Current levels of suppression of waterhyacinth in Florida by classical biological control agents

USDA-ARS?s Scientific Manuscript database

Waterhyacinth, Eichhornia crassipes, has been a global target for classical biological control efforts for decades. In Florida, herbicides are the primary tactic employed, usually without regard for the activities of the three biological control agents introduced intentionally during the 1970's, na...

Immunologic responses to therapeutic biologic agents.

PubMed

Purcell, R T; Lockey, R F

2008-01-01

Recombinant protein technology and the subsequent development of biologic agents for pharmacotherapy have greatly improved the treatment of a wide variety of diseases in humans. These products are subject to reactions not previously seen in other drug classes. Additionally, subtle alteration in the manufacture or administration of a biologic agent may cause reactions in subjects who previously tolerated it. This review highlights the unique immunologic reactions that are associated with the more commonly used biologic agents.

Climate warming increases biological control agent impact on a non-target species.

PubMed

Lu, Xinmin; Siemann, Evan; He, Minyan; Wei, Hui; Shao, Xu; Ding, Jianqing

2015-01-01

Climate change may shift interactions of invasive plants, herbivorous insects and native plants, potentially affecting biological control efficacy and non-target effects on native species. Here, we show how climate warming affects impacts of a multivoltine introduced biocontrol beetle on the non-target native plant Alternanthera sessilis in China. In field surveys across a latitudinal gradient covering their full distributions, we found beetle damage on A. sessilis increased with rising temperature and plant life history changed from perennial to annual. Experiments showed that elevated temperature changed plant life history and increased insect overwintering, damage and impacts on seedling recruitment. These results suggest that warming can shift phenologies, increase non-target effect magnitude and increase non-target effect occurrence by beetle range expansion to additional areas where A. sessilis occurs. This study highlights the importance of understanding how climate change affects species interactions for future biological control of invasive species and conservation of native species. © 2014 The Authors. Ecology Letters published by John Wiley & Sons Ltd and CNRS.

Cyprinid herpesvirus 3 as a potential biological control agent for carp (Cyprinus carpio) in Australia: susceptibility of non-target species.

PubMed

McColl, K A; Sunarto, A; Slater, J; Bell, K; Asmus, M; Fulton, W; Hall, K; Brown, P; Gilligan, D; Hoad, J; Williams, L M; Crane, M St J

2017-09-01

Carp (Cyprinus carpio L.) is a pest species in Australian waterways, and cyprinid herpesvirus 3 (CyHV-3) is being considered as a potential biological control (biocontrol) agent. An important consideration for any such agent is its target specificity. In this study, the susceptibility to CyHV-3 of a range of non-target species (NTS) was tested. The NTS were as follows: 13 native Australian, and one introduced, fish species; a lamprey species; a crustacean; two native amphibian species (tadpole and mature stages); two native reptilian species; chickens; and laboratory mice. Animals were exposed to 100-1000 times the approximate minimum amount of CyHV-3 required to cause disease in carp by intraperitoneal and/or bath challenge, and then examined clinically each day over the course of 28 days post-challenge. There were no clinical signs, mortalities or histological evidence consistent with a viral infection in a wide taxonomic range of NTS. Furthermore, there was no molecular evidence of infection with CyHV-3, and, in particular, all RT-PCRs for viral mRNA were negative. As a consequence, the results encourage further investigation of CyHV-3 as a potential biocontrol agent that is specific for carp. © 2016 John Wiley & Sons Ltd.

History of chemical and biological warfare agents.

PubMed

Szinicz, L

2005-10-30

Chemical and biological warfare agents constitute a low-probability, but high-impact risk both to the military and to the civilian population. The use of hazardous materials of chemical or biological origin as weapons and for homicide has been documented since ancient times. The first use of chemicals in terms of weapons of mass destruction goes back to World War I, when on April 22, 1915 large amounts of chlorine were released by German military forces at Ypres, Belgium. Until around the 1970s of the 20th century, the awareness of the threat by chemical and biological agents had been mainly confined to the military sector. In the following time, the development of increasing range delivery systems by chemical and biological agents possessors sensitised public attention to the threat emanating from these agents. Their proliferation to the terrorists field during the 1990s with the expanding scale and globalisation of terrorist attacks suggested that these agents are becoming an increasing threat to the whole world community. The following article gives a condensed overview on the history of use and development of the more prominent chemical and biological warfare agents.

Predicting the host range of Nystalea ebalea: secondary plant chemistry and host selection by a surrogate biological control agent of Schinus terebinthifolia

USDA-ARS?s Scientific Manuscript database

The safety of weed biological control depends upon the selection and utilization of the target weed by the agent while causing minimal harm to non-target species. Selection of weed species by biological control agents is determined by the presence of behavioral cues, generally host secondary plant c...

Networks of gold nanoparticles and bacteriophage as biological sensors and cell-targeting agents

PubMed Central

Souza, Glauco R.; Christianson, Dawn R.; Staquicini, Fernanda I.; Ozawa, Michael G.; Snyder, Evan Y.; Sidman, Richard L.; Miller, J. Houston; Arap, Wadih; Pasqualini, Renata

2006-01-01

Biological molecular assemblies are excellent models for the development of nanoengineered systems with desirable biomedical properties. Here we report an approach for fabrication of spontaneous, biologically active molecular networks consisting of bacteriophage (phage) directly assembled with gold (Au) nanoparticles (termed Au–phage). We show that when the phage are engineered so that each phage particle displays a peptide, such networks preserve the cell surface receptor binding and internalization attributes of the displayed peptide. The spontaneous organization of these targeted networks can be manipulated further by incorporation of imidazole (Au–phage–imid), which induces changes in fractal structure and near-infrared optical properties. The networks can be used as labels for enhanced fluorescence and dark-field microscopy, surface-enhanced Raman scattering detection, and near-infrared photon-to-heat conversion. Together, the physical and biological features within these targeted networks offer convenient multifunctional integration within a single entity with potential for nanotechnology-based biomedical applications. PMID:16434473

Biomaterials for mediation of chemical and biological warfare agents.

PubMed

Russell, Alan J; Berberich, Jason A; Drevon, Geraldine F; Koepsel, Richard R

2003-01-01

Recent events have emphasized the threat from chemical and biological warfare agents. Within the efforts to counter this threat, the biocatalytic destruction and sensing of chemical and biological weapons has become an important area of focus. The specificity and high catalytic rates of biological catalysts make them appropriate for decommissioning nerve agent stockpiles, counteracting nerve agent attacks, and remediation of organophosphate spills. A number of materials have been prepared containing enzymes for the destruction of and protection against organophosphate nerve agents and biological warfare agents. This review discusses the major chemical and biological warfare agents, decontamination methods, and biomaterials that have potential for the preparation of decontamination wipes, gas filters, column packings, protective wear, and self-decontaminating paints and coatings.

Trends in GPCR drug discovery: new agents, targets and indications.

PubMed

Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

2017-12-01

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

Multi-Agent Cooperative Target Search

PubMed Central

Hu, Jinwen; Xie, Lihua; Xu, Jun; Xu, Zhao

2014-01-01

This paper addresses a vision-based cooperative search for multiple mobile ground targets by a group of unmanned aerial vehicles (UAVs) with limited sensing and communication capabilities. The airborne camera on each UAV has a limited field of view and its target discriminability varies as a function of altitude. First, by dividing the whole surveillance region into cells, a probability map can be formed for each UAV indicating the probability of target existence within each cell. Then, we propose a distributed probability map updating model which includes the fusion of measurement information, information sharing among neighboring agents, information decay and transmission due to environmental changes such as the target movement. Furthermore, we formulate the target search problem as a multi-agent cooperative coverage control problem by optimizing the collective coverage area and the detection performance. The proposed map updating model and the cooperative control scheme are distributed, i.e., assuming that each agent only communicates with its neighbors within its communication range. Finally, the effectiveness of the proposed algorithms is illustrated by simulation. PMID:24865884

The development of targeted new agents to improve the outcome for children with leukemia.

PubMed

Bautista, Francisco; Van der Lugt, Jasper; Kearns, Pamela R; Mussai, Francis J; Zwaan, C Michel; Moreno, Lucas

2016-11-01

Survival rates in pediatric leukemia have greatly improved in the last decades but still a substantial number of patients will relapse and die. New agents are necessary to overcome the limitations of conventional chemotherapy and hematopoietic stem cell transplantation and to reduce their undesirable long-term toxicities. The identification of driving molecular alterations of leukemogenesis in subsets of patients will allow the incorporation of new-targeted therapies. Areas covered: In this article the authors present a detailed review of the most recent advances in targeted therapies for pediatric leukemias. A comprehensive description of the biological background, adult data and early clinical trials in pediatrics is provided. Expert opinion: Clinical trials are the way to evaluate new agents in pediatric cancer. The development of new drugs in pediatric leukemia must be preceded by a solid biological rationale. Agents in development exploit all possible vulnerabilities of leukemic cells. Drugs targeting cell surface antigens, intracellular signaling pathways and cell cycle inhibitors or epigenetic regulators are most prominent. Major advances have occurred thanks to new developments in engineering leading to optimized molecules such as anti-CD19 bi-specific T-cell engagers (e.g. blinatumomab) and antibody-drug conjugates. The integration of new-targeted therapies in pediatric chemotherapy-based regimens will lead to improved outcomes.

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

PubMed

Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pre-release biological control agent recommendations for swallow-wort (Vincetoxicum spp.) informed by demographic matrix models

USDA-ARS?s Scientific Manuscript database

Weed biological control workers have advocated for the advance assessment of agent efficacy in order to minimize the release of host-specific but ineffective agents. One method involves demographic matrix modeling of target weed populations in order to identify plant life stage transitions that cont...

The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease.

PubMed

Holleran, Grainne; Lopetuso, Loris; Petito, Valentina; Graziani, Cristina; Ianiro, Gianluca; McNamara, Deirdre; Gasbarrini, Antonio; Scaldaferri, Franco

2017-09-21

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date.

The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease

PubMed Central

Holleran, Grainne; Lopetuso, Loris; Petito, Valentina; Graziani, Cristina; Ianiro, Gianluca; McNamara, Deirdre; Gasbarrini, Antonio; Scaldaferri, Franco

2017-01-01

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date. PMID:28934123

Small mitochondria-targeting molecules as anti-cancer agents

PubMed Central

Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

2009-01-01

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

Combining Targeted Agents With Modern Radiotherapy in Soft Tissue Sarcomas

PubMed Central

Wong, Philip; Houghton, Peter; Kirsch, David G.; Finkelstein, Steven E.; Monjazeb, Arta M.; Xu-Welliver, Meng; Dicker, Adam P.; Ahmed, Mansoor; Vikram, Bhadrasain; Teicher, Beverly A.; Coleman, C. Norman; Machtay, Mitchell; Curran, Walter J.

2014-01-01

Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes. PMID:25326640

Indirect effects of host-specific biological control agents

Treesearch

Dean E. Pearson; Ragan M. Callaway

2003-01-01

Biological control is a crucial tool in the battle against biological invasions, but biocontrol agents can have a deleterious impact on native species. Recognition of risks associated with host shifting has increased the emphasis on host specificity of biocontrol agents for invasive weeds. However, recent studies indicate host-specific biocontrol agents can...

Biological agents for controlling excessive scarring.

PubMed

Berman, Brian

2010-01-01

The potential of various biological agents to reduce or prevent excessive scar formation has now been evaluated in numerous in-vitro studies, experimental animal models and preliminary clinical trials, in some cases with particularly promising results. Perhaps prominent among this group of biological agents, and, to some degree, possibly representing marketed compounds already being used 'off label' to manage excessive scarring, are the tumor necrosis factor alpha antagonist etanercept, and immune-response modifiers such as IFNalpha2b and imiquimod. Additional assessment of these novel agents is now justified with a view to reducing or preventing hypertrophic scars, keloid scars and the recurrence of post-excision keloid lesions.

Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents.

PubMed

Wilkes, Gail M

2018-01-01

Today, personalized cancer therapy with targeted agents has taken center stage, and offers individualized treatment to many. As the mysteries of the genes in a cell's DNA and their specific proteins are defined, advances in the understanding of cancer gene mutations and how cancer evades the immune system have been made. This article provides a basic and simplified understanding of the available (Food and Drug Administration- approved) molecularly and immunologically targeted agents in the USA. Other agents may be available in Asia, and throughout the USA and the world, many more agents are being studied. Nursing implications for drug classes are reviewed.

Isoindoline-1,3-dione derivatives targeting cholinesterases: design, synthesis and biological evaluation of potential anti-Alzheimer's agents.

PubMed

Guzior, Natalia; Bajda, Marek; Rakoczy, Jurand; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

2015-04-01

Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and β-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N-benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor (hAChE IC50=0.361μM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood-brain barrier indicated that the compound 3b would be able to cross the blood-brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer's agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Indirect nontarget effects of host-specific biological control agents: Implications for biological control

Treesearch

Dean E. Pearson; Ragan M. Callaway

2005-01-01

Classical biological control of weeds currently operates under the assumption that biological control agents are safe (i.e., low risk) if they do not directly attack nontarget species. However, recent studies indicate that even highly host-specific biological control agents can impact nontarget species through indirect effects. This finding has profound...

Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents

PubMed Central

Wilkes, Gail M.

