationship between the strain biocontrol ability and their in vitro studied traits was investigated to identify the most important factors to be considered for the selection of effective biocontrol agents. In fact, previous selection procedure relying only on in vitro antibacterial activity was shown to be not suitable in some cases. A direct plant-protection strategy was performed to screen the 32 Bacillus biocontrol agent candidates. Moreover, potential in vitro biocontrol traits were investigated including biofilm formation, motility, hemolytic activity, detection of lipopeptide biosynthetic genes ( sfp, ituC and bmyB ) and production of antibacterial compounds. The obtained results indicated high correlations of the efficiency of the biocontrol with the reduction of gall weight ( p = 0.000) and the antibacterial activity in vitro ( p = 0.000). Moreover, there was strong correlations of the efficiency of the biocontrol ( p = 0.004) and the reduction in gall weight ( p = 0.000) with the presence of the bmyB gene. This gene directs the synthesis of the lipopeptide bacillomycin belonging to the iturinic family of lipopeptides. These results were also confirmed by the two-way hierarchical cluster analysis and the correspondence analysis showing the relatedness of these four variables. According to the obtained results a new screening procedure of Bacillus biocontrol agents against crown gall disease could be advanced consisting on two step selection procedure. The first consists on selecting strains with high antibacterial activity in vitro or those harbouring the bmyB gene. Further selection has to be performed on tomato plants in vivo . Moreover, based on the results of the biocontrol assay, five potent strains exhibiting high biocontrol abilities were selected. They were identified as Bacillus subtilis or Bacillus amyloliquefaciens . These strains were found to produce either surfactin or surfactin and iturin lipopeptides. In conclusion, our study presented a new and effective method to evaluate the biocontrol ability of antagonistic Bacillus strains against crown gall disease that could increase the efficiency of screening method of biocontrol agents. Besides, the selected strains could be used as novel biocontrol agents against pathogenic Agrobacterium tumefaciens strains.

Antibiosis and bmyB Gene Presence As Prevalent Traits for the Selection of Efficient Bacillus Biocontrol Agents against Crown Gall Disease

PubMed Central

Frikha-Gargouri, Olfa; Ben Abdallah, Dorra; Bhar, Ilhem; Tounsi, Slim

2017-01-01

This study aimed to improve the screening method for the selection of Bacillus biocontrol agents against crown gall disease. The relationship between the strain biocontrol ability and their in vitro studied traits was investigated to identify the most important factors to be considered for the selection of effective biocontrol agents. In fact, previous selection procedure relying only on in vitro antibacterial activity was shown to be not suitable in some cases. A direct plant-protection strategy was performed to screen the 32 Bacillus biocontrol agent candidates. Moreover, potential in vitro biocontrol traits were investigated including biofilm formation, motility, hemolytic activity, detection of lipopeptide biosynthetic genes (sfp, ituC and bmyB) and production of antibacterial compounds. The obtained results indicated high correlations of the efficiency of the biocontrol with the reduction of gall weight (p = 0.000) and the antibacterial activity in vitro (p = 0.000). Moreover, there was strong correlations of the efficiency of the biocontrol (p = 0.004) and the reduction in gall weight (p = 0.000) with the presence of the bmyB gene. This gene directs the synthesis of the lipopeptide bacillomycin belonging to the iturinic family of lipopeptides. These results were also confirmed by the two-way hierarchical cluster analysis and the correspondence analysis showing the relatedness of these four variables. According to the obtained results a new screening procedure of Bacillus biocontrol agents against crown gall disease could be advanced consisting on two step selection procedure. The first consists on selecting strains with high antibacterial activity in vitro or those harbouring the bmyB gene. Further selection has to be performed on tomato plants in vivo. Moreover, based on the results of the biocontrol assay, five potent strains exhibiting high biocontrol abilities were selected. They were identified as Bacillus subtilis or Bacillus amyloliquefaciens. These strains were found to produce either surfactin or surfactin and iturin lipopeptides. In conclusion, our study presented a new and effective method to evaluate the biocontrol ability of antagonistic Bacillus strains against crown gall disease that could increase the efficiency of screening method of biocontrol agents. Besides, the selected strains could be used as novel biocontrol agents against pathogenic Agrobacterium tumefaciens strains. PMID:28855909

Joint chemical agent detector (JCAD): the future of chemical agent detection

NASA Astrophysics Data System (ADS)

Laljer, Charles E.

2003-08-01

The Joint Chemical Agent Detector (JCAD) has continued development through 2002. The JCAD has completed Contractor Validation Testing (CVT) that included chemical warfare agent testing, environmental testing, electromagnetic interferent testing, and platform integration validation. The JCAD provides state of the art chemical warfare agent detection capability to military and homeland security operators. Intelligence sources estimate that over twenty countries have active chemical weapons programs. The spread of weapons of mass destruction (and the industrial capability for manufacture of these weapons) to third world nations and terrorist organizations has greatly increased the chemical agent threat to U.S. interests. Coupled with the potential for U.S. involvement in localized conflicts in an operational or support capacity, increases the probability that the military Joint Services may encounter chemical agents anywhere in the world. The JCAD is a small (45 in3), lightweight (2 lb.) chemical agent detector for vehicle interiors, aircraft, individual personnel, shipboard, and fixed site locations. The system provides a common detection component across multi-service platforms. This common detector system will allow the Joint Services to use the same operational and support concept for more efficient utilization of resources. The JCAD detects, identifies, quantifies, and warns of the presence of chemical agents prior to onset of miosis. Upon detection of chemical agents, the detector provides local and remote audible and visual alarms to the operators. Advance warning will provide the vehicle crew and other personnel in the local area with the time necessary to protect themselves from the lethal effects of chemical agents. The JCAD is capable of being upgraded to protect against future chemical agent threats. The JCAD provides the operator with the warning necessary to survive and fight in a chemical warfare agent threat environment.

Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations

PubMed Central

LoPiccolo, Jaclyn; Blumenthal, Gideon M.; Bernstein, Wendy B.; Dennis, Phillip A.

2008-01-01

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection. PMID:18166498

Environmental Exposures, Epigenetic Changes and the Risk of Lupus

PubMed Central

Somers, Emily C; Richardson, Bruce C

2013-01-01

A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares. PMID:24763540

Development and verification of an agent-based model of opinion leadership.

PubMed

Anderson, Christine A; Titler, Marita G

2014-09-27

The use of opinion leaders is a strategy used to speed the process of translating research into practice. Much is still unknown about opinion leader attributes and activities and the context in which they are most effective. Agent-based modeling is a methodological tool that enables demonstration of the interactive and dynamic effects of individuals and their behaviors on other individuals in the environment. The purpose of this study was to develop and test an agent-based model of opinion leadership. The details of the design and verification of the model are presented. The agent-based model was developed by using a software development platform to translate an underlying conceptual model of opinion leadership into a computer model. Individual agent attributes (for example, motives and credibility) and behaviors (seeking or providing an opinion) were specified as variables in the model in the context of a fictitious patient care unit. The verification process was designed to test whether or not the agent-based model was capable of reproducing the conditions of the preliminary conceptual model. The verification methods included iterative programmatic testing ('debugging') and exploratory analysis of simulated data obtained from execution of the model. The simulation tests included a parameter sweep, in which the model input variables were adjusted systematically followed by an individual time series experiment. Statistical analysis of model output for the 288 possible simulation scenarios in the parameter sweep revealed that the agent-based model was performing, consistent with the posited relationships in the underlying model. Nurse opinion leaders act on the strength of their beliefs and as a result, become an opinion resource for their uncertain colleagues, depending on their perceived credibility. Over time, some nurses consistently act as this type of resource and have the potential to emerge as opinion leaders in a context where uncertainty exists. The development and testing of agent-based models is an iterative process. The opinion leader model presented here provides a basic structure for continued model development, ongoing verification, and the establishment of validation procedures, including empirical data collection.

Mobile Agents: A Distributed Voice-Commanded Sensory and Robotic System for Surface EVA Assistance

NASA Technical Reports Server (NTRS)

Clancey, William J.; Sierhuis, Maarten; Alena, Rick; Crawford, Sekou; Dowding, John; Graham, Jeff; Kaskiris, Charis; Tyree, Kim S.; vanHoof, Ronnie

2003-01-01

A model-based, distributed architecture integrates diverse components in a system designed for lunar and planetary surface operations: spacesuit biosensors, cameras, GPS, and a robotic assistant. The system transmits data and assists communication between the extra-vehicular activity (EVA) astronauts, the crew in a local habitat, and a remote mission support team. Software processes ("agents"), implemented in a system called Brahms, run on multiple, mobile platforms, including the spacesuit backpacks, all-terrain vehicles, and robot. These "mobile agents" interpret and transform available data to help people and robotic systems coordinate their actions to make operations more safe and efficient. Different types of agents relate platforms to each other ("proxy agents"), devices to software ("comm agents"), and people to the system ("personal agents"). A state-of-the-art spoken dialogue interface enables people to communicate with their personal agents, supporting a speech-driven navigation and scheduling tool, field observation record, and rover command system. An important aspect of the engineering methodology involves first simulating the entire hardware and software system in Brahms, and then configuring the agents into a runtime system. Design of mobile agent functionality has been based on ethnographic observation of scientists working in Mars analog settings in the High Canadian Arctic on Devon Island and the southeast Utah desert. The Mobile Agents system is developed iteratively in the context of use, with people doing authentic work. This paper provides a brief introduction to the architecture and emphasizes the method of empirical requirements analysis, through which observation, modeling, design, and testing are integrated in simulated EVA operations.

Synthesis and evaluation of novel caged DNA alkylating agents bearing 3,4-epoxypiperidine structure.

PubMed

Kawada, Yuji; Kodama, Tetsuya; Miyashita, Kazuyuki; Imanishi, Takeshi; Obika, Satoshi

2012-07-14

Previously, we reported that the 3,4-epoxypiperidine structure, whose design was based on the active site of DNA alkylating antitumor antibiotics, azinomycins A and B, possesses prominent DNA cleavage activity. In this report, novel caged DNA alkylating agents, which were designed to be activated by UV irradiation, were synthesized by the introduction of four photo-labile protecting groups to a 3,4-epoxypiperidine derivative. The DNA cleavage activity and cytotoxicity of the caged DNA alkylating agents were examined under UV irradiation. Four caged DNA alkylating agents showed various degrees of bioactivity depending on the photosensitivity of the protecting groups.

Comprehension and Production of Word Order in Stage I.

ERIC Educational Resources Information Center

Roberts, Kenneth

1983-01-01

The notion that partial control of full agent-action-patient word order in comprehension may precede its production was examined. Reversible active sentences including the verbs "kiss,""hug," and "tickle" were presented to a triad of listeners consisting of a test child, a familiar adult caretaker, and a familiar…

Teaching about Impulse and Momentum

ERIC Educational Resources Information Center

Franklin, Bill

2004-01-01

This American Association of Physics Teachers/Physics Teaching Resource Agents (APPT/PTRA) spiral-bound manual features labs and demos physics teachers can use to give students hands-on opportunities to learn about impulse and momentum. "Make-and-take activities" include AAPT Apparatus Contest winners "An Air Impulse Rocket," "A Fan Driven…

CNN Newsroom Classroom Guides, February 2001.

ERIC Educational Resources Information Center

Turner Educational Services, Inc., Atlanta, GA.

These classroom guides, designed to accompany the daily CNN (Cable News Network) Newsroom broadcasts for the month of February 2001, provide program rundowns, suggestions for class activities and discussion, student handouts, and a list of related news terms. Top stories include: Libyan intelligence agent is convicted of the Lockerbie bombing, and…

Landscape Context and Regional Patterns in Arkansas' Forests

Treesearch

Victor A. Rudis

2001-01-01

Abstract - Recent results from Forest Inventory and Analysis (FIA) surveys provided an opportunity to explore the spatial and temporal context for Arkansas’ forests, including associated range, recreation, water, and wildlife habitat resources. Noted were damage agents and multipurpose resource indicators: evidence of human-associated activities (...

Chemical Action of Halogenated Agents in Fire Extinguishing

NASA Technical Reports Server (NTRS)

Belles, Frank E.

1955-01-01

The action of halogenated agents in preventing flame propagation in fuel-air mixtures in laboratory tests is discussed in terms of a possible chemical mechanism. The mechanism chosen is that of chain-breaking reactions between agent and active particles (hydrogen and oxygen atoms and hydroxyl radicsls). Data from the literature on the flammability peaks of n-heptane agent-air mixtures are treated. Ratings of agent effectiveness in terms of the fuel equivalent of the agent, based on both fuel and agent concentrations at the peak, are proposed as preferable to ratings in terms of agent concentration alone. These fuel-equivalent ratings are roughly correlated by reactivities assigned to halogen and hydrogen atoms in the agent molecules. It is concluded that the presence of hydrogen in agent need not reduce its fire-fighting ability, provided there is enough halogen to make the agent nonflammable. A method is presented for estimating from quenching-distance data a rate constant for the reaction of agent with active particles. A quantitative result is obtained for methyl bromide. This rate constant predicts the observed peak concentration of methyl bromide quite well. However, more data are needed to prove the validity of the method. The assumption that hal.ogenatedagents act mainly by chain-bresking reactions with active particles is consistent with the experimental facts and should help guide the selection of agents for further tests.

The use of computer vision in an intelligent environment to support aging-in-place, safety, and independence in the home.

PubMed

Mihailidis, Alex; Carmichael, Brent; Boger, Jennifer

2004-09-01

This paper discusses the use of computer vision in pervasive healthcare systems, specifically in the design of a sensing agent for an intelligent environment that assists older adults with dementia during an activity of daily living. An overview of the techniques applied in this particular example is provided, along with results from preliminary trials completed using the new sensing agent. A discussion of the results obtained to date is presented, including technical and social issues that remain for the advancement and acceptance of this type of technology within pervasive healthcare.

Biological evaluation of benzosuberones.

PubMed

Behbehani, Haider; Dawood, Kamal M; Farghaly, Thoraya A

2018-01-01

Several natural products containing benzosuberone moiety are clinically reported as anti-tumor agents. Furthermore, several synthetic benzosuberones cited in this review exhibited wide range of theraputic activities such as bacteriostatic, anti-inflammatory, antidepressants and anti-tumor activities. Our recent review provides an overview of the different methods to synthesize the benzosuberones and their extensive biological activities. Areas covered: Thirty-two patents among 130 references are cited in this review that covered the recent inhibitory activities of the benzosuberone scaffolds and their broad area of biological applications up to the first quarter of 2017. The areas covered included anti-inflammatory, antimicrobial, antitumor, selective estrogen receptor, anti-obesity, beta-amyloid production, enzymes and HCV inhibitors in addition to anti-Alzheimer and anti-tuberculosis activities as well as several receptors antagonists. Expert opinion: It is important for medical and pharmaceutical researchers to prepare the first intensive review article concerning the highly biologically active benzosuberone derivatives where they are potent anti-inflammatory, immunosuppressive, antitumor activities and inhibitors of several enzymes. They are useful for treating abnormalities such as sleep disorders, eating disorders and reproductive disorders. Some of these compounds have potential as vascular disrupting agents to selectively target microvessels feeding tumors and some were potential leads for the development of promising therapeutic drugs.

Antimicrobial Activity of Ceftolozane-Tazobactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2011-2012)

PubMed Central

Flamm, Robert K.; Sader, Helio S.; Jones, Ronald N.

2013-01-01

Ceftolozane/tazobactam, a novel antimicrobial agent with activity against Pseudomonas aeruginosa (including drug-resistant strains) and other common Gram-negative pathogens (including most extended-spectrum-β-lactamase [ESBL]-producing Enterobacteriaceae strains), and comparator agents were susceptibility tested by a reference broth microdilution method against 7,071 Enterobacteriaceae and 1,971 P. aeruginosa isolates. Isolates were collected consecutively from patients in 32 medical centers across the United States during 2011 to 2012. Overall, 15.7% and 8.9% of P. aeruginosa isolates were classified as multidrug resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% of Enterobacteriaceae were classified as MDR and XDR. No pandrug-resistant (PDR) Enterobacteriaceae isolates and only one PDR P. aeruginosa isolate were detected. Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/2 μg/ml) agent tested against P. aeruginosa and demonstrated good activity against 310 MDR strains (MIC50/90, 2/8 μg/ml) and 175 XDR strains (MIC50/90, 4/16 μg/ml). Ceftolozane/tazobactam exhibited high overall activity (MIC50/90, 0.25/1 μg/ml) against Enterobacteriaceae and retained activity (MIC50/90, 4/>32 μg/ml) against many 601 MDR strains but not against the 86 XDR strains (MIC50, >32 μg/ml). Ceftolozane/tazobactam was highly potent (MIC50/90, 0.25/0.5 μg/ml) against 2,691 Escherichia coli isolates and retained good activity against most ESBL-phenotype E. coli isolates (MIC50/90, 0.5/4 μg/ml), but activity was low against ESBL-phenotype Klebsiella pneumoniae isolates (MIC50/90, 32/>32 μg/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary, ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary Enterobacteriaceae and P. aeruginosa isolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many MDR and XDR strains. PMID:24100499

Body malodours and their topical treatment agents.

PubMed

Kanlayavattanakul, M; Lourith, N

2011-08-01

Body malodour, including foot odour, suppresses social interaction by diminishing self-confidence and accelerating damage to the wearer's clothes and shoes. Most treatment agents, including aluminium anti-perspirant salts, inhibit the growth of malodourous bacteria. These metallic salts also reduce sweat by blocking the excretory ducts of sweat glands, minimizing the water source that supports bacterial growth. However, there are some drawback effects that limit the use of aluminium anti-perspirant salts. In addition, over-the-counter anti-perspirant and deodourant products may not be sufficiently effective for heavy sweaters, and strong malodour producers. Body odour treatment agents are rarely mentioned in the literature compared with other cosmetic ingredients. This review briefly summarizes the relationship among sweat, skin bacteria, and body odour; describes how odourous acids, thiols, and steroids are formed; and discusses the active ingredients, including metallic salts and herbs, that are used to treat body odour. A new class of ingredients that function by regulating the release of malodourants will also be described. These ingredients do not alter the balance of the skin flora. © 2011 The Authors. ICS © 2011 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

New and Emerging Treatment Options for Irritable Bowel Syndrome

PubMed Central

Lacy, Brian E.; Chey, William D.; Lembo, Anthony J.

2015-01-01

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with abdominal pain, diarrhea, constipation, or a mix of symptoms. The pathophysiology of IBS is not completely understood but appears to involve genetics, the gut microbiome, immune activation, altered intestinal permeability, and brain-gut interactions. There is no gold standard for diagnosis. Several sets of symptom-based guidelines exist. Treatment strategies for IBS may include both nonpharmacologic and pharmacologic approaches. Lifestyle modifications that aim to improve exercise, sleep, diet, and stress may be warranted. Recent data suggest that a gluten-free diet and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) may benefit some patients. For patients with diarrhea-predominant IBS, treatment options include the synthetic peripheral μ-opioid receptor agonist loperamide, antispasmodic agents, antidepressants, serotonin 5-HT3 antagonists, and the gut-specific antibiotic rifaximin. Ongoing research is evaluating the use of probiotics. For patients with constipation-predominant IBS, therapeutic strategies may include dietary fiber, laxatives, and the prosecretory agents lubiprostone and linaclotide. Research is continuing to optimize the use of available agents and evaluating new approaches to further improve the care of patients with IBS. PMID:26491416

Enhancement of the antifungal activity of antimicrobial drugs by Eugenia uniflora L.

PubMed

Santos, Karla K A; Matias, Edinardo F F; Tintino, Saulo R; Souza, Celestina E S; Braga, Maria F B M; Guedes, Gláucia M M; Costa, José G M; Menezes, Irwin R A; Coutinho, Henrique Douglas Melo

2013-07-01

Candidiasis is the most frequent infection by opportunistic fungi such as Candida albicans, Candida tropicalis, and Candida krusei. Ethanol extract from Eugenia uniflora was assayed, for its antifungal activity, either alone or combined with four selected chemotherapeutic antimicrobial agents, including anphotericin B, mebendazole, nistatin, and metronidazole against these strains. The obtained results indicated that the association of the extract of E. uniflora to metronidazole showed a potential antifungal activity against C. tropicalis. However, no synergistic activity against the other strains was observed, as observed when the extract was associated with the other, not enhancing their antifungal activity.

Multifunctional and biologically active matrices from multicomponent polymeric solutions

NASA Technical Reports Server (NTRS)

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor)

2010-01-01

The present invention relates to a biologically active functionalized electrospun matrix to permit immobilization and long-term delivery of biologically active agents. In particular the invention relates to a functionalized polymer matrix comprising a matrix polymer, a compatibilizing polymer and a biomolecule or other small functioning molecule. In certain aspects the electrospun polymer fibers comprise at least one biologically active molecule functionalized with low molecular weight heparin. Examples of active molecules that may be used with the multicomponent polymer of the invention include, for example, a drug, a biopolymer, for example a growth factor, a protein, a peptide, a nucleotide, a polysaccharide, a biological macromolecule or the like. The invention is further directed to the formation of functionalized crosslinked matrices, such as hydrogels, that include at least one functionalized compatibilizing polymer capable of assembly.

Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary

PubMed Central

Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi

2016-01-01

Objective The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Methods Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. Results Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. Conclusions Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment. PMID:26986199

Removal of gadolinium-based contrast agents: adsorption on activated carbon.

PubMed

Elizalde-González, María P; García-Díaz, Esmeralda; González-Perea, Mario; Mattusch, Jürgen

2017-03-01

Three carbon samples were employed in this work, including commercial (1690 m 2  g -1 ), activated carbon prepared from guava seeds (637 m 2  g -1 ), and activated carbon prepared from avocado kernel (1068 m 2  g -1 ), to study the adsorption of the following gadolinium-based contrast agents (GBCAs): gadoterate meglumine Dotarem®, gadopentetate dimeglumine Magnevist®, and gadoxetate disodium Primovist®. The activation conditions with H 3 PO 4 were optimized using a Taguchi methodology to obtain mesoporous materials. The best removal efficiency by square meter in a batch system in aqueous solution and model urine was achieved by avocado kernel carbon, in which mesoporosity prevails over microporosity. The kinetic adsorption curves were described by a pseudo-second-order equation, and the adsorption isotherms in the concentration range 0.5-6 mM fit the Freundlich equation. The chemical characterization of the surfaces shows that materials with a greater amount of phenolic functional groups adsorb the GBCA better. Adsorption strongly depends on the pH due to the combination of the following factors: contrast agent protonated forms and carbon surface charge. The tested carbon samples were able to adsorb 70-90% of GBCA in aqueous solution and less in model urine. This research proposes a method for the elimination of GBCA from patient urine before its discharge into wastewater.

Erotic Stimulus Processing under Amisulpride and Reboxetine: A Placebo-Controlled fMRI Study in Healthy Subjects

PubMed Central

Wiegers, Maike; Metzger, Coraline D.; Walter, Martin; Grön, Georg; Abler, Birgit

2015-01-01

Background: Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. Methods: Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4mg/d), the antidopaminergic agent amisulpride (200mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. Results: Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. Conclusions: In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents. PMID:25612894

Effects of surface active agents on DNAPL migration and distribution in saturated porous media.