2018-01-01

Today, personalized cancer therapy with targeted agents has taken center stage, and offers individualized treatment to many. As the mysteries of the genes in a cell's DNA and their specific proteins are defined, advances in the understanding of cancer gene mutations and how cancer evades the immune system have been made. This article provides a basic and simplified understanding of the available (Food and Drug Administration- approved) molecularly and immunologically targeted agents in the USA. Other agents may be available in Asia, and throughout the USA and the world, many more agents are being studied. Nursing implications for drug classes are reviewed. PMID:29607374

Ecological host-range of Lilioceris cheni (Coleoptera: Chrysomelidae), a biological control agent of Dioscorea bulbifera L.

USDA-ARS?s Scientific Manuscript database

Open-field host-specificity testing assesses the host-range of a biological control agent in a setting that permits the agent to use its full complement of host-seeking behaviors. This form of testing, particularly when it includes a no-choice phase in which the target weed is killed, may provide th...

DNA capture elements for rapid detection and identification of biological agents

NASA Astrophysics Data System (ADS)

Kiel, Johnathan L.; Parker, Jill E.; Holwitt, Eric A.; Vivekananda, Jeeva

2004-08-01

DNA capture elements (DCEs; aptamers) are artificial DNA sequences, from a random pool of sequences, selected for their specific binding to potential biological warfare agents. These sequences were selected by an affinity method using filters to which the target agent was attached and the DNA isolated and amplified by polymerase chain reaction (PCR) in an iterative, increasingly stringent, process. Reporter molecules were attached to the finished sequences. To date, we have made DCEs to Bacillus anthracis spores, Shiga toxin, Venezuelan Equine Encephalitis (VEE) virus, and Francisella tularensis. These DCEs have demonstrated specificity and sensitivity equal to or better than antibody.

Solid-water detoxifying reagents for chemical and biological agents

DOEpatents

Hoffman, Dennis M [Livermore, CA; Chiu, Ing Lap [Castro Valley, CA

2006-04-18

Formation of solid-water detoxifying reagents for chemical and biological agents. Solutions of detoxifying reagent for chemical and biological agents are coated using small quantities of hydrophobic nanoparticles by vigorous agitation or by aerosolization of the solution in the presence of the hydrophobic nanoparticles to form a solid powder. For example, when hydrophobic fumed silica particles are shaken in the presence of IN oxone solution in approximately a 95:5-weight ratio, a dry powder results. The hydrophobic silica forms a porous coating of insoluble fine particles around the solution. Since the chemical or biological agent tends to be hydrophobic on contact with the weakly encapsulated detoxifying solution, the porous coating breaks down and the detoxifying reagent is delivered directly to the chemical or biological agent for maximum concentration at the point of need. The solid-water (coated) detoxifying solutions can be blown into contaminated ventilation ducting or other difficult to reach sites for detoxification of pools of chemical or biological agent. Once the agent has been detoxified, it can be removed by flushing the area with air or other techniques.

Agent-based modelling in synthetic biology.

PubMed

Gorochowski, Thomas E

2016-11-30

Biological systems exhibit complex behaviours that emerge at many different levels of organization. These span the regulation of gene expression within single cells to the use of quorum sensing to co-ordinate the action of entire bacterial colonies. Synthetic biology aims to make the engineering of biology easier, offering an opportunity to control natural systems and develop new synthetic systems with useful prescribed behaviours. However, in many cases, it is not understood how individual cells should be programmed to ensure the emergence of a required collective behaviour. Agent-based modelling aims to tackle this problem, offering a framework in which to simulate such systems and explore cellular design rules. In this article, I review the use of agent-based models in synthetic biology, outline the available computational tools, and provide details on recently engineered biological systems that are amenable to this approach. I further highlight the challenges facing this methodology and some of the potential future directions. © 2016 The Author(s).

New biological agents in the treatment of multiple sclerosis.

PubMed

Buc, M

2018-01-01

Multiple sclerosis (MS) is an inflammatory disease induced by autoimmune processes. Their understanding has resulted in an introduction of biological agents to its treatment. Interferon beta and glatiramer acetate have been in clinical practice for more than 20 years. Nowadays, novel biologics, which target molecules involved in immunopathological processes more specifically have entered the scene. They are represented by monoclonal antibodies binding to molecules VLA4 (natalizumab), CD20 (ocrelizumab), CD52 (alemtuzumab) or alpha subunit of IL-2 receptor (daclizumab) or by small molecules such as those modulating the receptors involved in regulation of lymphocyte migration (fingolimod, ozanimod) or in induction of lymphopenia by apoptosis (dimethyl fumarate, cladribine). In the article, we shortly describe their efficacies, adverse reactions and perspectives of a future development in MS biologics. A treatment of neuromyelitis optica by monoclonal antibodies (rituximab, aquaporumab) is given too (Tab. 1, Fig. 2, Ref. 71).

Multi-Targeted Agents in Cancer Cell Chemosensitization: What We Learnt from Curcumin Thus Far.

PubMed

Bordoloi, Devivasha; Roy, Nand K; Monisha, Javadi; Padmavathi, Ganesan; Kunnumakkara, Ajaikumar B

2016-01-01

Research over the past several years has developed many mono-targeted therapies for the prevention and treatment of cancer, but it still remains one of the fatal diseases in the world killing 8.2 million people annually. It has been well-established that development of chemoresistance in cancer cells against mono-targeted chemotherapeutic agents by modulation of multiple survival pathways is the major cause of failure of cancer chemotherapy. Therefore, inhibition of these pathways by non-toxic multi-targeted agents may have profoundly high potential in preventing drug resistance and sensitizing cancer cells to chemotherapeutic agents. To study the potential of curcumin, a multi-targeted natural compound, obtained from the plant Turmeric (Curcuma longa) in combination with standard chemotherapeutic agents to inhibit drug resistance and sensitize cancer cells to these agents based on available literature and patents. An extensive literature survey was performed in PubMed and Google for the chemosensitizing potential of curcumin in different cancers published so far and the patents published during 2014-2015. Our search resulted in many in vitro, in vivo and clinical reports signifying the chemosensitizing potential of curcumin in diverse cancers. There were 160 in vitro studies, 62 in vivo studies and 5 clinical studies. Moreover, 11 studies reported on hybrid curcumin: the next generation of curcumin based therapeutics. Also, 34 patents on curcumin's biological activity have been retrieved. Altogether, the present study reveals the enormous potential of curcumin, a natural, non-toxic, multi-targeted agent in overcoming drug resistance in cancer cells and sensitizing them to chemotherapeutic drugs.

Vaccines against biologic agents: uses and developments.

PubMed

Ales, Noel C; Katial, Rohit K

2004-03-01

Although the Geneva protocol that prohibits the use of chemical and biologic weapons was ratified in 1925, many countries failed to accept this protocol: others stipulated retaliation, and some, like the United States, did not ratify the protocol for decades. This delay allowed the continued development of chemical and biologic agents. Members of the health care community are responsible for determining the best way to protect society from the potentially devastating effects of these biologic agents. Ideally,these diseases would be prevented from ever developing into systemic illnesses. In the past, vaccination has been a successful means of eradicating disease. Vaccines remain a hopeful therapy for the future, but time is short,and there are many obstacles.Information regarding bioterrorism agents and their treatments comes mainly from dated data or from in vitro or animal studies that may not apply to human treatment and disease. Additionally, the current threat of bioterrorism does not allow enough time for accurate, well-designed,controlled studies in humans before the release of investigational vaccines. Furthermore, some human studies would not be safe or ethical. Finally,many members of society suffer from illnesses that would put them at high risk to receive prophylactic vaccination. It is therefore naive to believe that vaccines would be the ultimate protection from these agents. In addition to vaccine development, there must be concurrent investigations into disease management and treatment. Even in instances in which vaccination is known to be an effective means of disease protection. biologic agents may be presented in a manner that renders vaccines ineffective. Virulent strains of organisms may be used, more than one organism may be used in tandem to increase virulence, and strains may be selected for antibiotic and vaccine resistance. Genetically engineered strains may use virulence factors other than those targeted in vaccines, and high

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.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

PubMed

Drgona, L; Gudiol, C; Lanini, S; Salzberger, B; Ippolito, G; Mikulska, M

2018-03-20

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All

A decontamination study of simulated chemical and biological agents

NASA Astrophysics Data System (ADS)

Uhm, Han S.; Lee, Han Y.; Hong, Yong C.; Shin, Dong H.; Park, Yun H.; Hong, Yi F.; Lee, Chong K.

2007-07-01

A comprehensive decontamination scheme of the chemical and biological agents, including airborne agents and surface contaminating agents, is presented. When a chemical and biological attack occurs, it is critical to decontaminate facilities or equipments to an acceptable level in a very short time. The plasma flame presented here may provide a rapid and effective elimination of toxic substances in the interior air in isolated spaces. As an example, a reaction chamber, with the dimensions of a 22cm diameter and 30cm length, purifies air with an airflow rate of 5000l/min contaminated with toluene, the simulated chemical agent, and soot from a diesel engine, the simulated aerosol for biological agents. Although the airborne agents in an isolated space are eliminated to an acceptable level by the plasma flame, the decontamination of the chemical and biological agents cannot be completed without cleaning surfaces of the facilities. A simulated sterilization study of micro-organisms was carried out using the electrolyzed ozone water. The electrolyzed ozone water very effectively kills endospores of Bacillus atrophaeus (ATCC 9372) within 3min. The electrolyzed ozone water also kills the vegetative micro-organisms, fungi, and virus. The electrolyzed ozone water, after the decontamination process, disintegrates into ordinary water and oxygen without any trace of harmful materials to the environment.

Aging Biology and Novel Targets for Drug Discovery

PubMed Central

McLachlan, Andrew J.; Quinn, Ronald J.; Simpson, Stephen J.; de Cabo, Rafael

2012-01-01

Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process. PMID:21693687

[Occupational exposure to biological agents intentionally used in Polish enterprises].

PubMed

Kozajda, Anna; Szadkowska-Stańczyk, Irena

2015-01-01

The paper presents the intentional use of biological agents for industrial, diagnostic and research purposes in Polish enterprises. The National Register of Biological Agents (Krajowy Rejestr Czynników Biologicznych - KRCB) is an online database that collects the data on the intentional use of biological agents at work in Poland. As of December 2013 there were 533 notifications in KRCB, mainly for diagnostic (73%), research (20%) and industrial purposes (7%). Mostly there were hospital diagnostic laboratories (37%), and other laboratories (35%), as well as higher education and research institutions (11%). In total, 4015 workers (91.7% of women, 8.3% of men) were exposed tobiological agents. Agents classified in risk group 2 were used in 518 enterprises, and in risk group 3 in 107 enterprises. Of those agents the following bacteria were the most frequently used: Escherichia coli except for non-pathogenic strains (455 enterprises and 3314 exposed workers); Staphylococcus aureus (445 and 3270); and Pseudomonas aeruginosa (406 and 2969, respectively). In 66 enterprises there were used biological agents recognized by the International Agency for Research on Cancer (IARC) as carcinogens. They are viruses: Epstein-Barr (7 enterprises, 181 exposed workers); hepatitis B (16 and 257); hepatitis C virus (15 and 243); human immunodefi- ciency virus (8 and 107); human papillomaviruses (2 and 4); parasites: Clonorchis viverrini (1 and 2 ); Clonorchos sinensis (1 and 2); Schistosoma haematobium (1 and 2) and bacteria Helicobacter pylori; (15 and 230, respectively). The National Register of Biological Agents at Work permits to evaluate the situation of occupational exposure to biological agents used intentionally in enterprises in Poland.

Molecular targeting agents in cancer therapy: science and society.

PubMed

Shaikh, Asim Jamal

2012-01-01

The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

Fiber-optic microsphere-based arrays for multiplexed biological warfare agent detection.

PubMed

Song, Linan; Ahn, Soohyoun; Walt, David R

2006-02-15

We report a multiplexed high-density DNA array capable of rapid, sensitive, and reliable identification of potential biological warfare agents. An optical fiber bundle containing 6000 individual 3.1-mum-diameter fibers was chemically etched to yield microwells and used as the substrate for the array. Eighteen different 50-mer single-stranded DNA probes were covalently attached to 3.1-mum microspheres. Probe sequences were designed for Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella melitensis, Clostridium botulinum, Vaccinia virus, and one biological warfare agent (BWA) simulant, Bacillus thuringiensis kurstaki. The microspheres were distributed into the microwells to form a randomized multiplexed high-density DNA array. A detection limit of 10 fM in a 50-microL sample volume was achieved within 30 min of hybridization for B. anthracis, Y. pestis, Vaccinia virus, and B. thuringiensis kurstaki. We used both specific responses of probes upon hybridization to complementary targets as well as response patterns of the multiplexed array to identify BWAs with high accuracy. We demonstrated the application of this multiplexed high-density DNA array for parallel identification of target BWAs in spiked sewage samples after PCR amplification. The array's miniaturized feature size, fabrication flexibility, reusability, and high reproducibility may enable this array platform to be integrated into a highly sensitive, specific, and reliable portable instrument for in situ BWA detection.