PubMed

Cheng, Zhou; Gao, Bin; Xu, Hongxia; Sun, Yuanyuan; Shi, Xiaoqing; Wu, Jichun

2016-11-15

Dissolved surface active agents such as surfactant and natural organic matter can affect the distribution and fate of dense nonaqueous liquids (DNAPLs) in soil and groundwater systems. This work investigated how two common groundwater surface active agents, humic acid (HA) and Tween 80, affected tetrachloroethylene (PCE) migration and source zone architecture in saturated porous media under environmentally relevant conditions. Batch experiments were first conducted to measure the contact angles and interfacial tensions (IFT) between PCE and quartz surface in water containing different amount of surface active agents. Results showed that the contact angle increased and IFT decreased with concentration of surface active agent increasing, and Tween 80 was much more effective than HA. Five 2-D flow cell experiments were then conducted. Correspondingly, Tween 80 showed strong effects on the migration and distribution of PCE in the porous media due to its ability to change the medium wettability from water-wet into intermediate/NAPL-wet. The downward migration velocities of the PCE in three Tween 80 cells were slower than those in the other two cells. In addition, the final saturation of the PCE in the cells containing surface active agents was higher than that in the water-only cell. Results from this work indicate that the presence of surface active agents in groundwater may strongly affect the fate and distribution of DNAPL through altering porous medium wettability. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents.

PubMed Central

Sears, S D; O'Hare, J

1988-01-01

We determined the susceptibilities of five strains of Trichomonas vaginalis, one of which was metronidazole resistant, to 50 antimicrobial agents. For the metronidazole-susceptible strains, the most active agents were metronidazole, tinidazole, mebendazole, furazolidone, and anisomycin. Against the resistant strain mebendazole, furazolidone, and anisomycin were the most active. Antifungal agents, beta-lactams, macrolides, aminoglycosides, and folic acid antagonists were ineffective against all strains. PMID:3258142

Agent-Based Scientific Workflow Composition

NASA Astrophysics Data System (ADS)

Barker, A.; Mann, B.

2006-07-01

Agents are active autonomous entities that interact with one another to achieve their objectives. This paper addresses how these active agents are a natural fit to consume the passive Service Oriented Architecture which is found in Internet and Grid Systems, in order to compose, coordinate and execute e-Science experiments. A framework is introduced which allows an e-Science experiment to be described as a MultiAgent System.

Selective Destruction Of Cells Infected With The Human Immunodeficiency Virus

DOEpatents

Keener, William K.; Ward, Thomas E.

2006-03-28

Compositions and methods for selectively killing a cell containing a viral protease are disclosed. The composition is a varient of a protein synthesis inactivating toxin wherein a viral protease cleavage site is interposed between the A and B chains. The variant of the type II ribosome-inactivating protein is activated by digestion of the viral protease cleavage site by the specific viral protease. The activated ribosome-inactivating protein then kills the cell by inactivating cellular ribosomes. A preferred embodiment of the invention is specific for human immunodeficiency virus (HIV) and uses ricin as the ribosome-inactivating protein. In another preferred embodiment of the invention, the variant of the ribosome-inactivating protein is modified by attachment of one or more hydrophobic agents. The hydrophobic agent facilitates entry of the variant of the ribosome-inactivating protein into cells and can lead to incorporation of the ribosome-inactivating protein into viral particles. Still another preferred embodiment of the invention includes a targeting moiety attached to the variants of the ribosome-inactivating protein to target the agent to HIV infectable cells.

Selective destruction of cells infected with human immunodeficiency virus

DOEpatents

Keener, William K.; Ward, Thomas E.

2003-09-30

Compositions and methods for selectively killing a cell containing a viral protease are disclosed. The composition is a variant of a protein synthesis inactivating toxin wherein a viral protease cleavage site is interposed between the A and B chains. The variant of the type II ribosome-inactivating protein is activated by digestion of the viral protease cleavage site by the specific viral protease. The activated ribosome-inactivating protein then kills the cell by inactivating cellular ribosomes. A preferred embodiment of the invention is specific for human immunodeficiency virus (HIV) and uses ricin as the ribosome-inactivating protein. In another preferred embodiment of the invention, the variant of the ribosome-inactivating protein is modified by attachment of one or more hydrophobic agents. The hydrophobic agent facilitates entry of the variant of the ribosome-inactivating protein into cells and can lead to incorporation of the ribosome-inactivating protein into viral particles. Still another preferred embodiment of the invention includes a targeting moiety attached to the variants of the ribosome-inactivating protein to target the agent to HIV infectable cells.

The Antimalarial Activities of Methylene Blue and the 1,4-Naphthoquinone 3-[4-(Trifluoromethyl)Benzyl]-Menadione Are Not Due to Inhibition of the Mitochondrial Electron Transport Chain

PubMed Central

Ehrhardt, Katharina; Ke, Hangjun; Vaidya, Akhil B.; Lanzer, Michael

2013-01-01

Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are “subversive substrates.” These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates. PMID:23439633

Tailored functionalization of iron oxide nanoparticles for MRI, drug delivery, magnetic separation and immobilization of biosubstances.

PubMed

Hola, Katerina; Markova, Zdenka; Zoppellaro, Giorgio; Tucek, Jiri; Zboril, Radek

2015-11-01

In this critical review, we outline various covalent and non-covalent approaches for the functionalization of iron oxide nanoparticles (IONPs). Tuning the surface chemistry and design of magnetic nanoparticles are described in relation to their applicability in advanced medical technologies and biotechnologies including magnetic resonance imaging (MRI) contrast agents, targeted drug delivery, magnetic separations and immobilizations of proteins, enzymes, antibodies, targeting agents and other biosubstances. We review synthetic strategies for the controlled preparation of IONPs modified with frequently used functional groups including amine, carboxyl and hydroxyl groups as well as the preparation of IONPs functionalized with other species, e.g., epoxy, thiol, alkane, azide, and alkyne groups. Three main coupling strategies for linking IONPs with active agents are presented: (i) chemical modification of amine groups on the surface of IONPs, (ii) chemical modification of bioactive substances (e.g. with fluorescent dyes), and (iii) the activation of carboxyl groups mainly for enzyme immobilization. Applications for drug delivery using click chemistry linking or biodegradable bonds are compared to non-covalent methods based on polymer modified condensed magnetic nanoclusters. Among many challenges, we highlight the specific surface engineering allowing both therapeutic and diagnostic applications (theranostics) of IONPs and magnetic/metallic hybrid nanostructures possessing a huge potential in biocatalysis, green chemistry, magnetic bioseparations and bioimaging. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.

PubMed

Singh, Rajesh K; Kumar, Sahil; Prasad, D N; Bhardwaj, T R

2018-05-10

Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Clinical roundtable monograph: Emerging treatment options for TKI-resistant chronic myelogenous leukemia.

PubMed

Cortes, Jorge; Radich, Jerald; Mauro, Michael J

2012-10-01

The development of tyrosine kinase inhibitors (TKIs) that inhibit signaling of the constitutive BCR-ABL protein revolutionized the treatment of chronic myelogenous leukemia (CML). These agents have dramatically changed the treatment landscape for CML, shifting the use of allogeneic stem cell transplantation to selected patients in the salvage setting. Four BCR-ABL TKIs are now commercially available for the treatment of CML: the first-generation TKI imatinib, and the second-generation TKIs dasatinib, nilotinib, and bosutinib. Continuous treatment with these agents induces durable responses in a high proportion of patients with chronic-phase CML. Research is focused on identifying which patients can discontinue therapy without a recurrence of disease. For the group of patients with resistance to TKIs, multiple alternative therapies are being evaluated. The third-generation TKI ponatinib is a BCR-ABL inhibitor that has demonstrated significant activity, including in patients with the TKI resistance mutation T315I. The homoharringtonine derivative omacetaxine mepesuccinate, which inhibits protein synthesis, has also demonstrated clinical activity in CML, including in patients with TKI resistance due to T315I and in patients who have TKI resistance despite no evidence of ABL mutations. It is essential that clinicians implement these new agents with care and change therapies only when appropriate in order to preserve as many options as possible for future use if needed.

Clinical development of BLZ-100 for real-time optical imaging of tumors during resection

NASA Astrophysics Data System (ADS)

Franklin, Heather L.; Miller, Dennis M.; Hedges, Teresa; Perry, Jeff; Parrish-Novak, Julia

2016-03-01

Complete initial resection can give cancer patients the best opportunity for long-term survival. There is unmet need in surgical oncology for optical imaging that enables simple and precise visualization of tumors and consistent contrast with surrounding normal tissues. Near-infrared (NIR) contrast agents and camera systems that can detect them represent an area of active research and development. The investigational Tumor Paint agent BLZ-100 is a conjugate of a chlorotoxin peptide and the NIR dye indocyanine green (ICG) that has been shown to specifically bind to a broad range of solid tumors. Clinical efficacy studies with BLZ-100 are in progress, a necessary step in bringing the product into clinical practice. To ensure a product that will be useful for and accepted by surgeons, the early clinical development of BLZ- 100 incorporates multiple tumor types and imaging devices so that surgeon feedback covers the range of anticipated clinical uses. Key contrast agent characteristics include safety, specificity, flexibility in timing between dose and surgery, and breadth of tumor types recognized. Imaging devices should use wavelengths that are optimal for the contrast agent, be sensitive enough that contrast agent dosing can be adjusted for optimal contrast, include real-time video display of fluorescence and white light image, and be simple for surgeons to use with minimal disruption of surgical flow. Rapid entry into clinical studies provides the best opportunity for early surgeon feedback, enabling development of agents and devices that will gain broad acceptance and provide information that helps surgeons achieve more complete and precise resections.

Pharmacological management of osteogenesis

PubMed Central

Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

2014-01-01

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

PubMed Central

Cragg, Gordon M.; Pezzuto, John M.

2016-01-01

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

Implications of environmental externalities assessments for solar thermal powerplants

NASA Astrophysics Data System (ADS)

Lee, A. D.; Baechler, M. C.

1991-03-01

Externalities are those impacts of one activity on other activities that are not priced in the marketplace. An externality is said to exist when two conditions hold: (1) the utility or operations of one economic agent, A, include nonmonetary variables whose values are chosen by another economic agent, B, without regard to the effects on A, and (2) B does not pay A compensation equal to the incremental costs inflicted on A. Electricity generation involves a wide range of potential and actual environmental impacts. Legislative, permitting, and regulatory requirements directly or indirectly control certain environmental impacts, implicitly causing them to become internalized in the cost of electricity generation. Electricity generation, however, often produces residual environmental impacts that meet the definition of an externality. Mechanisms have been developed by several states to include the costs associated with externalities in the cost-effectiveness analyses of new powerplants. This paper examines these costs for solar thermal plants and applies two states' scoring methodologies to estimate how including externalities would affect the levelized costs of power from a solar plant in the Pacific Northwest. It concludes that including externalities in the economics can reduce the difference between the levelized cost of a coal and solar plant by between 0.74 and 2.42 cents/kWh.

Comparison of Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to the Nerve Agents Cyclosarin and Tabun in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Comparison of extracellular striatal acetylcholine and brain seizure activity following...lethality; nerve agents; organophosphorus compounds; seizure activity ; tabun 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER...acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs John C

Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Dan; Wang, Jun; Wang, Limin

An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. Themore » proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.« less

Chemical composition and antifungal activity of Carica papaya Linn. seed essential oil against Candida spp.

PubMed

He, X; Ma, Y; Yi, G; Wu, J; Zhou, L; Guo, H

2017-05-01

In recent years, the incidence of clinical yeast infections has increased dramatically. Due to the extensive use of broad-spectrum antifungal agents, there has been a notable increase in drug resistance among infections yeast species. As one of the most popular natural antimicrobial agents, essential oils (EOs) have attracted a lot of attention from the scientific community. The aim of this study was to analyse the chemical composition and examine the antifungal activity of the EO extracted from the seeds of Carica papaya Linn. The papaya seed EO was analysed by gas chromatography-mass spectrometry. The major constituent is benzyl isothiocyanate (99·36%). The filter paper disc diffusion method and broth dilution method were employed. The EO showed inhibitory effect against all the tested Candida strains including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropical with inhibition zone diameters in the range of 14·2-33·2 mm, the minimal inhibitory concentrations (MICs) in the range of 4·0-16·0 μg ml -1 and the minimum fungicidal concentrations (MFCs) in the range of 16·0-64·0 μg ml -1 . Here, we found that the papaya seed EO has promising anticandida activity and identify C. papaya L. as a potential natural source of antifungal agents. The chemical composition and antifungal activity of essential oil of Carica papaya seeds were studied. The oil of papaya seeds could inhibit the growth of Candida spp. for the first report. Carica Papaya may be recognized as a possible new source of natural antifungal agents. © 2017 The Society for Applied Microbiology.