Manipulating biological agents and cells in micro-scale volumes for applications in medicine

PubMed Central

Tasoglu, Savas; Gurkan, Umut Atakan; Wang, ShuQi

2013-01-01

Recent technological advances provide new tools to manipulate cells and biological agents in micro/nano-liter volumes. With precise control over small volumes, the cell microenvironment and other biological agents can be bioengineered; interactions between cells and external stimuli can be monitored; and the fundamental mechanisms such as cancer metastasis and stem cell differentiation can be elucidated. Technological advances based on the principles of electrical, magnetic, chemical, optical, acoustic, and mechanical forces lead to novel applications in point-of-care diagnostics, regenerative medicine, in vitro drug testing, cryopreservation, and cell isolation/purification. In this review, we first focus on the underlying mechanisms of emerging examples for cell manipulation in small volumes targeting applications such as tissue engineering. Then, we illustrate how these mechanisms impact the aforementioned biomedical applications, discuss the associated challenges, and provide perspectives for further development. PMID:23575660

Biological agents and respiratory infections: Causative mechanisms and practice management.

PubMed

Takayanagi, Noboru

2015-09-01

Biological agents are increasingly being used to treat patients with immune-mediated inflammatory disease. In Japan, currently approved biological agents for patients with rheumatoid arthritis (RA) include tumor necrosis factor inhibitors, interleukin-6 receptor-blocking monoclonal antibody, and T-cell costimulation inhibitor. Rheumatologists have recognized that safety issues are critical aspects of treatment decisions in RA. Therefore, a wealth of safety data has been gathered from a number of sources, including randomized clinical trials and postmarketing data from large national registries. These data revealed that the most serious adverse events from these drugs are respiratory infections, especially pneumonia, tuberculosis, nontuberculous mycobacteriosis, and Pneumocystis jirovecii pneumonia, and that the most common risk factors associated with these respiratory infections are older age, concomitant corticosteroid use, and underlying respiratory comorbidities. Because of this background, in 2014, the Japanese Respiratory Society published their consensus statement of biological agents and respiratory disorders. This review summarizes this statement and adds recent evidence, especially concerning respiratory infections in RA patients, biological agents and respiratory infections, and practice management of respiratory infections in patients treated with biological agents. To decrease the incidence of infections and reduce mortality, we should know the epidemiology, risk factors, management, and methods of prevention of respiratory infections in patients receiving biological agents. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Agent-based models in translational systems biology

PubMed Central

An, Gary; Mi, Qi; Dutta-Moscato, Joyeeta; Vodovotz, Yoram

2013-01-01

Effective translational methodologies for knowledge representation are needed in order to make strides against the constellation of diseases that affect the world today. These diseases are defined by their mechanistic complexity, redundancy, and nonlinearity. Translational systems biology aims to harness the power of computational simulation to streamline drug/device design, simulate clinical trials, and eventually to predict the effects of drugs on individuals. The ability of agent-based modeling to encompass multiple scales of biological process as well as spatial considerations, coupled with an intuitive modeling paradigm, suggests that this modeling framework is well suited for translational systems biology. This review describes agent-based modeling and gives examples of its translational applications in the context of acute inflammation and wound healing. PMID:20835989

The acquisition of dangerous biological materials: Technical facts sheets to assist risk assessments of 46 potential BW agents

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

Aceto, Donato Gonzalo; Astuto-Gribble, Lisa M.; Gaudioso, Jennifer M.

Numerous terrorist organizations have openly expressed interest in producing and deploying biological weapons. However, a limiting factor for many terrorists has been the acquisition of dangerous biological agents, as evidenced by the very few successful instances of biological weapons use compared to the number of documented hoaxes. Biological agents vary greatly in their ability to cause loss of life and economic damage. Some agents, if released properly, can kill many people and cause an extensive number of secondary infections; other agents will sicken only a small number of people for a short period of time. Consequently, several biological agents canmore » potentially be used to perpetrate a bioterrorism attack but few are likely capable of causing a high consequence event. It is crucial, from a US national security perspective, to more deeply understand the likelihood that terrorist organizations can acquire the range of these agents. Few studies have attempted to comprehensively compile the technical information directly relevant to the acquisition of dangerous bacteria, viruses and toxins. In this report, technical fact sheets were assembled for 46 potentially dangerous biological agents. Much of the information was taken from various research sources which could ultimately and significantly expedite and improve bioterrorism threat assessments. By systematically examining a number of specific agent characteristics included in these fact sheets, it may be possible to detect, target, and implement measures to thwart future terrorist acquisition attempts. In addition, the information in these fact sheets may be used as a tool to help laboratories gain a rudimentary understanding of how attractive a method laboratory theft is relative to other potential acquisition modes.« less

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

PubMed Central

Zou, Huimin; Li, Ruixin; Hu, Hao; Hu, Yuanjia; Chen, Xin

2018-01-01

There is now compelling evidence that tumor necrosis factor (TNF)–TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity. PMID:29632537

Functionalized gold nanoparticle supported sensory mechanisms applied in detection of chemical and biological threat agents: a review.

PubMed

Upadhyayula, Venkata K K

2012-02-17

There is a great necessity for development of novel sensory concepts supportive of smart sensing capabilities in defense and homeland security applications for detection of chemical and biological threat agents. A smart sensor is a detection device that can exhibit important features such as speed, sensitivity, selectivity, portability, and more importantly, simplicity in identifying a target analyte. Emerging nanomaterial based sensors, particularly those developed by utilizing functionalized gold nanoparticles (GNPs) as a sensing component potentially offer many desirable features needed for threat agent detection. The sensitiveness of physical properties expressed by GNPs, e.g. color, surface plasmon resonance, electrical conductivity and binding affinity are significantly enhanced when they are subjected to functionalization with an appropriate metal, organic or biomolecular functional groups. This sensitive nature of functionalized GNPs can be potentially exploited in the design of threat agent detection devices with smart sensing capabilities. In the presence of a target analyte (i.e., a chemical or biological threat agent) a change proportional to concentration of the analyte is observed, which can be measured either by colorimetric, fluorimetric, electrochemical or spectroscopic means. This article provides a review of how functionally modified gold colloids are applied in the detection of a broad range of threat agents, including radioactive substances, explosive compounds, chemical warfare agents, biotoxins, and biothreat pathogens through any of the four sensory means mentioned previously. Copyright © 2011 Elsevier B.V. All rights reserved.

Advanced nanoelectronic architectures for THz-based biological agent detection

NASA Astrophysics Data System (ADS)

Woolard, Dwight L.; Jensen, James O.

2009-02-01

The U.S. Army Research Office (ARO) and the U.S. Army Edgewood Chemical Biological Center (ECBC) jointly lead and support novel research programs that are advancing the state-of-the-art in nanoelectronic engineering in application areas that have relevance to national defense and security. One fundamental research area that is presently being emphasized by ARO and ECBC is the exploratory investigation of new bio-molecular architectural concepts that can be used to achieve rapid, reagent-less detection and discrimination of biological warfare (BW) agents, through the control of multi-photon and multi-wavelength processes at the nanoscale. This paper will overview an ARO/ECBC led multidisciplinary research program presently under the support of the U.S. Defense Threat Reduction Agency (DTRA) that seeks to develop new devices and nanoelectronic architectures that are effective for extracting THz signatures from target bio-molecules. Here, emphasis will be placed on the new nanosensor concepts and THz/Optical measurement methodologies for spectral-based sequencing/identification of genetic molecules.

Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

NASA Astrophysics Data System (ADS)

Wang, Jinfeng; Zhang, Lin; Pan, Xiaoyan; Dai, Bingling; Sun, Ying; Li, Chuansheng; Zhang, Jie

2017-03-01

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.

Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

PubMed Central

Wang, Jinfeng; Zhang, Lin; Pan, Xiaoyan; Dai, Bingling; Sun, Ying; Li, Chuansheng; Zhang, Jie

2017-01-01

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis. PMID:28332573

'Petite' mutagenesis and mitotic crossing-over in yeast by DNA-targeted alkylating agents.

PubMed

Ferguson, L R; Turner, P M; Gourdie, T A; Valu, K K; Denny, W A

1989-12-01

Although the biological properties (cytotoxicity, mutagenicity and carcinogenicity) of alkylating agents result from their bonding interactions with DNA, such compounds generally do not show any special binding affinity for DNA. A series of acridine-linked aniline mustards of widely-varying alkylator reactivity have been designed as DNA-directed alkylating agents. We have considered whether such DNA targeting has an effect on mutagenic properties by evaluating this series of drugs in comparison with their untargeted counterparts for toxic, recombinogenic and mutagenic properties in Saccharomyces cerevisiae strain D5. The simple untargeted aniline mustards are effective inducers of mitotic crossing-over in this strain, but resemble other reported alkylators in being rather inefficient inducers of the "petite" or mitochondrial mutation in yeast. However, the majority of the DNA-targeted mustards were very efficient petite mutagens, while showing little evidence of mitotic crossing-over or other nuclear events. The 100% conversion of cells into petites and the lack of a differential between growing and non-growing cells are similar to the effects of the well characterised mitochondrial mutagen ethidium bromide. These data suggest very different modes of action between the DNA-targeted alkylators and their non-targeted counterparts.

Bacteriophage lambda: The path from biology to theranostic agent.

PubMed

Catalano, Carlos E

2018-03-13

Viral particles provide an attractive platform for the engineering of semisynthetic therapeutic nanoparticles. They can be modified both genetically and chemically in a defined manner to alter their surface characteristics, for targeting specific cell types, to improve their pharmacokinetic features and to attenuate (or enhance) their antigenicity. These advantages derive from a detailed understanding of virus biology, gleaned from decades of fundamental genetic, biochemical, and structural studies that have provided mechanistic insight into virus assembly pathways. In particular, bacteriophages offer significant advantages as nanoparticle platforms and several have been adapted toward the design and engineering of "designer" nanoparticles for therapeutic and diagnostic (theranostic) applications. The present review focuses on one such virus, bacteriophage lambda; I discuss the biology of lambda, the tools developed to faithfully recapitulate the lambda assembly reactions in vitro and the observations that have led to cooptation of the lambda system for nanoparticle design. This discussion illustrates how a fundamental understanding of virus assembly has allowed the rational design and construction of semisynthetic nanoparticles as potential theranostic agents and illustrates the concept of benchtop to bedside translational research. This article is categorized under: Biology-Inspired Nanomaterials> Protein and Virus-Based Structures Biology-Inspired Nanomaterials> Nucleic Acid-Based Structures. © 2018 Wiley Periodicals, Inc.

Chemical biology based on target-selective degradation of proteins and carbohydrates using light-activatable organic molecules.

PubMed

Toshima, Kazunobu

2013-05-01

Proteins and carbohydrates play crucial roles in a wide range of biological processes, including serious diseases. The development of novel and innovative methods for selective control of specific proteins and carbohydrates functions has attracted much attention in the field of chemical biology. In this account article, the development of novel chemical tools, which can degrade target proteins and carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced. This novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of proteins and carbohydrates but also novel therapeutic drugs targeting proteins and carbohydrates.

Chromatographic immunoassays: strategies and recent developments in the analysis of drugs and biological agents

PubMed Central

Matsuda, Ryan; Rodriguez, Elliott; Suresh, Doddavenkatanna; Hage, David S

2015-01-01

A chromatographic immunoassay is a technique in which an antibody or antibody-related agent is used as part of a chromatographic system for the isolation or measurement of a specific target. Various binding agents, detection methods, supports and assay formats have been developed for this group of methods, and applications have been reported that range from drugs, hormones and herbicides to peptides, proteins and bacteria. This review discusses the general principles and applications of chromatographic immunoassays, with an emphasis being given to methods and formats that have been developed for the analysis of drugs and biological agents. The relative advantages or limitations of each format are discussed. Recent developments and research in this field, as well as possible future directions, are also considered. PMID:26571109

Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety.

PubMed

Al-Mayouf, Sulaiman M; Alenazi, Abdullatif; AlJasser, Hind

2016-06-01

To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25-14) years and mean therapy duration was 14.7 (3-88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Detection of biological warfare agents using ultra violet-laser induced fluorescence LIDAR

NASA Astrophysics Data System (ADS)

Joshi, Deepti; Kumar, Deepak; Maini, Anil K.; Sharma, Ramesh C.

This review has been written to highlight the threat of biological warfare agents, their types and detection. Bacterial biological agent Bacillus anthracis (bacteria causing the disease anthrax) which is most likely to be employed in biological warfare is being discussed in detail. Standoff detection of biological warfare agents in aerosol form using Ultra violet-Laser Induced Fluorescence (UV-LIF) spectroscopy method has been studied. Range-resolved detection and identification of biological aerosols by both nano-second and non-linear femto-second LIDAR is also discussed. Calculated received fluorescence signal for a cloud of typical biological agent Bacillus globigii (Simulants of B. anthracis) at a location of ˜5.0 km at different concentrations in presence of solar background radiation has been described. Overview of current research efforts in internationally available working UV-LIF LIDAR systems are also mentioned briefly.

Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammatory Conditions.

PubMed

Frieder, Jillian; Kivelevitch, Dario; Haugh, Isabel; Watson, Ian; Menter, Alan

2018-01-01

Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-IL-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn's disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here we review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-IL-23 and anti-IL-17 biologic agents in psoriasis and other immune-mediated diseases. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Opportunities for improving risk communication during the permitting process for entomophagous biological control agents: A review of current systems

USDA-ARS?s Scientific Manuscript database

Concerns about potentially irreversible non-target impacts from the importation and release of entomophagous biological control agents (BCAs) have resulted in increasingly stringent import requirements by National Plant Protection Organizations. Despite numerous scientific publications on the poten...

Biological and targeted therapies of systemic lupus erythematosus: evidence and the state of the art.

PubMed

Mok, Chi Chiu

2017-07-01

Systemic lupus erythematosus (SLE) is a multi-systemic disease characterized by an unpredictable disease course and periods of remission and flare, leading to organ damage and mortality. Novel biological agents are being developed (targeting the lymphocytes, accessory molecules and cytokines) that aim to enhance the therapeutic efficacy when combined with standard therapies. Areas covered: This article updates recent data on the use of biological and targeted therapies in SLE. Expert commentary: B cells remain the main target of development of novel therapeutics in SLE. Similar to the intravenous preparation, subcutaneous belimumab has been shown to be superior to placebo when added to the standard of care in SLE. However, two phase III trials of epratuzumab and blisibimod did not meet their primary endpoints. Recent data on the inhibition of type I interferons (anifrolumab) appear promising. Newer calcineurin inhibitors and combination strategies using conventional immunosuppressive agents are being tested in lupus nephritis. Finally, international groups are developing consensus definitions on disease remission and low disease activity state to explore the benefits of the treat-to-target strategy in SLE. Hopefully, the armamentarium for the treatment of SLE can be expanded in the near future, so that the longevity and quality of life of patients can be further improved.

Detection of biological warfare agents using ultra violet-laser induced fluorescence LIDAR.

PubMed

Joshi, Deepti; Kumar, Deepak; Maini, Anil K; Sharma, Ramesh C

2013-08-01

This review has been written to highlight the threat of biological warfare agents, their types and detection. Bacterial biological agent Bacillus anthracis (bacteria causing the disease anthrax) which is most likely to be employed in biological warfare is being discussed in detail. Standoff detection of biological warfare agents in aerosol form using Ultra violet-Laser Induced Fluorescence (UV-LIF) spectroscopy method has been studied. Range-resolved detection and identification of biological aerosols by both nano-second and non-linear femto-second LIDAR is also discussed. Calculated received fluorescence signal for a cloud of typical biological agent Bacillus globigii (Simulants of B. anthracis) at a location of ~5.0 km at different concentrations in presence of solar background radiation has been described. Overview of current research efforts in internationally available working UV-LIF LIDAR systems are also mentioned briefly. Copyright © 2013 Elsevier B.V. All rights reserved.

Oxidative decontamination of chemical and biological warfare agents using L-Gel.

PubMed

Raber, Ellen; McGuire, Raymond

2002-08-05

A decontamination method has been developed using a single reagent that is effective both against chemical warfare (CW) and biological warfare (BW) agents. The new reagent, "L-Gel", consists of an aqueous solution of a mild commercial oxidizer, Oxone, together with a commercial fumed silica gelling agent, Cab-O-Sil EH-5. L-Gel is non-toxic, environmentally friendly, relatively non-corrosive, maximizes contact time because of its thixotropic nature, clings to walls and ceilings, and does not harm carpets or painted surfaces. The new reagent also addresses the most demanding requirements for decontamination in the civilian sector, including availability, low maintenance, ease of application and deployment by a variety of dispersal mechanisms, minimal training and acceptable expense. Experiments to test the effectiveness of L-Gel were conducted at Lawrence Livermore National Laboratory and independently at four other locations. L-Gel was tested against all classes of chemical warfare agents and against various biological warfare agent surrogates, including spore-forming bacteria and non-virulent strains of real biological agents. Testing showed that L-Gel is as effective against chemical agents and biological materials, including spores, as the best military decontaminants.

Agents in bioinformatics, computational and systems biology.

PubMed

Merelli, Emanuela; Armano, Giuliano; Cannata, Nicola; Corradini, Flavio; d'Inverno, Mark; Doms, Andreas; Lord, Phillip; Martin, Andrew; Milanesi, Luciano; Möller, Steffen; Schroeder, Michael; Luck, Michael

2007-01-01

The adoption of agent technologies and multi-agent systems constitutes an emerging area in bioinformatics. In this article, we report on the activity of the Working Group on Agents in Bioinformatics (BIOAGENTS) founded during the first AgentLink III Technical Forum meeting on the 2nd of July, 2004, in Rome. The meeting provided an opportunity for seeding collaborations between the agent and bioinformatics communities to develop a different (agent-based) approach of computational frameworks both for data analysis and management in bioinformatics and for systems modelling and simulation in computational and systems biology. The collaborations gave rise to applications and integrated tools that we summarize and discuss in context of the state of the art in this area. We investigate on future challenges and argue that the field should still be explored from many perspectives ranging from bio-conceptual languages for agent-based simulation, to the definition of bio-ontology-based declarative languages to be used by information agents, and to the adoption of agents for computational grids.

Curcumin: a promising agent targeting cancer stem cells.

PubMed

Zang, Shufei; Liu, Tao; Shi, Junping; Qiao, Liang

2014-01-01

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.

Decontamination of biological warfare agents by a microwave plasma torch

NASA Astrophysics Data System (ADS)

Lai, Wilson; Lai, Henry; Kuo, Spencer P.; Tarasenko, Olga; Levon, Kalle

2005-02-01

A portable arc-seeded microwave plasma torch running stably with airflow is described and applied for the decontamination of biological warfare agents. Emission spectroscopy of the plasma torch indicated that this torch produced an abundance of reactive atomic oxygen that could effectively oxidize biological agents. Bacillus cereus was chosen as a simulant of Bacillus anthracis spores for biological agent in the decontamination experiments. Decontamination was performed with the airflow rate of 0.393l/s, corresponding to a maximum concentration of atomic oxygen produced by the torch. The experimental results showed that all spores were killed in less than 8 s at 3 cm distance, 12 s at 4 cm distance, and 16 s at 5 cm distance away from the nozzle of the torch.

Trifluoromethyl-Substituted Iridium(III) Complexes: From Photophysics to Photooxidation of a Biological Target.

PubMed

Bevernaegie, Robin; Marcélis, Lionel; Laramée-Milette, Baptiste; De Winter, Julien; Robeyns, Koen; Gerbaux, Pascal; Hanan, Garry S; Elias, Benjamin

2018-02-05

Photodynamic therapeutic agents are of key interest in developing new strategies to develop more specific and efficient anticancer treatments. In comparison to classical chemotherapeutic agents, the activity of photodynamic therapeutic compounds can be finely controlled thanks to the light triggering of their photoreactivity. The development of type I photosensitizing agents, which do not rely on the production of ROS, is highly desirable. In this context, we developed new iridium(III) complexes which are able to photoreact with biomolecules; namely, our Ir(III) complexes can oxidize guanine residues under visible light irradiation. We report the synthesis and extensive photophysical characterization of four new Ir(III) complexes, [Ir(ppyCF 3 ) 2 (N^N)] + [ppyCF 3 = 2-(3,5-bis(trifluoromethyl)phenyl)pyridine) and N^N = 2,2'-dipyridyl (bpy); 2-(pyridin-2-yl)pyrazine (pzpy); 2,2'-bipyrazine (bpz); 1,4,5,8-tetraazaphenanthrene (TAP)]. In addition to an extensive experimental and theoretical study of the photophysics of these complexes, we characterize their photoreactivity toward model redox-active targets and the relevant biological target, the guanine base. We demonstrate that photoinduced electron transfer takes place between the excited Ir(III) complex and guanine which leads to the formation of stable photoproducts, indicating that the targeted guanine is irreversibly damaged. These results pave the way to the elaboration of new type I photosensitizers for targeting cancerous cells.

Introduction to economic modeling for clinical rheumatologists: application to biologic agents in rheumatoid arthritis.

PubMed

Marra, Carlo A; Bansback, Nick; Anis, Aslam H; Shojania, Kamran

2011-03-01

Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory, progressive musculoskeletal disease that affects 0.5-1.0% of the adult population in Western countries. The joint destruction and progressive functional disability associated with uncontrolled RA result in tremendous impacts on health-related quality of life, ability to work, and mortality. In addition, the treatment of the disease and associated complications exact a substantial economic burden to the patients, their families, and society. In the last decade, several biological agents (biologics) have been approved for use in RA, revolutionizing treatment. These biologics, which target cytokines such as tumor necrosis factor or lymphocytes such as B or T cells, reduce functional disability and substantially slow the progression of joint damage. However, because these agents typically cost ten to 100 times more than existing available older drug therapies, there has been worldwide concern regarding their impact on healthcare budgets. As such, there has been increased attention towards economic evaluation as a means to determine whether, and in which subgroup of patients, these newer, more expensive agents confer appropriate value for their additional cost. Indeed, evaluations have guided coverage decisions for both private and public health insurance agencies such as the National Institute for Health and Clinical Excellence in the UK. The use of economic evaluations to determine value for money for these agents has attracted both debate and controversy. Some of the controversy is related to the appropriateness of the structure of, and assumptions underlying, the decision models employed to estimate the long-term costs and benefits of these agents over existing therapies. To fully appreciate the debate, one must first understand the basic principles of economic evaluation and the necessity for using decision models to evaluate cost effectiveness. To understand the basic principles of economic

Agent Collaborative Target Localization and Classification in Wireless Sensor Networks

PubMed Central

Wang, Xue; Bi, Dao-wei; Ding, Liang; Wang, Sheng

2007-01-01

Wireless sensor networks (WSNs) are autonomous networks that have been frequently deployed to collaboratively perform target localization and classification tasks. Their autonomous and collaborative features resemble the characteristics of agents. Such similarities inspire the development of heterogeneous agent architecture for WSN in this paper. The proposed agent architecture views WSN as multi-agent systems and mobile agents are employed to reduce in-network communication. According to the architecture, an energy based acoustic localization algorithm is proposed. In localization, estimate of target location is obtained by steepest descent search. The search algorithm adapts to measurement environments by dynamically adjusting its termination condition. With the agent architecture, target classification is accomplished by distributed support vector machine (SVM). Mobile agents are employed for feature extraction and distributed SVM learning to reduce communication load. Desirable learning performance is guaranteed by combining support vectors and convex hull vectors. Fusion algorithms are designed to merge SVM classification decisions made from various modalities. Real world experiments with MICAz sensor nodes are conducted for vehicle localization and classification. Experimental results show the proposed agent architecture remarkably facilitates WSN designs and algorithm implementation. The localization and classification algorithms also prove to be accurate and energy efficient.

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

[Preparation and preliminary evaluation of KGDS-targeted ultrasound contrast agent].

PubMed

Gao, Feng; Ding, Yanfei; Sheng, Xiaoxi; Wang, Wei; Liang, Qi; Luo, Zhuoqiong; Zhou, Ping; Li, Hui

2009-12-01

To prepare a thrombus-targeted ultrasonic contrast agent and to investigate its targeted ability to fresh blood clots. We first synthesized FITC-KGDS-Palm compound, and then prepared thrombus-targeted microbubbles using "ultrasound & high speed shearing method". Fluorescence labeling thrombus-specific peptides and KGDS, directed at the activated glycoprotein(GP)IIb/IIIa receptor of platelets were attached to the surface of lipid microbubbles. The concentration and size of TUCA were measured by Malvern Zeta Sizer Nano-ZS590 and Coulter counter. Immunofluorescence was applied to confirm the conjugation. The conjunct ratio was assessed by flow cytometer (FCM). The KGDS-TUCA was straw yellow turbid liquor, and the concentration was 1.5 x 10(9)/mL, and the average size was 1.5 microm. The targeted microbubbles conjugated with the thrombus-specific peptides showed bright green rings by fluorescence microscope. FCM demonstrated that the wavelength of shell of KGDS-TUCA changed greatly, and the conjunct ratio was 90.04%. In vitro study showed KGDS-TUCA remained stable for 48 h at 4 degree C and target-attached to blood clots and showed good stability. The ultrasound & high speed shearing method to prepare TUCA is easy and in favor of purification. KGDS-TUCA has high specific biological activity. The conjunct ratio and stability of KGDS-TUCA are excellent.

Technological advancements for the detection of and protection against biological and chemical warfare agents.

PubMed

Eubanks, Lisa M; Dickerson, Tobin J; Janda, Kim D

2007-03-01

There is a growing need for technological advancements to combat agents of chemical and biological warfare, particularly in the context of the deliberate use of a chemical and/or biological warfare agent by a terrorist organization. In this tutorial review, we describe methods that have been developed both for the specific detection of biological and chemical warfare agents in a field setting, as well as potential therapeutic approaches for treating exposure to these toxic species. In particular, nerve agents are described as a typical chemical warfare agent, and the two potent biothreat agents, anthrax and botulinum neurotoxin, are used as illustrative examples of potent weapons for which countermeasures are urgently needed.

Agroterrorism, Biological Crimes, and Biological Warfare Targeting Animal Agriculture

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

Wilson, Terry M.; Logan-Henfrey, Linda; Weller, Richard E.

2000-04-12

There is a rising level of concern that agriculture might be targeted for economic sabotage by terrorists. Knowledge gathered about the Soviet Union biological weapons program and Iraq following the Gulf War, confirmed that animals and agricultural crops were targets of bioweapon development. These revelations are particularly disturbing in light of the fact that both countries are States Parties to the Biological and Toxin Weapons Convention that entered into force in 1975. The potential for misusing biotechnology to create more virulent pathogens and the lack of international means to detect unethical uses of new technologies to create destructive bioweapons ismore » of increasing concern. Disease outbreaks, whether naturally occurring or intentionally, involving agricultural pathogens that destroy livestock and crops would have a profound impact on a country's infrastructure, economy and export markets. This chapter deals with the history of agroterrorism, biological crimes and biological warfare directed toward animal agriculture, specifically, horses, cattle, swine, sheep, goats, and poultry.« less

Impact of Release Rates on the Effectiveness of Augmentative Biological Control Agents

PubMed Central

Crowder, David W.