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

PubMed Central

2016-01-01

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

PubMed

Lockridge, Oksana; Norgren, Robert B; Johnson, Rudolph C; Blake, Thomas A

2016-09-19

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.

Selected Essential Oils as Antifungal Agents Against Antibiotic-Resistant Candida spp.: In Vitro Study on Clinical and Food-Borne Isolates.

PubMed

Rajkowska, Katarzyna; Kunicka-Styczyńska, Alina; Maroszyńska, Marta

2017-01-01

Candida spp. cause significant health problems, inducing various types of superficial and deep-seated mycoses in humans. As a result of the increasing antibiotic resistance among pathogenic yeasts, the interest in alternative agents of antifungal activity is growing. This study evaluated the antimicrobial activity of selected essential oils (EOs) against Candida clinical and food-borne strains, including antibiotic-resistant isolates, in relation to yeast cell surface hydrophobicity (CSH). Candida strains showed different range of susceptibility to tea tree, thyme, peppermint, and clove oils, and peppermint oil demonstrated the lowest anticandidal activity with minimal inhibitory concentrations (MICs) of 0.03-8.0% v/v. MIC values for thyme and clove oils ranged from 0.03% to 0.25% v/v, and for tea tree oil-from 0.12% to 2.0% v/v. The exception was Candida tropicalis food-borne strain, the growth of which was inhibited after application of EOs at concentration of 8% v/v. Due to diverse yeast susceptibility to EOs, isolates were divided into five clusters in a principal component analysis model, each containing both clinical and food-borne strains. Hydrophobic properties of yeast were also diversified, and 37% of clinical and 50% of food-borne strains exhibited high hydrophobicity. The study indicates high homology of clinical and food-borne Candida isolates in relation to their susceptibility to anticandidal agents and hydrophobic properties. The susceptibility of yeasts to EOs could be partially related to their CSH. High antifungal activity of examined EOs, also against antibiotic-resistant isolates, indicates their usefulness as agents preventing the development of Candida strains of different origin.

Prevention of ER-Negative Breast Cancer

PubMed Central

Li, Yuxin

2014-01-01

The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer. PMID:19213564

Comparative in vitro activity of a pharmacokinetically enhanced oral formulation of amoxicillin/clavulanic acid (2000/125 mg twice daily) against 9172 respiratory isolates collected worldwide in 2000.

PubMed

Koeth, Laura M; Jacobs, Michael R; Good, Caryn E; Bajaksouzian, Saralee; Windau, Anne; Jakielaszek, Charles; Saunders, Kay A

2004-11-01

A new, pharmacokinetically enhanced, oral formulation of amoxicillin/clavulanic acid has been developed to overcome resistance in the major bacterial respiratory pathogen Streptococcus pneumoniae, while maintaining excellent activity against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase producing strains. This study was conducted to provide in vitro susceptibility data for amoxicillin/clavulanic acid and 16 comparator agents against the key respiratory tract pathogens. Susceptibility testing was performed on 9172 isolates collected from 95 centers in North America, Europe, Australia, and Hong Kong by broth microdilution MIC determination, according to NCCLS methods, using amoxicillin/clavulanic acid and 16 comparator antimicrobial agents. Results were interpreted according to NCCLS breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints based on oral dosing regimens. Overall, 93.5% of Streptococcus pneumoniae isolates were susceptible to amoxicillin/clavulanic acid at the current susceptible breakpoint of < or =2 microg/mL and 97.3% at the PK/PD susceptible breakpoint of < or =4 microg/mL for the extended release formulation. Proportions of isolates that were penicillin intermediate and resistant were 13% and 16.5%, respectively, while 25% were macrolide resistant and 21.8% trimethoprim/sulfamethoxazole resistant. 21.9% of Haemophilus influenzae were beta-lactamase producers and 16.8% trimethoprim/sulfamethoxazole resistant, >99% of isolates were susceptible to amoxicillin/clavulanic acid, cefixime, ciprofloxacin and levofloxacin at NCCLS breakpoints. The most active agents against Moraxella catarrhalis were amoxicillin/clavulanic acid, macrolides, cefixime, fluoroquinolones, and doxycycline. Overall, 13% of Streptococcus pyogenes were resistant to macrolides. The extended release formulation of amoxicillin/clavulanic acid has potential for empiric use against many respiratory tract infections worldwide due to its activity against species resistant to many agents currently in use.

Bovine brain pyroglutamyl aminopeptidase (type-1): purification and characterisation of a neuropeptide-inactivating peptidase.

PubMed

Cummins, P M; O'Connor, B

1996-08-01

Pyroglutamyl aminopeptidase type-1 (PAP-I) is reported to be a soluble, broad specificity aminopeptidase, capable of removing the pyroglutamic acid (pGlu) residue from the amino terminus of pGlu-peptides (e.g. TRH, LHRH, neurotensin and bombesin). The central aim of this study was to undertake, for the first time, the complete purification and characterisation of a PAP activity observed within the cytosolic fraction of bovine whole brain and to compare the properties of the enzyme with previous findings. A series of chromatographic steps (DEAE-Sepharose, Sephacryl S-200 and Activated Thiol Sepharose 4B) generated a soluble PAP activity purified to near homogeneity with a total active yield of 6.6% The enzyme displayed a native molecular mass of approximately 23,700 Da, which compares well with that value obtained under denaturing conditions via SDS-PAGE (24,000 Da), suggesting that the enzyme exists as a monomer. The expression of PAP activity displayed an absolute requirement for the presence of a disulphide bond-reducing agent such as DTT, whilst optimum activity was observed at pH 8.5. strong inhibition of PAP activity was observed with a number of different agents, including transition metal ions, sulphydryl-blocking agents and 2-pyrrolidone (a pGlu analog). A broad pyroglutamyl substrate specificity, which excludes substrates commencing with the pGlu-Pro bond, was also demonstrated for the bovine brain enzyme. Based on a comparison of these findings with those reported for PAP-I in other mammalian tissues, the soluble PAP activity observed in bovine whole brain can tentatively be classified as a pyroglutamyl aminopeptidase type-1 (EC 3.4.19.3).

Recent advances in inflammasome biology.

PubMed

Place, David E; Kanneganti, Thirumala-Devi

2018-02-01

The inflammasome is a complex of proteins that through the activity of caspase-1 and the downstream substrates gasdermin D, IL-1β, and IL-18 execute an inflammatory form of cell death termed pyroptosis. Activation of this complex often involves the adaptor protein ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. Here we discuss new regulatory mechanisms that have been identified for the canonical inflammasomes, the most recently identified NLRP9b inflammasome, and the new gasdermin family of proteins that mediate pyroptosis and other forms of regulated cell death. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeted Ablation of CML Stem Cells

DTIC Science & Technology

2007-01-01

centuries .12 More recently, PTL has been found to have several other properties, including antitumor activity, inhibition of DNA synthesis, and...as a chemopreventive agent in a UVB-induced skin cancer animal model. 21 PTL is a potent inhibitor of NF-B activation and has been shown to directly...diluted in phosphate buffer saline (PBS). Ara-C was obtained from Sigma ( St Louis, MO). Total cell numbers were determined before and after culture for

Oxidation of Benzoin to Benzil Using Alumina-Supported Active MnO2

NASA Astrophysics Data System (ADS)

Crouch, R. David; Holden, Michael S.; Burger, Jennifer S.

2001-07-01

The use of alumina-supported active MnO2 to oxidize benzoin to benzil is described. The advantages of this reagent include ease of handling and separation from the product and lower toxicity than previously reported supported oxidizing agents. The product is purified by elution through a simple chromatography column consisting of a silica gel-packed Pasteur pipet. Students' yields are comparable to yields from other reported oxidation methods.

Current Treatment of Chronic Lymphocytic Leukemia.

PubMed

Jamroziak, Krzysztof; Puła, Bartosz; Walewski, Jan

2017-01-01

A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the TP53 gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the TP53 gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.

Targeted Therapy for Breast Cancer Prevention

PubMed Central

den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

2013-01-01

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma

PubMed Central

Jones, Jeffrey A.; Rupert, Amy S.; Poi, Ming; Phelps, Mitch A.; Andritsos, Leslie; Baiocchi, Robert; Benson, Don M.; Blum, Kristie A.; Christian, Beth; Flynn, Joseph; Penza, Sam; Porcu, Pierluigi; Grever, Michael R.; Byrd, John C.

2014-01-01

Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. PMID:23959599

Synthesis and structure-activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents.

PubMed

Stolić, Ivana; Čipčić Paljetak, Hana; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav

2015-01-27

Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A Three-Way Transcriptomic Interaction Study of a Biocontrol Agent (Clonostachys rosea), a Fungal Pathogen (Helminthosporium solani), and a Potato Host (Solanum tuberosum).

PubMed

Lysøe, Erik; Dees, Merete W; Brurberg, May Bente

2017-08-01

Helminthosporium solani causes silver scurf, which affects the quality of potato. The biocontrol agent Clonostachys rosea greatly limited the severity of silver scurf symptoms and amount of H. solani genomic DNA in laboratory experiments. Transcriptomic analysis during interaction showed that H. solani gene expression was highly reduced when coinoculated with the biocontrol agent C. rosea, whereas gene expression of C. rosea was clearly boosted as a response to the pathogen. The most notable upregulated C. rosea genes were those encoding proteins involved in cellular response to oxidative stress, proteases, G-protein signaling, and the methyltransferase LaeA. The most notable potato response to both fungi was downregulation of defense-related genes and mitogen-activated protein kinase kinase kinases. At a later stage, this shifted, and most potato defense genes were turned on, especially those involved in terpenoid biosynthesis when H. solani was present. Some biocontrol-activated defense-related genes in potato were upregulated during early interaction with C. rosea alone that were not triggered by H. solani alone. Our results indicate that the reductions of silver scurf using C. rosea are probably due to a combination of mechanisms, including mycoparasitism, biocontrol-activated stimulation of plant defense mechanisms, microbial competition for nutrients, space, and antibiosis.

Larrea tridentata: A novel source for anti-parasitic agents active against Entamoeba histolytica, Giardia lamblia and Naegleria fowleri.

PubMed

Bashyal, Bharat; Li, Linfeng; Bains, Trpta; Debnath, Anjan; LaBarbera, Daniel V

2017-08-01

Protozoan parasites infect and kill millions of people worldwide every year, particularly in developing countries where access to clean fresh water is limited. Among the most common are intestinal parasites, including Giardia lamblia and Entamoeba histolytica. These parasites wreak havoc on the epithelium lining the small intestines (G. lamblia) and colon (E. histolytica) causing giardiasis and amebiasis, respectively. In addition, there are less common but far more deadly pathogens such as Naegleria fowleri that thrive in warm waters and infect the central nervous systems of their victims via the nasal passages. Despite their prevalence and associated high mortality rates, there remains an unmet need to identify more effective therapeutics for people infected with these opportunistic parasites. To address this unmet need, we have surveyed plants and traditional herbal medicines known throughout the world to identify novel antiparasitic agents with activity against G. lamblia, E. histolytica, and N. fowleri. Herein, we report Larrea tridentata, known as creosote bush, as a novel source for secondary metabolites that display antiparasitic activity against all three pathogens. This report also characterizes the lignan compound classes, nordihydroguairetic acid and demethoxyisoguaiacin, as novel antiparasitic lead agents to further develop more effective drug therapy options for millions of people worldwide.