2007-01-01

To access the effect of augmentative biological control agents, 31 articles were reviewed that investigated the impact of release rates of 35 augmentative biological control agents on the control of 42 arthropod pests. In 64% of the cases, the release rate of the biological control agent did not significantly affect the density or mortality of the pest insect. Results where similar when parasitoidsor predators were utilized as the natural enemy. Within any order of natural enemy, there were more cases where release rates did not affect augmentative biological control than cases where release rates were significant. There were more cases in which release rates did not affect augmentative biological control when pests were from the orders Hemiptera, Acari, or Diptera, but not with pests from the order Lepidoptera. In most cases, there was an optimal release rate that produced effective control of a pest species. This was especially true when predators were used as a biological control agent. Increasing the release rate above the optimal rate did not improve control of the pest and thus would be economically detrimental. Lower release rates were of ten optimal when biological control was used in conjunction with insecticides. In many cases, the timing and method of biological control applications were more significant factors impacting the effectiveness of biological control than the release rate. Additional factors that may limit the relative impact of release rates include natural enemy fecundity, establishment rates, prey availability, dispersal, and cannibalism. PMID:20307240

The multicolored Asian lady beetle, Harmonia axyridis: A review of its biology, uses in biological control, and non-target impacts

PubMed Central

Koch, R L

2003-01-01

Throughout the last century, the multicolored Asian lady beetle, Harmonia axyridis (Pallas) has been studied quite extensively, with topics ranging from genetics and evolution to population dynamics and applied biological control being covered. Much of the early work on H. axyridis was conducted in the native Asian range. From the 1980's to the present, numerous European and North American studies have added to the body of literature on H. axyridis. H. axyridis has recently gained attention in North America both as a biological control agent and as a pest. This literature review was compiled for two reasons. First, to assist other researchers as a reference, summarizing most of the voluminous body of literature on H. axyridis pertaining to its biology, life history, uses in biological control, and potential non-target impacts. Secondly, to be a case study on the impacts of an exotic generalist predator. PMID:15841248

Finding off-targets, biological pathways, and target diseases for chymase inhibitors via structure-based systems biology approach.

PubMed

Arooj, Mahreen; Sakkiah, Sugunadevi; Cao, Guang Ping; Kim, Songmi; Arulalapperumal, Venkatesh; Lee, Keun Woo

2015-07-01

Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors. © 2014 Wiley Periodicals, Inc.

Biological Select Agents and Toxins: Risk-Based Assessment Management and Oversight.

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

Burnett, LouAnn Crawford; Brodsky, Benjamin H.

Sandia National Laboratories' International Biological and Chemical Threat Reduction (SNL/IBCTR) conducted, on behalf of the Federal Select Agent Program (FSAP), a review of risk assessment in modern select agent laboratories. This review and analysis consisted of literature review, interviews of FSAP staff, entities regulated by FSAP, and deliberations of an expert panel. Additionally, SNL/IBCTR reviewed oversight mechanisms used by industries, US agencies, and other countries for high-consequence risks (e.g, nuclear, chemical, or biological materials, aviation, off-shore drilling, etc.) to determine if alternate oversight mechanisms existed that might be applicable to FSAP oversight of biological select agents and toxins. This reportmore » contains five findings, based on these reviews and analyses, with recommendations and suggested actions for FSAP to consider.« less

Targeting targeted agents: open issues for clinical trial design.

PubMed

Bria, Emilio; Di Maio, Massimo; Carlini, Paolo; Cuppone, Federica; Giannarelli, Diana; Cognetti, Francesco; Milella, Michele

2009-05-22

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

Oxidizer gels for detoxification of chemical and biological agents

DOEpatents

Hoffman, Dennis M.; McGuire, Raymond R.

2002-01-01

A gel composition containing oxidizing agents and thickening or gelling agents is used to detoxify chemical and biological agents by application directly to a contaminated area. The gelling agent is a colloidal material, such as silica, alumina, or alumino-silicate clays, which forms a viscous gel that does not flow when applied to tilted or contoured surfaces. Aqueous or organic solutions of oxidizing agents can be readily gelled with less than about 30% colloidal material. Gel preparation is simple and suitable for field implementation, as the gels can be prepared at the site of decontamination and applied quickly and uniformly over an area by a sprayer. After decontamination, the residue can be washed away or vacuumed up for disposal.

Biological agents with potential for misuse: a historical perspective and defensive measures.

PubMed

Bhalla, Deepak K; Warheit, David B

2004-08-15

Biological and chemical agents capable of producing serious illness or mortality have been used in biowarfare from ancient times. Use of these agents has progressed from crude forms in early and middle ages, when snakes and infected cadavers were used as weapons in battles, to sophisticated preparations for use during and after the second World War. Cults and terrorist organizations have attempted the use of biological agents with an aim to immobilize populations or cause serious harm. The reasons for interest in these agents by individuals and organizations include relative ease of acquisition, potential for causing mass casualty or panic, modest financing requirement, availability of technology, and relative ease of delivery. The Centers for Disease Control and Prevention has classified Critical Biological Agents into three major categories. This classification was based on several criteria, which include severity of impact on human health, potential for delivery in a weapon, capacity to cause panic and special needs for development, and stockpiling of medication. Agents that could cause the greatest harm following deliberate use were placed in category A. Category B included agents capable of producing serious harm and significant mortality but of lower magnitude than category A agents. Category C included emerging pathogens that could be developed for mass dispersion in future and their potential as a major health threat. A brief description of the category A bioagents is included and the pathophysiology of two particularly prominent agents, namely anthrax and smallpox, is discussed in detail. The potential danger from biological agents and their ever increasing threat to human populations have created a need for developing technologies for their early detection, for developing treatment strategies, and for refinement of procedures to ensure survival of affected individuals so as to attain the ultimate goal of eliminating the threat from intentional use of

Biology of Leptoypha hospita (Hemiptera: Tingidae), a Potential Biological Control Agent of Chinese Privet

Treesearch

Yanzhuo Zhang; James L. Hanula; Scott Horn; Kristine Braman; Jianghua Sun

2011-01-01

The biology of Leptoypha hospita Drake et Poor (Hemiptera: Tingidae), a potential biological control agent from China for Chinese privet, Ligustrum sinense Lour., was studied in quarantine in the United States. Both nymphs and adults feed on Chinese privet mesophyll cells that lead to a bleached appearance of leaves and dieback of branch tips. L. hospita has five...

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

The effects of the slug biological control agent, Phasmarhabditis hermaphrodita (Nematoda), on non-target aquatic molluscs.

PubMed

Morley, N J; Morritt, D

2006-06-01

The nematode Phasmarhabditis hermaphrodita is used as a commercial biological control agent of slugs in the UK. Although it is known to affect other terrestrial mollusc species, its effects on freshwater molluscs are not known. The present study investigated the effects of P. hermaphrodita on the survival of juvenile Lymnaea stagnalis and Physa fontinalis, two common freshwater snails, at 'spray tank' concentration and a 50% diluted 'spray tank' concentration over a 14-day period. Survival of L. stagnalis was significantly reduced at both application levels but P. fontinalis suffered no mortalities over the experimental period. The possible differential mechanisms of pathology between the two host species are discussed.

Renal toxicity of anticancer agents targeting HER2 and EGFR.

PubMed

Cosmai, Laura; Gallieni, Maurizio; Porta, Camillo

2015-12-01

EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents.

Detecting agency from the biological motion of veridical vs animated agents

PubMed Central

Kelley, William M.; Heatherton, Todd F.; Macrae, C. Neil

2007-01-01

The ability to detect agency is fundamental for understanding the social world. Underlying this capacity are neural circuits that respond to patterns of intentional biological motion in the superior temporal sulcus and temporoparietal junction. Here we show that the brain's blood oxygenation level dependent (BOLD) response to such motion is modulated by the representation of the actor. Dynamic social interactions were portrayed by either live-action agents or computer-animated agents, enacting the exact same patterns of biological motion. Using an event-related design, we found that the BOLD response associated with the perception and interpretation of agency was greater when identical physical movements were performed by real rather than animated agents. This finding has important implications for previous work on biological motion that has relied upon computer-animated stimuli and demonstrates that the neural substrates of social perception are finely tuned toward real-world agents. In addition, the response in lateral temporal areas was observed in the absence of instructions to make mental inferences, thus demonstrating the spontaneous implementation of the intentional stance. PMID:18985141

Targeting tumor glycolysis by a mitotropic agent.

PubMed

Ganapathy-Kanniappan, Shanmugasundaram

2016-01-01

Metabolic reprogramming is one of the hallmarks of cancer. Altered metabolism in cancer cells is exemplified by enhanced glucose utilization, a biochemical signature that is clinically exploited for cancer diagnosis using positron-emission tomography and computed tomography imaging. Accordingly, disrupting the glucose metabolism of cancer cells has been contemplated as a potential therapeutic strategy against cancer. Experimental evidences indicate that targeting glucose metabolism by inhibition of glycolysis or oxidative phosphorylation promotes anticancer effects. Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic toxicity. Recently, using nanotechnology, Marrache and Dhar have documented the feasibility of delivering a glycolytic inhibitor through triphenylphosphonium (TPP), a mitotropic agent that selectively targets mitochondria based on membrane potential. Furthermore, by utilizing gold nanoparticles the investigators also demonstrated the potential for simultaneous induction of photothermal therapy, thus facilitating an additional line of attack on cancer cells. The report establishes that specific inhibition of tumor glycolysis is achievable through TPP-dependent selective targeting of cancer cells. This nanotechnological approach involving TPP-guided selective delivery of an antiglycolytic agent complemented with photothermal therapy provides a new window of opportunity for effective and specific targeting of tumor glycolysis.

Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents.

PubMed

Cheson, Bruce D; Heitner Enschede, Sari; Cerri, Elisa; Desai, Monali; Potluri, Jalaja; Lamanna, Nicole; Tam, Constantine

2017-11-01

Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control. Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for

Heterapoderopsis bicallosicollis (Coleoptera: Attelabidae): a potential biological control agent for Triadica sebifera.

PubMed

Wang, Yi; Ding, Jianqing; Wheeler, Gregory S; Purcell, Matthew F; Zhang, Guoan

2009-08-01

Native to China, Chinese tallow, Triadica sebifera L. Small (Euphorbiaceae), is an invasive plant in the southeastern United States. The leaf-rolling weevil, Heterapoderopsis bicallosicollis Voss, is a common herbivore attacking this plant in China. To evaluate its potential as a biological control agent of T. sebifera, biology and host specificity of this weevil were studied in China. H. bicallosicollis occurs over a wide, native, geographic range and its immatures successfully develop at 15-35 degrees C, indicating its physiological potential to establish and persist throughout the range of climatic conditions where the target plant grows in the United States. Adults make feeding holes on leaves. Before oviposition, the female makes a sealed leaf roll called a nidus and then lays one to two eggs inside. Eggs, larvae, and pupae develop within nidi, and larvae survive only when they develop inside the nidi. This requirement makes the weevil highly host specific to T. sebifera. In laboratory no-choice tests of 54 species from eight families, adults fed on only 3 plant species, T. sebifera, Sapium chihsinianum S. K. Lee, and Phyllanthus urinaria L. and only oviposited on T. sebifera. These results were confirmed where, in multiple-choice tests, adults only oviposited on T. sebifera. Given that T. sebifera is the only species in the genus Triadica in the United States, the results of this study suggest that H. bicallosicollis is a potential biological control agent of T. sebifera and should be considered to be imported into quarantine in the United States for further tests on native North American species.

Stable-isotope fingerprints of biological agents as forensic tools.

PubMed

Horita, Juske; Vass, Arpad A

2003-01-01

Naturally occurring stable isotopes of light elements in chemical and biological agents may possess unique "stable-isotope fingerprints" depending on their sources and manufacturing processes. To test this hypothesis, two strains of bacteria (Bacillus globigii and Erwinia agglomerans) were grown under controlled laboratory conditions. We observed that cultured bacteria cells faithfully inherited the isotopic composition (hydrogen, carbon, and nitrogen) of media waters and substrates in predictable manners in terms of bacterial metabolism and that even bacterial cells of the same strain, which grew in media water and substrates of different isotopic compositions, have readily distinguishable isotopic signatures. These "stable-isotopic fingerprints" of chemical and biological agents can be used as forensic tools in the event of biochemical terrorist attacks.

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.

Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies?

PubMed

Angelini, Daniel J; Dorsey, Russell M; Willis, Kristen L; Hong, Charles; Moyer, Robert A; Oyler, Jonathan; Jensen, Neil S; Salem, Harry

2013-01-01

Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high. Recent evidence suggests that human stem cells may provide significant therapeutic options for ALI and ARDS in the near future. The threat posed by CWAs and biological toxins for both civilian populations and military personnel is growing, thus understanding the mechanisms of toxicity and potential therapies is critical. This review will outline the pulmonary toxic effects of some of the most common CWAs and biological toxins as well as the potential role of stem cells in treating these types of toxic lung injuries.

The pharmacology and toxicology of three new biologic agents used in pulmonary medicine.

PubMed

Albertson, T E; Walby, W F; Allen, R P; Tharratt, R S

1995-01-01

Biological agents have played an important role in the evolution of modern medical therapeutics. Recent advances in biologicals have in part been stimulated by the biotechnology revolution seen over the last several years. Toxicologists need to be aware of the proposed mechanisms and approved and experimental uses of these new biologic agents. Further, controversies about their use, efficacy, cost issues and potential toxicities should be known. Often these drugs are designed for small patient populations thus limiting the availability of human toxicological data bases. This paper reviews the pharmacology and toxicology of three new biologics (recombinant human DNase I, alpha 1-protease inhibitor, and nitric oxide). These agents appear to have important roles in treating specific diseases or disease states seen in pulmonary medicine.

Targeting the androgen receptor in prostate and breast cancer – several new agents in development

PubMed Central

Proverbs-Singh, Tracy; Feldman, Jarett L.; Morris, Michael J.; Autio, Karen A.; Traina, Tiffany A.

2016-01-01

Prostate cancer and breast cancer share similarities as hormone-sensitive cancers with a wide heterogeneity of both phenotype and biology. The androgen receptor (AR) is a hormone receptor involved in both benign and malignant processes. Targeting androgen synthesis and the AR pathway has been and remains central to prostate cancer therapy. Recently, there is increased interest in the role of the AR in breast cancer development and growth, with data suggesting AR co-expression with estrogen, progesterone and human epidermal growth factor receptors, across all intrinsic subtypes of breast cancer. Targeting the AR axis is an evolving field with novel therapies in development which may ultimately be applicable for both tumor types. In this review, we offer an overview of available agents which target the AR axis in both prostate and breast cancer and provide insight into the novel drugs in development for targeting this signaling pathway. PMID:25722318

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

PubMed Central

Liu, Shuang

2008-01-01

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

Biology and preliminary host range assessment of two potential kudzu biological control agents

Treesearch

Matthew J. Fyre; Judith Hough-Goldstein; Jiang-Hua Sun

2007-01-01

Two insect species from China, Gonioctena tredecimmaclliata (Jacoby) (Coleoptera: Chrysomelidae) and Ornatalcides (Mesalcidodes) trifidus (Pascoe) (Coleoptera: Curculionidae), were studied in quarantine in the United States as potential biological control agents for kudzu, Pueraria nwntana variety Zobata (Willd.) Maesen and S. Almeida...

Aptamer-Targeted Gold Nanoparticles As Molecular-Specific Contrast Agents for Reflectance Imaging

PubMed Central

2008-01-01

Targeted metallic nanoparticles have shown potential as a platform for development of molecular-specific contrast agents. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In this study, we investigated the development of aptamer-based gold nanoparticles as contrast agents, using aptamers as targeting agents and gold nanoparticles as imaging agents. We devised a novel conjugation approach using an extended aptamer design where the extension is complementary to an oligonucleotide sequence attached to the surface of the gold nanoparticles. The chemical and optical properties of the aptamer−gold conjugates were characterized using size measurements and oligonucleotide quantitation assays. We demonstrate this conjugation approach to create a contrast agent designed for detection of prostate-specific membrane antigen (PSMA), obtaining reflectance images of PSMA(+) and PSMA(−) cell lines treated with the anti-PSMA aptamer−gold conjugates. This design strategy can easily be modified to incorporate multifunctional agents as part of a multimodal platform for reflectance imaging applications. PMID:18512972

Targeted therapies: a nursing perspective.

PubMed

Kay, Polly

2006-02-01

To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. Research articles. Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Biological warfare agents as threats to potable water.

PubMed Central

Burrows, W D; Renner, S E

1999-01-01

Nearly all known biological warfare agents are intended for aerosol application. Although less effective as potable water threats, many are potentially capable of inflicting heavy casualties when ingested. Significant loss of mission capability can be anticipated even when complete recovery is possible. Properly maintained field army water purification equipment can counter this threat, but personnel responsible for the operation and maintenance of the equipment may be most at risk of exposure. Municipal water treatment facilities would be measurably less effective. Some replicating (infectious) agents and a few biotoxins are inactivated by chlorine disinfection; for others chlorine is ineffective or of unknown efficacy. This report assesses the state of our knowledge of agents as potable water threats and contemplates the consequences of intentional or collateral contamination of potable water supplies by 18 replicating agents and 9 biotoxins known or likely to be weaponized or otherwise used as threats. PMID:10585901

The biology of Mur ligases as an antibacterial target.

PubMed

Kouidmi, Imène; Levesque, Roger C; Paradis-Bleau, Catherine

2014-10-01

With antibiotic resistance mechanisms increasing in diversity and spreading among bacterial pathogens, the development of new classes of antibacterial agents against judiciously chosen targets is a high-priority task. The biochemical pathway for peptidoglycan biosynthesis is one of the best sources of antibacterial targets. Within this pathway are the Mur ligases, described in this review as highly suitable targets for the development of new classes of antibacterial agents. The amide ligases MurC, MurD, MurE and MurF function with the same catalytic mechanism and share conserved amino acid regions and structural features that can conceivably be exploited for the design of inhibitors that simultaneously target more than one enzyme. This would provide multi-target antibacterial weapons with minimized likelihood of target-mediated resistance development. © 2014 John Wiley & Sons Ltd.

Role of chemotherapy and molecularly targeted agents in the treatment of adenoid cystic carcinoma of the lacrimal gland.

PubMed

Le Tourneau, Christophe; Razak, Albiruni R A; Levy, Christine; Calugaru, Valentin; Galatoire, Olivier; Dendale, Rémi; Desjardins, Laurence; Gan, Hui K

2011-11-01

Adenoid cystic carcinoma (ACC) is the most common malignant epithelial cancer of the lacrimal gland. Despite a slow rate of growth, ACCs are ultimately associated with poor clinical outcome. Given the rarity of this disease, most recommendations regarding therapy are guided by expert opinion and retrospective data rather than level 1 evidence. Surgery and postoperative radiation therapy are commonly used as initial local treatment. In patients at high risk of recurrence, concomitant platinum-based chemotherapy may be added to postoperative radiotherapy in an attempt to enhance radio-sensitivity. While encouraging responses have been reported with intra-arterial neoadjuvant chemotherapy, this strategy is associated with substantial toxicity and should be considered investigational. For patients with metastatic disease not amenable to surgery or radiotherapy, chemotherapy may have a role based on its modest efficacy in non-lacrimal ACC. Similarly, molecular targeted agents may have a role, although the agents tested to date in non-lacrimal ACC have been disappointing. A better understanding of the biology of ACC will be crucial to the future success of developing targeted agents for this disease.

Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

PubMed

Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

2016-05-05

Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

Functional Agents to Biologically Control Deoxynivalenol Contamination in Cereal Grains

PubMed Central

Tian, Ye; Tan, Yanglan; Liu, Na; Liao, Yucai; Sun, Changpo; Wang, Shuangxia; Wu, Aibo

2016-01-01

Mycotoxins, as microbial secondary metabolites, frequently contaminate cereal grains and pose a serious threat to human and animal health around the globe. Deoxynivalenol (DON), a commonly detected Fusarium mycotoxin, has drawn utmost attention due to high exposure levels and contamination frequency in the food chain. Biological control is emerging as a promising technology for the management of DON contamination. Functional biological control agents (BCAs), which include antagonistic microbes, natural fungicides derived from plants and detoxification enzymes, can be used to control DON contamination at different stages of grain production. In this review, studies regarding different biological agents for DON control in recent years are summarized for the first time. Furthermore, this article highlights the significance of BCAs for controlling DON contamination, as well as the need for more practical and efficient BCAs concerning food safety. PMID:27064760

Disinfection of biological agents in the field using a mobile ...

EPA Pesticide Factsheets

Report The Army’s Net Zero Initiative is an energy-conservation program that focuses on energy as well as water and waste usage procedures. All Net Zero projects are geared toward helping the military installation or community become more sustainable and resilient, with an emphasis on taking a systems approach. Net Zero projects must advance the state of the science and are focused on three general topic areas: water, energy, and waste, and the nexuses among them. This project examined the inactivation and/or removal of biological contaminants in dirty wash water using a portable ozone-UV AOP process. The strain of E. coli used in these experiments is not a biological warfare agent, but acts as a surrogate for certain of the vegetative biological agents such as the enterohemorrhagic strain designated E. coli 0157:H7.

Pythium species and isolate diversity influence inhibition by the biological control agent Streptomyces lydicus

USDA-ARS?s Scientific Manuscript database

Disease control of soilborne pathogens by biological control agents has often been inconsistent under field conditions. One factor that may contribute to this inconsistency is the variability in response among pathogen populations and/or communities to the selected biological control agent. One hund...

Babybot: a biologically inspired developing robotic agent

NASA Astrophysics Data System (ADS)

Metta, Giorgio; Panerai, Francesco M.; Sandini, Giulio

2000-10-01

The study of development, either artificial or biological, can highlight the mechanisms underlying learning and adaptive behavior. We shall argue whether developmental studies might provide a different and potentially interesting perspective either on how to build an artificial adaptive agent, or on understanding how the brain solves sensory, motor, and cognitive tasks. It is our opinion that the acquisition of the proper behavior might indeed be facilitated because within an ecological context, the agent, its adaptive structure and the environment dynamically interact thus constraining the otherwise difficult learning problem. In very general terms we shall describe the proposed approach and supporting biological related facts. In order to further analyze these aspects from the modeling point of view, we shall demonstrate how a twelve degrees of freedom baby humanoid robot acquires orienting and reaching behaviors, and what advantages the proposed framework might offer. In particular, the experimental setup consists of five degrees-of-freedom (dof) robot head, and an off-the-shelf six dof robot manipulator, both mounted on a rotating base: i.e. the torso. From the sensory point of view, the robot is equipped with two space-variant cameras, an inertial sensor simulating the vestibular system, and proprioceptive information through motor encoders. The biological parallel is exploited at many implementation levels. It is worth mentioning, for example, the space- variant eyes, exploiting foveal and peripheral vision in a single arrangement, the inertial sensor providing efficient image stabilization (vestibulo-ocular reflex).

Airborne exposure limits for chemical and biological warfare agents: is everything set and clear?

PubMed

Sabelnikov, Alex; Zhukov, Vladimir; Kempf, C Ruth

2006-08-01

Emergency response strategies (guidelines) for biological, chemical, nuclear, or radiological terrorist events should be based on scientifically established exposure limits for all the agents or materials involved. In the case of a radiological terrorist event, emergency response guidelines (ERG) have been worked out. In the case of a terrorist event with the use of chemical warfare (CW) agents the situation is not that clear, though the new guidelines and clean-up values are being generated based on re-evaluation of toxicological and risk data. For biological warfare (BW) agents, such guidelines do not yet exist. In this paper the current status of airborne exposure limits (AELs) for chemical and biological warfare (CBW) agents are reviewed. Particular emphasis is put on BW agents that lack such data. An efficient, temporary solution to bridge the gap in experimental infectious data and to set provisional AELs for BW agents is suggested. It is based on mathematically generated risks of infection for BW agents grouped by their alleged ID50 values in three categories: with low, intermediate and high ID50 values.

Nanoparticle-labeled DNA capture elements for detection and identification of biological agents

NASA Astrophysics Data System (ADS)

Kiel, Johnathan L.; Holwitt, Eric A.; Parker, Jill E.; Vivekananda, Jeevalatha; Franz, Veronica

2004-12-01

Aptamers, synthetic DNA capture elements (DCEs), can be made chemically or in genetically engineered bacteria. DNA capture elements are artificial DNA sequences, from a random pool of sequences, selected for their specific binding to potential biological warfare or terrorism agents. These sequences were selected by an affinity method using filters to which the target agent was attached and the DNA isolated and amplified by polymerase chain reaction (PCR) in an iterative, increasingly stringent, process. The probes can then be conjugated to Quantum Dots and super paramagnetic nanoparticles. The former provide intense, bleach-resistant fluorescent detection of bioagent and the latter provide a means to collect the bioagents with a magnet. The fluorescence can be detected in a flow cytometer, in a fluorescence plate reader, or with a fluorescence microscope. To date, we have made DCEs to Bacillus anthracis spores, Shiga toxin, Venezuelan Equine Encephalitis (VEE) virus, and Francisella tularensis. DCEs can easily distinguish Bacillus anthracis from its nearest relatives, Bacillus cereus and Bacillus thuringiensis. Development of a high through-put process is currently being investigated.

Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis.

PubMed

Danese, Silvio; Fiorino, Gionata; Peyrin-Biroulet, Laurent; Lucenteforte, Ersilia; Virgili, Gianni; Moja, Lorenzo; Bonovas, Stefanos

2014-05-20

Biological agents are emerging treatment options for the management of ulcerative colitis (UC). To assess the comparative efficacy and harm of biological agents in adult patients with moderately to severely active UC who are naive to biological agents. MEDLINE, EMBASE, and Cochrane Library from inception through December 2013, without language restrictions, and ClinicalTrials.gov, European Medicines Agency, and U.S. Food and Drug Administration Web sites. Randomized, placebo-controlled or head-to-head trials assessing biological agents as induction or maintenance therapy for moderately to severely active UC. Two reviewers independently abstracted study data and outcomes and rated each trial's risk of bias. There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo. Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials. Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option.