Larrea tridentata: A novel source for anti-parasitic agents active against Entamoeba histolytica, Giardia lamblia and Naegleria fowleri

PubMed Central

Bains, Trpta; Debnath, Anjan

2017-01-01

Protozoan parasites infect and kill millions of people worldwide every year, particularly in developing countries where access to clean fresh water is limited. Among the most common are intestinal parasites, including Giardia lamblia and Entamoeba histolytica. These parasites wreak havoc on the epithelium lining the small intestines (G. lamblia) and colon (E. histolytica) causing giardiasis and amebiasis, respectively. In addition, there are less common but far more deadly pathogens such as Naegleria fowleri that thrive in warm waters and infect the central nervous systems of their victims via the nasal passages. Despite their prevalence and associated high mortality rates, there remains an unmet need to identify more effective therapeutics for people infected with these opportunistic parasites. To address this unmet need, we have surveyed plants and traditional herbal medicines known throughout the world to identify novel antiparasitic agents with activity against G. lamblia, E. histolytica, and N. fowleri. Herein, we report Larrea tridentata, known as creosote bush, as a novel source for secondary metabolites that display antiparasitic activity against all three pathogens. This report also characterizes the lignan compound classes, nordihydroguairetic acid and demethoxyisoguaiacin, as novel antiparasitic lead agents to further develop more effective drug therapy options for millions of people worldwide. PMID:28793307

Serologic Evidence of Human Monocytic and Granulocytic Ehrlichiosis in Israel

PubMed Central

Keysary, Avi; Amram, Lili; Keren, Gershon; Sthoeger, Zev; Potasman, Israel; Jacob, Amir; Strenger, Carmella; Dawson, Jacqueline E.

1999-01-01

We conducted a retrospective serosurvey of 1,000 persons in Israel who had fever of undetermined cause to look for Ehrlichia chaffeensis antibodies. Four of five cases with antibodies reactive to E. chaffeensis were diagnosed in the summer, when ticks are more active. All patients had influenzalike symptoms with high fever. None of the cases was fatal. Three serum samples were also seroreactive for antibodies to E. canis, and one was also reactive to the human granulocytic ehrlichiosis (HGE) agent. The titer to the HGE agent in this patient was higher than the serum titer to E. chaffeensis, and the Western blot analysis also indicated that the HGE agent was the primary cause of infection. We present the first serologic evidence that the agents of human monocytic ehrlichiosis (HME) and HGE are present in Israel. Therefore, human ehrlichiosis should be included in the differential diagnoses for persons in Israel who have been exposed to ticks and have influenzalike symptoms. PMID:10603210

Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention.

PubMed

Fajardo, Alexandra M; Piazza, Gary A

2015-07-15

Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs. Copyright © 2015 the American Physiological Society.

Chemoprevention in gastrointestinal physiology and disease. Anti-inflammatory approaches for colorectal cancer chemoprevention

PubMed Central

Piazza, Gary A.

2015-01-01

Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs. PMID:26021807

Sequencing of ALK Inhibitors in ALK+ Non-Small Cell Lung Cancer.

PubMed

Gadgeel, Shirish M

2017-06-01

Major therapeutic advances have occurred over the last several years in the management of advanced ALK+ NSCLC patients. Crizotinib was the first agent approved for the management of ALK+ NSCLC patients after it demonstrated significantly greater clinical benefit compared to chemotherapy. Several next generation ALK inhibitors have demonstrated clinical benefit in patients with crizotinib refractory NSCLC patients including in the CNS. Based on available data, therapy with a next generation ALK inhibitor can be initiated following therapy with crizotinib without any assessment of the molecular mechanisms of resistance. The appropriate therapy for patients with progressive disease following two ALK inhibitors is not well defined. In patients with an ALK-resistant mutation in their tumor, an ALK inhibitor with activity against the mutation would be the most appropriate therapy. In others, chemotherapy and PD-1 directed agents can be considered. Clinical data suggests that ALK+ patients are less likely to benefit from PD-1 directed agents and therefore chemotherapy should be considered prior to these agents for the management of ALK+ NSCLC patients.

[The use of complex interval models for predicting activity of non-nucleoside reverse transcriptase activity].

PubMed

Burliaeva, E V; Tarkhov, A E; Burliaev, V V; Iurkevich, A M; Shvets, V I

2002-01-01

Searching of new anti-HIV agents is still crucial now. In general, researches are looking for inhibitors of certain HIV's vital enzymes, especially for reverse transcriptase (RT) inhibitors. Modern generation of anti-HIV agents represents non-nucleoside reverse transcriptase inhibitors (NNRTIs). They are much less toxic than nucleoside analogues and more chemically stable, thus being slower metabolized and emitted from the human body. Thus, search of new NNRTIs is actual today. Synthesis and study of new anti-HIV drugs is very expensive. So employment of the activity prediction techniques for such a search is very beneficial. This technique allows predicting the activities for newly proposed structures. It is based on the property model built by investigation of a series of known compounds with measured activity. This paper presents an approach of activity prediction based on "structure-activity" models designed to form a hypothesis about probably activity interval estimate. This hypothesis formed is based on structure descriptor domains, calculated for all energetically allowed conformers for each compound in the studied sef. Tetrahydroimidazobenzodiazipenone (TIBO) derivatives and phenylethyltiazolyltiourea (PETT) derivatives illustrated the predictive power of this method. The results are consistent with experimental data and allow to predict inhibitory activity of compounds, which were not included into the training set.

[Cutaneous Malassezia infections and Malassezia associated dermatoses: An update].

PubMed

Nenoff, P; Krüger, C; Mayser, P

2015-06-01

The lipophilic yeast fungus Malassezia (M.) spp. is the only fungal genus or species which is part of the physiological human microbiome. Today, at least 14 different Malassezia species are known; most of them can only be identified using molecular biological techniques. As a facultative pathogenic microorganism, Malassezia represents the causative agent both of superficial cutaneous infections and of blood stream infections. Pityriasis versicolor is the probably most frequent infection caused by Malassezia. Less common, Malassezia folliculitis occurs. There is only an episodic report on Malassezia-induced onychomycosis. Seborrhoeic dermatitis represents a Malassezia-associated inflammatory dermatosis. In addition, Malassezia allergenes should be considered as the trigger of "Head-Neck"-type atopic dermatitis. Ketoconazole possesses the strongest in vitro activity against Malassezia, and represents the treatment of choice for topical therapy of pityriasis versicolor. Alternatives include other azole antifungals but also the allylamine terbinafine and the hydroxypyridone antifungal agent ciclopirox olamine. "Antiseborrhoeic" agents, e.g. zinc pyrithione, selenium disulfide, and salicylic acid, are also effective in pityriasis versicolor. The drug of choice for oral treatment of pityriasis versicolor is itraconazole; an effective alternative represents fluconazole. Seborrhoeic dermatitis is best treated with topical medication, including topical corticosteroids and antifungal agents like ketoconazole or sertaconazole. Calcineurin inhibitors, e.g. pimecrolimus and tacrolimus, are reliable in seborrhoeic dermatitis, however are used off-label.

Effect of Viscous Agents on Corneal Density in Dry Eye Disease.

PubMed

Wegener, Alfred R; Meyer, Linda M; Schönfeld, Carl-Ludwig

2015-10-01

To investigate the effect of the viscous agents, hydroxypropyl methylcellulose (HPMC), carbomer, povidone, and a combination of HPMC and povidone on corneal density in patients with dry eye disease. In total, 98 eyes of 49 patients suffering from dry eye and 65 eyes of 33 healthy age-matched individuals were included in this prospective, randomized study. Corneal morphology was documented with Scheimpflug photography and corneal density was analyzed in 5 anatomical layers (epithelium, bowman membrane, stroma, descemet's membrane, and endothelium). Corneal density was evaluated for the active ingredients HPMC, carbomer, povidone, and a combination of HPMC and povidone as the viscous agents contained in the artificial tear formulations used by the dry eye patients. Data were compared to the age-matched healthy control group without medication. Corneal density in dry eye patients was reduced in all 5 anatomical layers compared to controls. Corneal density was highest and very close to control in patients treated with HPMC containing ocular lubricants. Patients treated with lubricants, including carbomer as the viscous agent displayed a significant reduction of corneal density in layers 1 and 2 compared to control. HPMC containing ocular lubricants can help to maintain physiological corneal density and may be beneficial in the treatment of dry eye disease.

Age-Related Inducibility of Carboxylesterases by the Antiepileptic Agent Phenobarbital and Implications in Drug Metabolism and Lipid Accumulation 1, 2

PubMed Central

Xiao, Da; Chen, Yi-Tzai; Yang, Dongfang; Yan, Bingfang

2014-01-01

Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID:22513142

Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches.

PubMed

Morales, Inelia; Guzmán-Martínez, Leonardo; Cerda-Troncoso, Cristóbal; Farías, Gonzalo A; Maccioni, Ricardo B

2014-01-01

Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of τ and β-amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti-inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments.

Emerging Agents for the Treatment of Advanced, Imatinib-Resistant Gastrointestinal Stromal Tumors: Current Status and Future Directions.

PubMed

Bauer, Sebastian; Joensuu, Heikki

2015-08-01

Imatinib is strongly positioned as the recommended first-line agent for most patients with advanced gastrointestinal stromal tumor (GIST) due to its good efficacy and tolerability. Imatinib-resistant advanced GIST continues to pose a therapeutic challenge, likely due to the frequent presence of multiple mutations that confer drug resistance. Sunitinib and regorafenib are approved as second- and third-line agents, respectively, for patients whose GIST does not respond to imatinib or who do not tolerate imatinib, and their use is supported by large randomized trials. ATP-mimetic tyrosine kinase inhibitors provide clinical benefit even in heavily pretreated GIST suggesting that oncogenic dependency on KIT frequently persists. Several potentially useful tyrosine kinase inhibitors with distinct inhibitory profiles against both KIT ATP-binding domain and activation loop mutations have not yet been fully evaluated. Agents that have been found promising in preclinical models and early clinical trials include small molecule KIT and PDGFRA mutation-specific inhibitors, heat shock protein inhibitors, histone deacetylase inhibitors, allosteric KIT inhibitors, KIT and PDGFRA signaling pathway inhibitors, and immunological approaches including antibody-drug conjugates. Concomitant or sequential administration of tyrosine kinase inhibitors with KIT signaling pathway inhibitors require further evaluation, as well as rotation of tyrosine kinase inhibitors as a means to suppress drug-resistant cell clones.

Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches

PubMed Central

Morales, Inelia; Guzmán-Martínez, Leonardo; Cerda-Troncoso, Cristóbal; Farías, Gonzalo A.; Maccioni, Ricardo B.

2014-01-01

Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of τ and β-amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti-inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments. PMID:24795567

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma.

PubMed

Beck, Joseph Thaddeus; Ismail, Amen; Tolomeo, Christina

2014-09-01

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included. Copyright © 2014 Elsevier Ltd. All rights reserved.

Superfund Record of Decision (EPA Region 4): Ciba-Geigy, Washington County, Mcintosh, AL. (Second remedial action), September 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1991-09-30

The 1,500-acre Ciba-Geigy site is an active chemical manufacturer in an industrial area in McIntosh, Washington County, Alabama. From 1952 to present, Ciba-Geigy, formerly Geigy Chemical Corporation, has produced various chemicals including DDT, laundry products, herbicides, insecticides, agricultural chelating agents, sequestering agents, plastic resins and additives, antioxidants, and specialty chemicals. In 1985, EPA issued a RCRA permit that included a corrective action plan requiring Ciba-Geigy to remove and treat ground water and surface water contamination at the site. In 1987, as part of the corrective action plan requirements, Ciba-Geigy installed an additional wastewater treatment system and ground water monitoring wells.more » The ROD addresses highly contaminated soil and sludge at 10 of the 11 former waste management areas as OU2. The primary contaminants of concern affecting the soil, sludge, and debris are VOCs including benzene and toluene; other organics including PCBs and pesticides (e.g., DDT); and metals including lead. The selected remedial action for the site is included.« less

Multi-stage complex contagions.