Targeted delivery of cancer-specific multimodal contrast agents for intraoperative detection of tumor boundaries and therapeutic margins

NASA Astrophysics Data System (ADS)

Xu, Ronald X.; Xu, Jeff S.; Huang, Jiwei; Tweedle, Michael F.; Schmidt, Carl; Povoski, Stephen P.; Martin, Edward W.

2010-02-01

Background: Accurate assessment of tumor boundaries and intraoperative detection of therapeutic margins are important oncologic principles for minimal recurrence rates and improved long-term outcomes. However, many existing cancer imaging tools are based on preoperative image acquisition and do not provide real-time intraoperative information that supports critical decision-making in the operating room. Method: Poly lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) were synthesized by a modified double emulsion method. The MB and NB surfaces were conjugated with CC49 antibody to target TAG-72 antigen, a human glycoprotein complex expressed in many epithelial-derived cancers. Multiple imaging agents were encapsulated in MBs and NBs for multimodal imaging. Both one-step and multi-step cancer targeting strategies were explored. Active MBs/NBs were also fabricated for therapeutic margin assessment in cancer ablation therapies. Results: The multimodal contrast agents and the cancer-targeting strategies were tested on tissue simulating phantoms, LS174 colon cancer cell cultures, and cancer xenograft nude mice. Concurrent multimodal imaging was demonstrated using fluorescence and ultrasound imaging modalities. Technical feasibility of using active MBs and portable imaging tools such as ultrasound for intraoperative therapeutic margin assessment was demonstrated in a biological tissue model. Conclusion: The cancer-specific multimodal contrast agents described in this paper have the potential for intraoperative detection of tumor boundaries and therapeutic margins.

Outcome of Molecular Targeted Agents Plus Chemotherapy for Second-Line Therapy of Metastatic Colorectal Cancer: A Meta-Analysis of Randomized Trials.

PubMed

Pei, Xueqing; Liu, Yu; Sun, Liwei; Zhang, Jun; Fang, Yuanyuan; Liao, Xin; Liu, Jian; Zhang, Cuntai; Yin, Tiejun

2016-12-01

The aim of this study was to evaluate the efficacy and toxicity of molecular targeted agents plus chemotherapy compared with chemotherapy alone as second-line therapy for patients with metastatic colorectal cancer (mCRC). We identified randomized controlled trials that compared molecular targeted agents plus chemotherapy with chemotherapy alone by searching the PubMed and Embase databases for articles published between January 2000 and September 2015. The outcome measures included progression-free survival, overall survival, objective response rate, and adverse events. Two investigators independently performed the information retrieval, screening, and data extraction. Stata 10.0 software was used to statistically analyze the extracted data. In accordance with our inclusion criteria, 11 trials, with a total of 7440 patients, were included in this meta-analysis through rounds of selection. We divided the biologic agents used into 3 subgroups based on the type of biologic agents-vascular endothelial growth factor (VEGF) inhibitor, epidermal growth factor receptor inhibitor, and other pathway inhibitors. Our results suggested that the regimen of a molecular targeted agent plus chemotherapy had a significant advantage in progression-free survival, overall survival, and objective response rate over chemotherapy alone (hazard ratio, 0.74; 95% confidence interval [CI], 0.70-0.78; hazard ratio, 0.88; 95% CI, 0.83-0.93; risk ratio, 2.24; 95% CI: 1.58-3.17, respectively). However, the rate of grade ≥ 3 adverse events was also higher in the combination therapy arm (risk ratio, 1.25; 95% CI, 1.17-1.33). Subgroup analysis showed that the combination of VEGF inhibitor with chemotherapy had a significant advantage in PFS, OS, and ORR over chemotherapy alone, but there was also a higher risk ratio in adverse events for this combination compared with the control group. In conclusion, a molecular targeted agent, especially VEGF inhibitor, plus chemotherapy is a worthwhile

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

PubMed Central

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-01-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane–modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. PMID:26874280

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging.

PubMed

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-04-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane-modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. Copyright © 2016 Elsevier Ltd. All rights reserved.

Open-target sparse sensing of biological agents using DNA microarray

PubMed Central

2011-01-01

Background Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. Results A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R2)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R2)) = 0.77, CI = 0.95) with nearly 100% specificity. Conclusions We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated

New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases.

PubMed

Méry-Bossard, L; Bagny, K; Chaby, G; Khemis, A; Maccari, F; Marotte, H; Perrot, J L; Reguiai, Z; Sigal, M L; Avenel-Audran, M; Boyé, T; Grasland, A; Gillard, J; Jullien, D; Toussirot, E

2017-01-01

The development of vitiligo during treatment with biological agents is an unusual event and only a few isolated cases have been reported. To describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease; and also to report the clinical course of pre-existing vitiligo under biological therapy. This nationwide multicentre, retrospective study, carried out between July 2013 and January 2015, describes the characteristics of a large series of 18 patients (psoriasis N = 8, inflammatory rheumatic diseases N = 8, ulcerative colitis N = 1, uveitis N = 1) who developed new-onset vitiligo while receiving a biological agent. TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Outcome was favourable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients (psoriasis N = 5, inflammatory rheumatic diseases N = 10, inflammatory bowel diseases N = 2, SAPHO N = 1) who had pre-existing vitiligo when treatment with a biological agent started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. Vitiligo may thus emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favourable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo. © 2016 European Academy of Dermatology and Venereology.

High-throughput assay for optimising microbial biological control agent production and delivery

USDA-ARS?s Scientific Manuscript database

Lack of technologies to produce and deliver effective biological control agents (BCAs) is a major barrier to their commercialization. A myriad of variables associated with BCA cultivation, formulation, drying, storage, and reconstitution processes complicates agent quality maximization. An efficie...

Impacts of biological control and invasive species on a non-target native Hawaiian insect.

PubMed

Johnson, M Tracy; Follett, Peter A; Taylor, Andrew D; Jones, Vincent P

2005-02-01

The potential for classical biological control to cause unintended harm to native species was evaluated in the case of the endemic Hawaiian koa bug, Coleotichus blackburniae White (Hemiptera: Scutelleridae), and parasitoids introduced to Hawaii for control of an agricultural pest, the southern green stink bug, Nezara viridula (L.) (Hemiptera: Pentatomidae). Parasitism of C. blackburniae eggs, nymphs and adults by biocontrol agents was quantified across a wide range of habitats and compared to other sources of mortality. Egg mortality due to the biocontrol agent Trissolcus basalis Wollaston (Hymenoptera: Scelionidae) was low (maximum 26%) and confined to elevations below 500 m on a single host plant. Predation, mainly by alien spiders and ants, was the greatest source of egg mortality (maximum 87%). Parasitism of adult C. blackburniae by the biocontrol agent Trichopoda pilipes (F.) (Diptera: Tachinidae) was near zero at 21 of 24 sites surveyed. Three sites with high bug density had higher levels of T. pilipes parasitism, reaching maxima of 70% among adult female bugs, 100% among males and 50% among fifth instars. Male-biased parasitism indicated that T. pilipes is adapted to using male aggregation pheromone for finding C. blackburniae hosts. The relative impacts of biocontrol agents and other sources of mortality were compared using life tables. Invasive species, particularly generalist egg predators, had the greatest impacts on C. blackburniae populations. Effects of intentionally introduced parasitoids were relatively minor, although the tachinid T. pilipes showed potential for large impacts at individual sites. In retrospect, non-target attacks by biological control agents on C. blackburniae were predictable, but the environmental range and magnitude of impacts would have been difficult to foresee.

Chemical biology 2012: from drug targets to biological systems and back.

PubMed

Socher, Elke; Grossmann, Tom N

2013-01-02

Multiple sites sharing a common target: This year's EMBO conference on chemical biology encouraged over 340 researchers to come to Heidelberg, Germany, and discuss the use of diverse chemical strategies and tools to investigate biological questions and better understand cellular processes. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Predicting the size-dependent tissue accumulation of agents released from vascular targeted nanoconstructs

NASA Astrophysics Data System (ADS)

de Tullio, Marco D.; Singh, Jaykrishna; Pascazio, Giuseppe; Decuzzi, Paolo

2014-03-01

Vascular targeted nanoparticles have been developed for the delivery of therapeutic and imaging agents in cancer and cardiovascular diseases. However, at authors' knowledge, a comprehensive systematic analysis on their delivery efficiency is still missing. Here, a computational model is developed to predict the vessel wall accumulation of agents released from vascular targeted nanoconstructs. The transport problem for the released agent is solved using a finite volume scheme in terms of three governing parameters: the local wall shear rate , ranging from to ; the wall filtration velocity , varying from to ; and the agent diffusion coefficient , ranging from to . It is shown that the percentage of released agent adsorbing on the vessel walls in the vicinity of the vascular targeted nanoconstructs reduces with an increase in shear rate , and with a decrease in filtration velocity and agent diffusivity . In particular, in tumor microvessels, characterized by lower shear rates () and higher filtration velocities (), an agent with a diffusivity (i.e. a 50 nm particle) is predicted to deposit on the vessel wall up to of the total released dose. Differently, drug molecules, exhibiting a smaller size and much higher diffusion coefficient (), are predicted to accumulate up to . In healthy vessels, characterized by higher and lower , the largest majority of the released agent is redistributed directly in the circulation. These data suggest that drug molecules and small nanoparticles only can be efficiently released from vascular targeted nanoconstructs towards the diseased vessel walls and tissue.

Simulated experiment for elimination of chemical and biological warfare agents by making use of microwave plasma torch

NASA Astrophysics Data System (ADS)

Hong, Yong C.; Kim, Jeong H.; Uhm, Han S.

2004-02-01

The threat of chemical and biological warfare agents in a domestic terrorist attack and in military conflict is increasing worldwide. Elimination and decontamination of chemical and biological warfare (CBW) agents are immediately required after such an attack. Simulated experiment for elimination of CBW agents by making use of atmospheric-pressure microwave plasma torches is carried out. Elimination of biological warfare agents indicated by the vitrification or burnout of sewage sludge powders and decomposition of toluene gas as a chemical agent stimulant are presented. A detailed characterization for the elimination of the simulant chemicals using Fourier transform infrared and gas chromatography is also presented.

PEGylated Peptide-Based Imaging Agents for Targeted Molecular Imaging.

PubMed

Wu, Huizi; Huang, Jiaguo

2016-01-01

Molecular imaging is able to directly visualize targets and characterize cellular pathways with a high signal/background ratio, which requires a sufficient amount of agents to uptake and accumulate in the imaging area. The design and development of peptide based agents for imaging and diagnosis as a hot and promising research topic that is booming in the field of molecular imaging. To date, selected peptides have been increasingly developed as agents by coupling with different imaging moieties (such as radiometals and fluorophore) with the help of sophisticated chemical techniques. Although a few successes have been achieved, most of them have failed mainly caused by their fast renal clearance and therefore low tumor uptakes, which may limit the effectively tumor retention effect. Besides, several peptide agents based on nanoparticles have also been developed for medical diagnostics. However, a great majority of those agents shown long circulation times and accumulation over time into the reticuloendothelial system (RES; including spleen, liver, lymph nodes and bone marrow) after systematic administration, such long-term severe accumulation probably results in the possible likelihood of toxicity and potentially induces health hazards. Recently reported design criteria have been proposed not only to enhance binding affinity in tumor region with long retention, but also to improve clearance from the body in a reasonable amount of time. PEGylation has been considered as one of the most successful modification methods to prolong tumor retention and improve the pharmacokinetic and pharmacodynamic properties for peptide-based imaging agents. This review summarizes an overview of PEGylated peptides imaging agents based on different imaging moieties including radioisotopes, fluorophores, and nanoparticles. The unique concepts and applications of various PEGylated peptide-based imaging agents are introduced for each of several imaging moieties. Effects of PEGylation on

Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival

PubMed Central

B. Kumar, Nagi; Dhurandhar, Medha; Aggarwal, Bharat; Anant, Shrikant; Daniel, Kenyon; Deng, Gary; Djeu, Julie; Dou, Jinhui; Hawk, Ernest; Jayaram, B.; Jia, Libin; Joshi, Rajendra; Kararala, Madhuri; Karunagaran, Devarajan; Kucuk, Omer; Kumar, Lalit; Malafa, Mokenge; Samathanam, G. J.; Sarkar, Fazlul; Siddiqi, Maqsood; Singh, Rana P.; Srivastava, Anil; White, Jeffrey D.

2013-01-01

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop. PMID:24279005

Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival.

PubMed

Kumar, Nagi B; Dhurandhar, Medha; Aggarwal, Bharat; Anant, Shrikant; Daniel, Kenyon; Deng, Gary; Djeu, Julie; Dou, Jinhui; Hawk, Ernest; Jayaram, B; Jia, Libin; Joshi, Rajendra; Kararala, Madhuri; Karunagaran, Devarajan; Kucuk, Omer; Kumar, Lalit; Malafa, Mokenge; Samathanam, G J; Sarkar, Fazlul; Siddiqi, Maqsood; Singh, Rana P; Srivastava, Anil; White, Jeffrey D

2013-02-01

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop.

Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Hughes, Ryan; Page, Brandi R.; Isom, Scott; Lucas, John T.; McTyre, Emory R.; Houseknecht, Kristin W.; Ayala-Peacock, Diandra N.; Bourland, Daniel J.; Hinson, William H.; Laxton, Adrian W.; Tatter, Stephen B.; Debinski, Waldemar; Watabe, Kounosuke; Chan, Michael D.