PubMed

Melnik, Sergey; Ward, Jonathan A; Gleeson, James P; Porter, Mason A

2013-03-01

The spread of ideas across a social network can be studied using complex contagion models, in which agents are activated by contact with multiple activated neighbors. The investigation of complex contagions can provide crucial insights into social influence and behavior-adoption cascades on networks. In this paper, we introduce a model of a multi-stage complex contagion on networks. Agents at different stages-which could, for example, represent differing levels of support for a social movement or differing levels of commitment to a certain product or idea-exert different amounts of influence on their neighbors. We demonstrate that the presence of even one additional stage introduces novel dynamical behavior, including interplay between multiple cascades, which cannot occur in single-stage contagion models. We find that cascades-and hence collective action-can be driven not only by high-stage influencers but also by low-stage influencers.

Multi-stage complex contagions

NASA Astrophysics Data System (ADS)

Melnik, Sergey; Ward, Jonathan A.; Gleeson, James P.; Porter, Mason A.

2013-03-01

The spread of ideas across a social network can be studied using complex contagion models, in which agents are activated by contact with multiple activated neighbors. The investigation of complex contagions can provide crucial insights into social influence and behavior-adoption cascades on networks. In this paper, we introduce a model of a multi-stage complex contagion on networks. Agents at different stages—which could, for example, represent differing levels of support for a social movement or differing levels of commitment to a certain product or idea—exert different amounts of influence on their neighbors. We demonstrate that the presence of even one additional stage introduces novel dynamical behavior, including interplay between multiple cascades, which cannot occur in single-stage contagion models. We find that cascades—and hence collective action—can be driven not only by high-stage influencers but also by low-stage influencers.

Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents.

PubMed

Bi, Chongwen; Zhang, Na; Yang, Peng; Ye, Cheng; Wang, Yanxiang; Fan, Tianyun; Shao, Rongguang; Deng, Hongbin; Song, Danqing

2017-02-09

A series of 12 N -substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N '-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N '-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC 50 between 0.55 and 1.7 μM. The underlying mechanism of 6b against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound 6b is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.

First Discovery of Acetone Extract from Cottonseed Oil Sludge as a Novel Antiviral Agent against Plant Viruses

PubMed Central

Zhao, Lei; Feng, Chaohong; Hou, Caiting; Hu, Lingyun; Wang, Qiaochun; Wu, Yunfeng

2015-01-01

A novel acetone extract from cottonseed oil sludge was firstly discovered against plant viruses including Tobacco mosaic virus (TMV), Rice stripe virus (RSV) and Southern rice black streaked dwarf virus (SRBSDV). Gossypol and β-sitosterol separated from the acetone extract were tested for their effects on anti-TMV and analysed by nuclear magnetic resonance (NMR) assay. In vivo and field trials in different geographic distributions and different host varieties declared that this extract mixture was more efficient than the commercial agent Ningnanmycin with a broad spectrum of anti-plant-viruses activity. No phytotoxic activity was observed in the treated plants and environmental toxicology showed that this new acetone extract was environmentally friendly, indicating that this acetone extract has potential application in the control of plant virus in the future. PMID:25705894

First discovery of acetone extract from cottonseed oil sludge as a novel antiviral agent against plant viruses.

PubMed

Zhao, Lei; Feng, Chaohong; Hou, Caiting; Hu, Lingyun; Wang, Qiaochun; Wu, Yunfeng

2015-01-01

A novel acetone extract from cottonseed oil sludge was firstly discovered against plant viruses including Tobacco mosaic virus (TMV), Rice stripe virus (RSV) and Southern rice black streaked dwarf virus (SRBSDV). Gossypol and β-sitosterol separated from the acetone extract were tested for their effects on anti-TMV and analysed by nuclear magnetic resonance (NMR) assay. In vivo and field trials in different geographic distributions and different host varieties declared that this extract mixture was more efficient than the commercial agent Ningnanmycin with a broad spectrum of anti-plant-viruses activity. No phytotoxic activity was observed in the treated plants and environmental toxicology showed that this new acetone extract was environmentally friendly, indicating that this acetone extract has potential application in the control of plant virus in the future.

Bacillus subtilis extracytoplasmic function (ECF) sigma factors and defense of the cell envelope.

PubMed

Helmann, John D

2016-04-01

Bacillus subtilis provides a model for investigation of the bacterial cell envelope, the first line of defense against environmental threats. Extracytoplasmic function (ECF) sigma factors activate genes that confer resistance to agents that threaten the integrity of the envelope. Although their individual regulons overlap, σ(W) is most closely associated with membrane-active agents, σ(X) with cationic antimicrobial peptide resistance, and σ(V) with resistance to lysozyme. Here, I highlight the role of the σ(M) regulon, which is strongly induced by conditions that impair peptidoglycan synthesis and includes the core pathways of envelope synthesis and cell division, as well as stress-inducible alternative enzymes. Studies of these cell envelope stress responses provide insights into how bacteria acclimate to the presence of antibiotics. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Tetracyclines, sulfonamides and metronidazole].

PubMed

Pérez-Trallero, Emilio; Iglesias, Luis

2003-11-01

Tetracyclines form a group of natural and semisynthetic products that acts inhibiting the bacterial protein synthesis. They are bacteriostatic agents, exhibiting activity against a wide range of organisms, but they are at the present of limited use because of their acquired resistance. Doxycycline is currently the most frequently used tetracycline in human medicine and it is included in the List of Essential Medicines of the World Health Organization. Sulfonamides are synthetic, broad-spectrum bacteriostatic antibiotics. They were the first effective systemic antimicrobial agents. Their mode of action is based on the inhibition of DNA synthesis. Due to their toxicity and high adquired resistance their use is currently very low. Metronidazole is the main compound of 5-nitroimidazole family. It is a very active bactericidal antibiotic against anaerobic and some microaerophilic bacteria and it is still very useful in the treatment of bacterian and parasitic infections.

Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages.

PubMed

Mamani-Matsuda, Maria; Rambert, Jérôme; Malvy, Denis; Lejoly-Boisseau, Hélène; Daulouède, Sylvie; Thiolat, Denis; Coves, Sara; Courtois, Pierrette; Vincendeau, Philippe; Mossalayi, M Djavad

2004-03-01

In addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-alpha and nitric oxide derivatives. In the present study, quercetin (3,3',4',5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-alpha and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.

Appropriateness of gram-negative agent use at a tertiary care hospital in the setting of significant antimicrobial resistance.

PubMed

Vora, Neil M; Kubin, Christine J; Furuya, E Yoko

2015-01-01

Background.  Practicing antimicrobial stewardship in the setting of widespread antimicrobial resistance among gram-negative bacilli, particularly in urban areas, is challenging. Methods.  We conducted a retrospective cross-sectional study at a tertiary care hospital with an established antimicrobial stewardship program in New York, New York to determine appropriateness of use of gram-negative antimicrobials and to identify factors associated with suboptimal antimicrobial use. Adult inpatients who received gram-negative agents on 2 dates, 1 June 2010 or 1 December 2010, were identified through pharmacy records. Clinical data were collected for each patient. Use of gram-negative agents was deemed optimal or suboptimal through chart review and according to hospital guidelines. Data were compared using χ(2) or Fischer's exact test for categorical variables and Student t test or Mann-Whitney U test for continuous variables. Results.  A total of 356 patients were included who received 422 gram-negative agents. Administration was deemed suboptimal in 26% of instances, with the most common reason being spectrum of activity too broad. In multivariable analysis, being in an intensive care unit (adjusted odds ratio [aOR], .49; 95% confidence interval [CI], .29-.84), having an infectious diseases consultation within the previous 7 days (aOR, .52; 95% CI, .28-.98), and having a history of multidrug-resistant gram-negative bacilli within the past year (aOR, .24; 95% CI, .09-.65) were associated with optimal gram-negative agent use. Beta-lactam/beta-lactamase inhibitor combination drug use (aOR, 2.6; 95% CI, 1.35-5.16) was associated with suboptimal use. Conclusions.  Gram-negative agents were used too broadly despite numerous antimicrobial stewardship program activities.

Newer antiatherosclerosis treatment strategies.

PubMed

Aggarwal, Amitesh; Singh, Safal

2011-01-01

Atherosclerosis has been a target of much clinical and molecular research. As a result of this extensive research, it is amply clear that atherogenesis is a multifactorial process involving an interplay of metabolic, immune and inflammatory mechanisms. Antiatherosclerotic strategies are today aiming for a multipronged approach targeting each arm of this multifactorial process. The newer agents under development can be divided into three broad categories: anti-inflammatory agents, modulators of intermediary metabolism and antiatherosclerosis vaccines. Potential targets for anti-inflammatory agents include inhibition of conversion of low-density lipoprotein (LDL) to oxidised LDL, blocking or downregulation of cell adhesion molecules, chemokine modulation and macrophage receptor blockade. Beyond inhibition of plaque formation, efforts are also ongoing to develop agents which stabilise the plaque by increasing its fibrous content and inhibiting its disruption. So far as research in the sphere of intermediary metabolism is concerned, the focus is now primarily on raising high-density lipoprotein and promoting reverse cholesterol transport; potential targets include cholesteryl ester transfer protein, liver X-receptor, lecithin cholesterol acyltransferase and high-density lipoprotein mimetics. Acyl-coenzymeA: cholesterol acyltransferase is another enzyme whose selective and differential inhibition is under active investigation. The concept of immunisation against a non-communicable disease such as atherosclerosis is still in its nascent stages. However, with increasing evidence to suggest the role of antigen-specific T-cell-mediated immunity in atherogenesis, this approach is potentially promising. Possible antigens under evaluation include oxidised LDL and its subparticles, heat-shock proteins and cholesteryl ester transfer protein. With cardiovascular disease being the single leading cause of death worldwide, the development of a safe and successful antiatherosclerosis strategy (possibly employing a combination of agents acting at various levels) will indeed be a major 21st-century achievement.

Identification and Characterization of Novel Catalytic Bioscavengers of Organophosphorus Nerve Agents

DTIC Science & Technology

2013-01-01

hydrolase activity . These strains are Ammoniphilus oxalaticus, Haloarcula sp., and Micromonospora aurantiaca. Lysates from A. oxalaticus had...warfare agents [1–3]. OP nerve agents readily bind covalently to the active site serine in acetylcho- linesterase (AChE), thereby inhibiting the ability...muscarinic receptors, whereas 2-pralidoxime chloride, an oxime nucleophile, reactivates AChE by displacing the phospho- nyl group left on the active site

Activity induced phase transition in mixtures of active and passive agents

NASA Astrophysics Data System (ADS)

Sinha Mahapatra, Pallab; Kulkarni, Ajinkya

2017-11-01

Collective behaviors of self-propelling agents are ubiquitous in nature that produces interesting patterns. The objective of this study is to investigate the phase transition in mixtures of active and inert agents suspended in a liquid. A modified version of the Vicsek Model has been used (see Ref.), where the particles are modeled as soft disks with finite mass, confined in a square domain. The particles are required to align their local motion to their immediate neighborhood, similar to the Vicsek model. We identified the transition from disorganized thermal-like motion to an organized vortical motion. We analyzed the nature of the transition by using different order parameters. Furthermore the switching between the phases has been investigated via artificial nucleation of randomly picked active agents spanning the entire domain. Finally the motivation for this phase transition has been explained via average dissipation and the mean square displacement (MSD) of the agents.

Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential.

PubMed

Gangjee, Aleem; Pavana, Roheeth Kumar; Ihnat, Michael A; Thorpe, Jessica E; Disch, Bryan C; Bastian, Anja; Bailey-Downs, Lora C; Hamel, Ernest; Bai, Rouli

2014-05-08

Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

Anticancer agents derived from natural cinnamic acids.

PubMed

Su, Ping; Shi, Yaling; Wang, Jinfeng; Shen, Xiuxiu; Zhang, Jie

2015-01-01

Cancer is the most dangerous disease that causes deaths all over the world. Natural products have afforded a rich source of drugs in a number of therapeutic fields including anticancer agents. Many significant drugs have been derived from natural sources by structural optimization of natural products. Cinnamic acid has gained great interest due to its antiproliferative, antioxidant, antiangiogenic and antitumorigenic potency. Currently it has been observed that cinnamic acid and its analogs such as caffeic acid, sinapic acid, ferulic acid, and isoferulic acid display various pharmacological activities, such as immunomodulation, anti-inflammation, anticancer and antioxidant. They have served to be the major sources of potential leading anticancer compounds. In this review, we focus on the anticancer potency of cinnamic acid derivatives and novel strategies to design these derivatives. We hope this review will be useful for researchers who are interested in developing anticancer agents.

Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions.

PubMed

Ocaña, Alberto; Amir, Eitan

2009-12-01

Aberrant activation of HER2 through overexpression has been shown to play an important role in some breast cancers. Therapies against this receptor including the monoclonal antibody, trastuzumab, or the small tyrosine kinase inhibitor, lapatinib have shown to improve the prognosis of such patients. Despite overexpressing HER2, some patients do not respond to these targeted treatments or progress after a short period of time. Irreversible tyrosine kinase inhibitors have been developed to bypass several pathways that could be involved in this resistance. In vitro, these agents have been shown to be more potent and to prolong target inhibition. Clinical development of these agents is ongoing and early results are promising. This review will describe the biologic rationale that justifies the development of these agents in breast cancer focusing on the current status and future directions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Zonghai; Amine, Khalil; Belharouak, Ilias

An active material for an electrochemical device wherein a surface of the active material is modified by a surface modification agent, wherein the surface modification agent is an organometallic compound.

Arsenic compounds as anticancer agents.

PubMed

Wang, Z Y

2001-08-01

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

PubMed Central

Drawz, Sarah M.; Papp-Wallace, Krisztina M.

2014-01-01

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria. PMID:24379206

Automating CapCom Using Mobile Agents and Robotic Assistants

NASA Technical Reports Server (NTRS)

Clancey, William J.; Sierhuis, Maarten; Alena, Richard L.; Graham, Jeffrey S.; Tyree, Kim S.; Hirsh, Robert L.; Garry, W. Brent; Semple, Abigail; Shum, Simon J. Buckingham; Shadbolt, Nigel;

What Sensing Tells Us: Towards a Formal Theory of Testing for Dynamical Systems

NASA Technical Reports Server (NTRS)

McIlraith, Sheila; Scherl, Richard

2005-01-01

Just as actions can have indirect effects on the state of the world, so too can sensing actions have indirect effects on an agent's state of knowledge. In this paper, we investigate "what sensing actions tell us", i.e., what an agent comes to know indirectly from the outcome of a sensing action, given knowledge of its actions and state constraints that hold in the world. To this end, we propose a formalization of the notion of testing within a dialect of the situation calculus that includes knowledge and sensing actions. Realizing this formalization requires addressing the ramification problem for sensing actions. We formalize simple tests as sensing actions. Complex tests are expressed in the logic programming language Golog. We examine what it means to perform a test, and how the outcome of a test affects an agent's state of knowledge. Finally, we propose automated reasoning techniques for test generation and complex-test verification, under certain restrictions. The work presented in this paper is relevant to a number of application domains including diagnostic problem solving, natural language understanding, plan recognition, and active vision.

In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents.

PubMed

Nakatsuka, Matthew A; Barback, Christopher V; Fitch, Kirsten R; Farwell, Alexander R; Esener, Sadik C; Mattrey, Robert F; Cha, Jennifer N; Goodwin, Andrew P

2013-12-01

The use of microbubbles as ultrasound contrast agents is one of the primary methods to diagnose deep venous thrombosis. However, current microbubble imaging strategies require either a clot sufficiently large to produce a circulation filling defect or a clot with sufficient vascularization to allow for targeted accumulation of contrast agents. Previously, we reported the design of a microbubble formulation that modulated its ability to generate ultrasound contrast from interaction with thrombin through incorporation of aptamer-containing DNA crosslinks in the encapsulating shell, enabling the measurement of a local chemical environment by changes in acoustic activity. However, this contrast agent lacked sufficient stability and lifetime in blood to be used as a diagnostic tool. Here we describe a PEG-stabilized, thrombin-activated microbubble (PSTA-MB) with sufficient stability to be used in vivo in circulation with no change in biomarker sensitivity. In the presence of actively clotting blood, PSTA-MBs showed a 5-fold increase in acoustic activity. Specificity for the presence of thrombin and stability under constant shear flow were demonstrated in a home-built in vitro model. Finally, PSTA-MBs were able to detect the presence of an active clot within the vena cava of a rabbit sufficiently small as to not be visible by current non-specific contrast agents. By activating in non-occlusive environments, these contrast agents will be able to detect clots not diagnosable by current contrast agents. Copyright © 2013 Elsevier Ltd. All rights reserved.

From Shards to Stained Glass: Crowdsourcing an E-Book

ERIC Educational Resources Information Center

Fontichiaro, Kristin

2012-01-01

In this article, the author discusses crowdsourcing an e-book--gathering wide, diverse opinions from the school library community (including academics, practitioners, vendors, and others), and gathering those results in a free e-book. As e-book publishers, school librarians could be active agents, bolstering community energy, creating a forum for…

Blast-induced Mild Traumatic Brain Injury

DTIC Science & Technology

2010-01-01

concentration with agents such as psychostimulants, or improving compensatory strategies through cognitive- behavioral therapies. Pharmacological interventions...participate in educational activities and support groups. Some examples of general educational content include (1) compensatory strategies for impaired...or simple, ranging from electronic transmitters to trip wires, tilt switches, motion detectors, or thermal or pressure-sensitive switches. lEOs are

Final Report-Rail Sensor Testbed Program: Active Agents in Containers for Transport Chain Security

DTIC Science & Technology

2011-03-21

information. These trust approaches have been applied to a variety of regimes, including virtual communities [14], email [15] and ecommerce [16...2004(http://www .arxiv.org/abs/cond-mat/0402143). 16. Melnik, M., Aim, J., Does a seller’s eCommerce reputation matter? evidence from eBay auctions

Low cost bioluminescence imaging as an alternative to in vivo bioassays for quantifying biologically active staphylococcal enterotoxin type E

USDA-ARS?s Scientific Manuscript database

Staphylococcus aureus is a major causative agent implicated in outbreaks of food poisoning, acting through the production of a range of toxins including staphylococcal enterotoxin type E (SEE). While tests such as enzyme-linked immunosorbent (ELISA) exist to detect the toxin molecules, existing meth...

9 CFR 121.17 - Records.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Records. 121.17 Section 121.17 Animals... AGENTS AND TOXINS § 121.17 Records. (a) An individual or entity required to register under this part must maintain complete records relating to the activities covered by this part. Such records must include: (1...

9 CFR 121.17 - Records.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Records. 121.17 Section 121.17 Animals... AGENTS AND TOXINS § 121.17 Records. (a) An individual or entity required to register under this part must maintain complete records relating to the activities covered by this part. Such records must include: (1...

9 CFR 121.17 - Records.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Records. 121.17 Section 121.17 Animals... AGENTS AND TOXINS § 121.17 Records. (a) An individual or entity required to register under this part must maintain complete records relating to the activities covered by this part. Such records must include: (1...

Protective effects of Aloe vera-based diets in Eimeria maxima-infected broiler chickens

USDA-ARS?s Scientific Manuscript database

Aloes have been widely used for a broad range of pharmacological activities, including parasitic problems. Avian coccidiosis is the most costly and wide-spread parasitic disease in the poultry industry, and has been mainly controlled by the use of chemotherapeutic agents. Due to the emergence of dru...

Biosecurity for animal facilities and associated laboratories.

PubMed

Richmond, Jonathan Y; Nesby-O'Dell, Shanna

2003-01-01

Although working with human pathogens and zoonotic agents has always carried a certain degree of danger, current events have resulted in an increased focus on the subject, including new regulations. The authors discuss a number of risk assessment and management activities that animal research facilities should use to evaluate strengthen their current programs.

Clinical presentation, diagnosis, and pharmacotherapy of patients with primary brain tumors.

PubMed

Newton, H B; Turowski, R C; Stroup, T J; McCoy, L K

1999-01-01

To briefly review the clinical presentation and diagnosis of patients with primary brain tumors, followed by an in-depth survey of the pertinent pharmacotherapy. A detailed search of the neurologic, neurosurgical, and oncologic literature for basic science research, clinical studies, and review articles related to chemotherapy and pharmacotherapy of primary brain tumors. Relevant studies on tissue culture systems, animals, and humans examining the mechanisms of action, pharmacokinetics, clinical pharmacology, and treatment results of chemotherapeutic agents for primary brain tumors. In addition, studies of pharmacologic agents administered for supportive care and symptom control are reviewed. Primary brain tumors derive from cells within the intracranial cavity and generally present with headache, seizure activity, cognitive changes, and weakness. They are diagnosed most efficiently with magnetic resonance imaging. After diagnosis, the most common supportive medications include corticosteroids, gastric acid inhibitors, and anticonvulsants. Chemotherapy is adjunctive treatment for patients with malignant tumors and selected recurrent or progressive benign neoplasms. In general, the most effective chemotherapeutic drugs are alkylating agents such as the nitrosoureas, procarbazine, cisplatin, and carboplatin. Other agents used include cyclophosphamide, methotrexate, vincristine, and etoposide. Angiogenesis inhibitors and gene therapy comprise some of the novel therapeutic strategies under investigation. The efficacy of chemotherapy for primary brain tumors remains modest. Novel agents must be discovered that are more specific and attack tumor cells at the molecular level of tumorigenesis. Furthermore, strategies must be developed to counteract the pervasive problem of brain tumor chemoresistance.

Role of Glutamate Release and Metabotropic Autoreceptors in Seizureogenic Actions of Cholinomimetic Agents

DTIC Science & Technology

2001-10-01

produced by centrally-active cholinomimetic agents and to evaluate possible palliative treatments for central cholinomimetic toxicity. The scope of...REPORT: 10/01/00-09/30/01 AWARD NUMBER: DAMD17-98-1-8617 evaluation of the effects by intracerebral infusion of the organophosphate agent paraoxon on EEG...agents. Previously, we had reported successful induction of seizure-like changes in EEG activity of anesthetized rats following intracerebral infusion

Animal Venom Peptides: Potential for New Antimicrobial Agents.

PubMed

Primon-Barros, Muriel; José Macedo, Alexandre

2017-01-01

Microbial infections affect people worldwide, causing diseases with significant impact on public health, indicating the need for research and development of new antimicrobial agents. Animal venoms represent a vast and largely unexploited source of biologically active molecules with attractive candidates for the development of novel therapeutics. Venoms consist of complex mixtures of molecules, including antimicrobial peptides (AMPs). Since the discovery of AMPs, they have been studied as promising new antimicrobial drugs. Amongst the remarkable sources of AMPs with known antimicrobial activities are ants, bees, centipedes, cone snails, scorpions, snakes, spiders, and wasps. The antimicrobial tests against bacteria, protozoans, fungi and viruses using 170 different peptides isolated directly from crude venoms or cDNA libraries of venom glands are listed and discussed in this review, as well as hemolytic ativity. The potential of venoms as source of new compounds, including AMPs, is extensively discussed. Currently, there are six FDA-approved drugs and many others are undergoing preclinical and clinical trials. The search for antimicrobial "weapons" makes the AMPs from venoms promising candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Designing novel cellulase systems through agent-based modeling and global sensitivity analysis.

PubMed

Apte, Advait A; Senger, Ryan S; Fong, Stephen S

2014-01-01

Experimental techniques allow engineering of biological systems to modify functionality; however, there still remains a need to develop tools to prioritize targets for modification. In this study, agent-based modeling (ABM) was used to build stochastic models of complexed and non-complexed cellulose hydrolysis, including enzymatic mechanisms for endoglucanase, exoglucanase, and β-glucosidase activity. Modeling results were consistent with experimental observations of higher efficiency in complexed systems than non-complexed systems and established relationships between specific cellulolytic mechanisms and overall efficiency. Global sensitivity analysis (GSA) of model results identified key parameters for improving overall cellulose hydrolysis efficiency including: (1) the cellulase half-life, (2) the exoglucanase activity, and (3) the cellulase composition. Overall, the following parameters were found to significantly influence cellulose consumption in a consolidated bioprocess (CBP): (1) the glucose uptake rate of the culture, (2) the bacterial cell concentration, and (3) the nature of the cellulase enzyme system (complexed or non-complexed). Broadly, these results demonstrate the utility of combining modeling and sensitivity analysis to identify key parameters and/or targets for experimental improvement.

Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

PubMed Central

Oláh, Attila; Tóth, Balázs I.; Borbíró, István; Sugawara, Koji; Szöllõsi, Attila G.; Czifra, Gabriella; Pál, Balázs; Ambrus, Lídia; Kloepper, Jennifer; Camera, Emanuela; Ludovici, Matteo; Picardo, Mauro; Voets, Thomas; Zouboulis, Christos C.; Paus, Ralf; Bíró, Tamás

2014-01-01

The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris. PMID:25061872

Levofloxacin for the treatment of community-acquired pneumonia.

PubMed

Lynch, Joseph P; File, Thomas M; Zhanel, George G

2006-10-01

New respiratory fluoroquinolones (FQs), such as levofloxacin, offer many improved qualities over older agents, such as ciprofloxacin. These include retaining excellent Gram-negative bacilli activity, with improved Gram-positive activity. New FQ-like levofloxacin possesses greater bioavailabilty and a longer serum half-life compared with ciprofloxacin, allowing for once-daily dosing, which may improve patient adherence. The high bioavailability of levofloxacin allows for rapid step-down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve patient quality of life. Levofloxacin has been evaluated for the treatment of community-acquired pneumonia (CAP) in numerous randomized clinical trials. Most published studies have used the 500 mg dose, although more recent studies have investigated the 750 mg dose once daily. These trials demonstrate that levofloxacin is effective and safe for the treatment of CAP, displaying relatively mild adverse effects that are more or less comparable with ciprofloxacin. Levofloxacin has much to offer in terms of bacterial eradication, including for resistant respiratory pathogens. However, ciprofloxacin-resistant organisms are becoming more prevalent so prudence must be exercised when prescribing this agent.

Designing novel cellulase systems through agent-based modeling and global sensitivity analysis

PubMed Central

Apte, Advait A; Senger, Ryan S; Fong, Stephen S

2014-01-01

Experimental techniques allow engineering of biological systems to modify functionality; however, there still remains a need to develop tools to prioritize targets for modification. In this study, agent-based modeling (ABM) was used to build stochastic models of complexed and non-complexed cellulose hydrolysis, including enzymatic mechanisms for endoglucanase, exoglucanase, and β-glucosidase activity. Modeling results were consistent with experimental observations of higher efficiency in complexed systems than non-complexed systems and established relationships between specific cellulolytic mechanisms and overall efficiency. Global sensitivity analysis (GSA) of model results identified key parameters for improving overall cellulose hydrolysis efficiency including: (1) the cellulase half-life, (2) the exoglucanase activity, and (3) the cellulase composition. Overall, the following parameters were found to significantly influence cellulose consumption in a consolidated bioprocess (CBP): (1) the glucose uptake rate of the culture, (2) the bacterial cell concentration, and (3) the nature of the cellulase enzyme system (complexed or non-complexed). Broadly, these results demonstrate the utility of combining modeling and sensitivity analysis to identify key parameters and/or targets for experimental improvement. PMID:24830736

Saffron as an antidote or a protective agent against natural or chemical toxicities.

PubMed

Razavi, Bibi Marjan; Hosseinzadeh, Hossein

2015-05-01

Saffron (Crocus sativus) is an extensively used food additive for its color and taste. Since ancient times this plant has been introduced as a marvelous medicine throughout the world. The wide spectrum of saffron pharmacological activities is related to its major constituents including crocin, crocetin and safranal. Based on several studies, saffron and its active ingredients have been used as an antioxidant, antiinflammatory and antinociceptive, antidepressant, antitussive, anticonvulsant, memory enhancer, hypotensive and anticancer. According to the literatures, saffron has remarkable therapeutic effects. The protective effects of saffron and its main constituents in different tissues including brain, heart, liver, kidney and lung have been reported against some toxic materials either natural or chemical toxins in animal studies.In this review article, we have summarized different in vitro and animal studies in scientific databases which investigate the antidotal and protective effects of saffron and its major components against natural toxins and chemical-induced toxicities. Due to the lake of human studies, further investigations are required to ascertain the efficacy of saffron as an antidote or a protective agent in human intoxication.

The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature.

PubMed

Moll, Jennifer L; Brown, Candace S

2011-04-01

The monoamine neurotransmitters serotonin, dopamine, and norepinephrine play an important role in many medical and psychological conditions, including sexual responsiveness and behavior. Pharmacological agents that modulate monoamines may help alleviate sexual dysfunction. To provide an overview of pharmacological agents that modulate monoamines and their use in the treatment of sexual dysfunction. EMBASE and PubMed search for articles published between 1950 and 2010 using key words "sexual dysfunction,"monoamines,"monoaminergic receptors," and "generic names for pharmacological agents." To assess the literature evaluating the efficacy of monoamine pharmacologic agents used in the treatment of sexual dysfunction. The literature primarily cites the use of monoaminergic agents to treat sexual side effects from serotonergic reuptake inhibitors (SSRIs), with bupropion, buspirone and ropinirole providing the most convincing evidence. Controlled trials have shown that bupropion improves overall sexual dysfunction, but not frequency of sexual activity in depressed and nondepressed patients. Nefazodone and apomorphine have been used to treat sexual dysfunction, but their use is limited by significant side effect and safety profiles. New research on pharmacologic agents with subtype selectivity at dopaminergic and serotonergic receptors and those that possess dual mechanisms of action are being investigated. There has been tremendous progress over the past 50 years in understanding the role of monoamines in sexual function and the effect of pharmacologic agents which stimulate or antagonize monoaminergic receptors on sexual dysfunction. Nevertheless, large, double-blind, placebo-controlled studies evaluating the efficacy of currently available agents in populations without comorbid disorders are limited, preventing adequate interpretation of data. Continued research on sexual function and specific receptor subtypes will result in the development of more selective pharmacologic agents with the goal of increasing efficacy without the dose-limiting side effects of nonselective agents. © 2011 International Society for Sexual Medicine.

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir.

PubMed

Cheng, Guofeng; Tian, Yang; Doehle, Brian; Peng, Betty; Corsa, Amoreena; Lee, Yu-Jen; Gong, Ruoyu; Yu, Mei; Han, Bin; Xu, Simin; Dvory-Sobol, Hadas; Perron, Michel; Xu, Yili; Mo, Hongmei; Pagratis, Nikos; Link, John O; Delaney, William

2016-01-11

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50 values equivalent to those for the wild type. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

PubMed Central

Tian, Yang; Doehle, Brian; Peng, Betty; Corsa, Amoreena; Lee, Yu-Jen; Gong, Ruoyu; Yu, Mei; Han, Bin; Xu, Simin; Dvory-Sobol, Hadas; Perron, Michel; Xu, Yili; Mo, Hongmei; Pagratis, Nikos; Link, John O.; Delaney, William

2016-01-01

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50 values equivalent to those for the wild type. PMID:26824950

Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents.

PubMed

Ooi, N; Eady, E A; Cove, J H; O'Neill, A J

2015-02-01

To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component. Antistaphylococcal activity was evaluated by broth microdilution and by time-kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin. All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25-128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4-256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

PubMed Central

Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

2015-01-01

Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID:26643333

Synthesis, anti-MRSA, and anti-VRE activity of hemin conjugates with amino acids and branched peptides.

PubMed

Okorochenkov, Sergei A; Zheltukhina, Galina A; Mirchink, Elena P; Isakova, Elena B; Feofanov, Alexey V; Nebolsin, Vladimir E

2013-10-01

The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides. Arginine-containing hemin conjugates demonstrated high antibacterial activity against Gram-positive bacteria including methicillin- and vancomycin-resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes. © 2013 John Wiley & Sons A/S.

Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm

PubMed Central

Hernandez-Delgadillo, Rene; Velasco-Arias, Donaji; Diaz, David; Arevalo-Niño, Katiushka; Garza-Enriquez, Marianela; De la Garza-Ramos, Myriam A; Cabral-Romero, Claudio

2012-01-01

Background and methods Despite continuous efforts, the increasing prevalence of resistance among pathogenic bacteria to common antibiotics has become one of the most significant concerns in modern medicine. Nanostructured materials are used in many fields, including biological sciences and medicine. While some bismuth derivatives has been used in medicine to treat vomiting, nausea, diarrhea, and stomach pain, the biocidal activity of zerovalent bismuth nanoparticles has not yet been studied. The objective of this investigation was to analyze the antimicrobial activity of bismuth nanoparticles against oral bacteria and their antibiofilm capabilities. Results Our results showed that stable colloidal bismuth nanoparticles had 69% antimicrobial activity against Streptococcus mutans growth and achieved complete inhibition of biofilm formation. These results are similar to those obtained with chlorhexidine, the most commonly used oral antiseptic agent. The minimal inhibitory concentration of bismuth nanoparticles that interfered with S. mutans growth was 0.5 mM. Conclusion These results suggest that zerovalent bismuth nanoparticles could be an interesting antimicrobial agent to be incorporated into an oral antiseptic preparation. PMID:22619547

Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities.

PubMed

Wang, Changhao; Carter-Cooper, Brandon; Du, Yixuan; Zhou, Jie; Saeed, Musabbir A; Liu, Jinbing; Guo, Min; Roembke, Benjamin; Mikek, Clinton; Lewis, Edwin A; Lapidus, Rena G; Sintim, Herman O

2016-08-08

G-quadruplex ligands have been touted as potential anticancer agents, however, none of the reported G-quadruplex-interactive small molecules have gone past phase II clinical trials. Recently it was revealed that diminazene (berenil, DMZ) actually binds to G-quadruplexes 1000 times better than DNA duplexes, with dissociation constants approaching 1 nM. DMZ however does not have strong anticancer activities. In this paper, using a panel of biophysical tools, including NMR, FRET melting assay and FRET competition assay, we discovered that monoamidine analogues of DMZ bearing alkyne substitutes selectively bind to G-quadruplexes. The lead DMZ analogues were shown to be able to target c-MYC G-quadruplex both in vitro and in vivo. Alkyne DMZ analogues display respectable anticancer activities (single digit micromolar GI50) against ovarian (OVCAR-3), prostate (PC-3) and triple negative breast (MDA-MB-231) cancer cell lines and represent interesting new leads to develop anticancer agents. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the “Supply Problem”

PubMed Central

Gomes, Nelson G. M.; Dasari, Ramesh; Chandra, Sunena; Kiss, Robert; Kornienko, Alexander

2016-01-01

Marine invertebrates provide a rich source of metabolites with anticancer activities and several marine-derived agents have been approved for the treatment of cancer. However, the limited supply of promising anticancer metabolites from their natural sources is a major hurdle to their preclinical and clinical development. Thus, the lack of a sustainable large-scale supply has been an important challenge facing chemists and biologists involved in marine-based drug discovery. In the current review we describe the main strategies aimed to overcome the supply problem. These include: marine invertebrate aquaculture, invertebrate and symbiont cell culture, culture-independent strategies, total chemical synthesis, semi-synthesis, and a number of hybrid strategies. We provide examples illustrating the application of these strategies for the supply of marine invertebrate-derived anticancer agents. Finally, we encourage the scientific community to develop scalable methods to obtain selected metabolites, which in the authors’ opinion should be pursued due to their most promising anticancer activities. PMID:27213412