2015-01-01

Background To determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases. Methods Between 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups. Results Patients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001). Conclusions Targeted agent use with SRS appears to improve survival and intracranial outcomes. PMID:26087184

What magnitude are observed non-target impacts from weed biocontrol?

PubMed

Suckling, David Maxwell; Sforza, René François Henri

2014-01-01

A systematic review focused by plant on non-target impacts from agents deliberately introduced for the biological control of weeds found significant non-target impacts to be rare. The magnitude of direct impact of 43 biocontrol agents on 140 non-target plants was retrospectively categorized using a risk management framework for ecological impacts of invasive species (minimal, minor, moderate, major, massive). The vast majority of agents introduced for classical biological control of weeds (>99% of 512 agents released) have had no known significant adverse effects on non-target plants thus far; major effects suppressing non-target plant populations could be expected to be detectable. Most direct non-target impacts on plants (91.6%) were categorized as minimal or minor in magnitude with no known adverse long-term impact on non-target plant populations, but a few cacti and thistles are affected at moderate (n = 3), major (n = 7) to massive (n = 1) scale. The largest direct impacts are from two agents (Cactoblastis cactorum on native cacti and Rhinocyllus conicus on native thistles), but these introductions would not be permitted today as more balanced attitudes exist to plant biodiversity, driven by both society and the scientific community. Our analysis shows (as far as is known), weed biological control agents have a biosafety track record of >99% of cases avoiding significant non-target impacts on plant populations. Some impacts could have been overlooked, but this seems unlikely to change the basic distribution of very limited adverse effects. Fewer non-target impacts can be expected in future because of improved science and incorporation of wider values. Failure to use biological control represents a significant opportunity cost from the certainty of ongoing adverse impacts from invasive weeds. It is recommended that a simple five-step scale be used to better communicate the risk of consequences from both action (classical biological control) and no

What Magnitude Are Observed Non-Target Impacts from Weed Biocontrol?

PubMed Central

Suckling, David Maxwell; Sforza, René François Henri

2014-01-01

A systematic review focused by plant on non-target impacts from agents deliberately introduced for the biological control of weeds found significant non-target impacts to be rare. The magnitude of direct impact of 43 biocontrol agents on 140 non-target plants was retrospectively categorized using a risk management framework for ecological impacts of invasive species (minimal, minor, moderate, major, massive). The vast majority of agents introduced for classical biological control of weeds (>99% of 512 agents released) have had no known significant adverse effects on non-target plants thus far; major effects suppressing non-target plant populations could be expected to be detectable. Most direct non-target impacts on plants (91.6%) were categorized as minimal or minor in magnitude with no known adverse long-term impact on non-target plant populations, but a few cacti and thistles are affected at moderate (n = 3), major (n = 7) to massive (n = 1) scale. The largest direct impacts are from two agents (Cactoblastis cactorum on native cacti and Rhinocyllus conicus on native thistles), but these introductions would not be permitted today as more balanced attitudes exist to plant biodiversity, driven by both society and the scientific community. Our analysis shows (as far as is known), weed biological control agents have a biosafety track record of >99% of cases avoiding significant non-target impacts on plant populations. Some impacts could have been overlooked, but this seems unlikely to change the basic distribution of very limited adverse effects. Fewer non-target impacts can be expected in future because of improved science and incorporation of wider values. Failure to use biological control represents a significant opportunity cost from the certainty of ongoing adverse impacts from invasive weeds. It is recommended that a simple five-step scale be used to better communicate the risk of consequences from both action (classical biological control) and no

Studies in Multifunctional Drug Development: Preparation and Evaluation of 11beta-Substituted Estradiol-Drug Conjugates, Cell Membrane Targeting Imaging Agents, and Target Multifunctional Nanoparticles

NASA Astrophysics Data System (ADS)

Dao, KinhLuan Lenny D.

Cancer is the second leading cause of death after cardiovascular disease in the United State. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against the anticancer drugs after prolonged treatment. Therefore, alleviating the systemic cytotoxicity and side effects, improving in tumor selectivity, high potency, and therapeutic efficacy are still major obstacles in the area of anticancer drug development. A more promising approach for developing a selective agent for cancer is to conjugate a potent therapeutic drug, or an imaging agent with a targeting group, such as antibody or a high binding-specificity small molecule, that selectively recognize the overexpressed antigens or proteins on tumor cells. My research combines several approaches to describe this strategy via using different targeting molecules to different diseases, as well as different potent cytotoxic drugs for different therapies. Three studies related to the preparation and biological evaluation of new therapeutic agents, such as estradiol-drug hybrids, cell membrane targeted molecular imaging agents, and multifunctional NPs will be discussed. The preliminary results of these studies indicated that our new reagents achieved their initial objectives and can be further improved for optimized synthesis and in vivo experiments. The first study describes the method in which we employed a modular assembly approach to synthesize a novel 11beta-substituted steroidal anti-estrogen. The key intermediate was synthesized

Evaluation of "shotgun" proteomics for identification of biological threat agents in complex environmental matrixes: experimental simulations.

PubMed

Verberkmoes, Nathan C; Hervey, W Judson; Shah, Manesh; Land, Miriam; Hauser, Loren; Larimer, Frank W; Van Berkel, Gary J; Goeringer, Douglas E

2005-02-01

There is currently a great need for rapid detection and positive identification of biological threat agents, as well as microbial species in general, directly from complex environmental samples. This need is most urgent in the area of homeland security, but also extends into medical, environmental, and agricultural sciences. Mass-spectrometry-based analysis is one of the leading technologies in the field with a diversity of different methodologies for biothreat detection. Over the past few years, "shotgun"proteomics has become one method of choice for the rapid analysis of complex protein mixtures by mass spectrometry. Recently, it was demonstrated that this methodology is capable of distinguishing a target species against a large database of background species from a single-component sample or dual-component mixtures with relatively the same concentration. Here, we examine the potential of shotgun proteomics to analyze a target species in a background of four contaminant species. We tested the capability of a common commercial mass-spectrometry-based shotgun proteomics platform for the detection of the target species (Escherichia coli) at four different concentrations and four different time points of analysis. We also tested the effect of database size on positive identification of the four microbes used in this study by testing a small (13-species) database and a large (261-species) database. The results clearly indicated that this technology could easily identify the target species at 20% in the background mixture at a 60, 120, 180, or 240 min analysis time with the small database. The results also indicated that the target species could easily be identified at 20% or 6% but could not be identified at 0.6% or 0.06% in either a 240 min analysis or a 30 h analysis with the small database. The effects of the large database were severe on the target species where detection above the background at any concentration used in this study was impossible, though the three

Implementation of Multi-Agent Object Attention System Based on Biologically Inspired Attractor Selection

NASA Astrophysics Data System (ADS)

Hashimoto, Ryoji; Matsumura, Tomoya; Nozato, Yoshihiro; Watanabe, Kenji; Onoye, Takao

A multi-agent object attention system is proposed, which is based on biologically inspired attractor selection model. Object attention is facilitated by using a video sequence and a depth map obtained through a compound-eye image sensor TOMBO. Robustness of the multi-agent system over environmental changes is enhanced by utilizing the biological model of adaptive response by attractor selection. To implement the proposed system, an efficient VLSI architecture is employed with reducing enormous computational costs and memory accesses required for depth map processing and multi-agent attractor selection process. According to the FPGA implementation result of the proposed object attention system, which is accomplished by using 7,063 slices, 640×512 pixel input images can be processed in real-time with three agents at a rate of 9fps in 48MHz operation.

Nitric oxide: cancer target or anticancer agent?

PubMed

Mocellin, Simone

2009-03-01

Despite the improved understanding of nitric oxide (NO) biology and the large amount of preclinical experiments testing its role in cancer development and progression, it is still debated whether NO should be considered a potential anticancer agent or instead a carcinogen. The complexity of NO effects within a cell and the variability of the final biological outcome depending upon NO levels makes it highly challenging to determine the therapeutic value of interfering with the activity of this intriguing gaseous messenger. This uncertainty has so far halted the clinical implementation of NO-based therapeutics in the field of oncology. Accordingly, only an in depth knowledge of the mechanisms leading to experimental tumor regression or progression in response to NO will allow us to exploit this molecule to fight cancer.

Treatment with biologic agents improves the prognosis of patients with rheumatoid arthritis and amyloidosis.

PubMed

Kuroda, Takeshi; Tanabe, Naohito; Kobayashi, Daisuke; Sato, Hiroe; Wada, Yoko; Murakami, Shuichi; Saeki, Takako; Nakano, Masaaki; Narita, Ichiei

2012-07-01

Reactive amyloid A (AA) amyloidosis is a serious and life-threatening systemic complication of rheumatoid arthritis (RA). We evaluated the safety of therapy with anti-tumor necrosis factor and anti-interleukin 6 biologic agents in RA patients with reactive AA amyloidosis, together with prognosis and hemodialysis (HD)-free survival, in comparison with patients with AA amyloidosis without such therapy. One hundred thirty-three patients with an established diagnosis of reactive AA amyloidosis participated in the study. Clinical data were assessed from patient records at the time of amyloid detection and administration of biologics. Survival was calculated from the date when amyloid was first demonstrated histologically or the date when biologic therapy was started until the time of death or to the end of 2010 for surviving patients. Patients who had started HD were selected for inclusion only after the presence of amyloid was demonstrated. Fifty-three patients were treated with biologic agents (biologic group) and 80 were not (nonbiologic group). Survival rate was significantly higher in the biologic group than in the nonbiologic group. Nine patients in the biologics group and 33 in the nonbiologic group started HD. Biologic therapy had a tendency for reduced risk of initiation of HD without any statistical significance. Patients with amyloidosis have a higher mortality rate, but the use of biologic agents can reduce risk of death. The use of biologics may not significantly influence the HD-free survival rate.

Synthesis, biological targeting and photophysics of quantum dots

NASA Astrophysics Data System (ADS)

Clarke, Samuel Jon

Quantum dots (QDs) are inorganic nanoparticles that have exceptional optical properties. Currently, QDs have failed to reach their potential as fluorescent probes in live cells, due to the nontrivial requirements for biological interfacing. The goal of this thesis is to address technical hurdles related to the reproducible synthesis of QDs, strategies for the specific targeting of QDs to biological cells and to understanding and exploitation of the photophysical properties. High quality QDs of varying composition (CdSe, CdTe and core/shell CdSe/ZnS) were synthesized with an organometallic method. To prepare biocompatible QDs, three strategies were used. The simplest strategy used small mercaptocarboxylic acids, while performance improvements were realized with engineered-peptide and lipid-micelle coatings. For specific biological targeting of the QDs, conjugation strategies were devised to attach biomolecules, while spectroscopic characterization methods were developed to assess conjugation efficiencies. To target gram-negative bacterial cells, an electrostatic self-assembly method was used to attach an antibiotic selective for this class of bacteria, polymyxin B. To target dopamine neurotransmitter receptor, a covalent conjugation method was used to attach dopamine, the endogenous ligand for that receptor. It was shown that dopamine molecule enabled electron transfer to QDs and the photophysics was studied in detail. A novel conjugation and targeting strategy was explored to enable the selective binding of QDs to polyhistidine epitopes on membrane proteins. Epifluorescence microscopy was used to evaluate the biological activity of the three QD probes. Combined, they add to the QD 'toolkit' for live-cell imaging. Finally, due to its negative implications in biological imaging, the fluorescent intermittency (blinking) of CdTe QDs was investigated. It was shown that mercaptocarboxylic acids contribute to the blinking suppression of the QDs, results that may aid in

What magnitude are observed non-target impacts from weed biocontrol?

USDA-ARS?s Scientific Manuscript database

A systematic review focused by plant on non-target impacts from agents deliberately introduced for the biological control of weeds found significant non-target impacts to be rare. The magnitude of direct impact of 43 biocontrol agents on 140 non-target plants was retrospectively categorized using a ...

New agents for prostate cancer.

PubMed

Agarwal, N; Di Lorenzo, G; Sonpavde, G; Bellmunt, J

2014-09-01

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid

Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales.

PubMed

Ioannidis, John P A; Karassa, Fotini B; Druyts, Eric; Thorlund, Kristian; Mills, Edward J

2013-11-01

Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.

Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation, and photothermal effects†

PubMed Central

Tong, Ling; Wei, Qingshan; Wei, Alexander; Cheng, Ji-Xin

2009-01-01

Gold nanorods (NRs) have plasmon-resonant absorption and scattering in the near-infrared (NIR) region, making them attractive probes for in vitro and in vivo imaging. In the cellular environment, NRs can provide scattering contrast for darkfield microscopy, or emit a strong two-photon luminescence (TPL) due to plasmon-enhanced two-photon absorption. NRs have also been employed in biomedical imaging modalities such as optical coherence tomography (OCT) or photoacoustic tomography (PAT). Careful control over surface chemistry enhances the capacity of NRs as biological imaging agents by enabling cell-specific targeting, and by increasing their dispersion stability and circulation lifetimes. NRs can also efficiently convert optical energy into heat, and inflict localized damage to tumor cells. Laser-induced heating of NRs can disrupt cell membrane integrity and homeostasis, resulting in Ca2+ influx and the depolymerization of the intracellular actin network. The combination of plasmon-resonant optical properties, intense local photothermal effects, and robust surface chemistry render gold NRs as promising theragnostic agents. PMID:19161395

Preparation of near-infrared-labeled targeted contrast agents for clinical translation

NASA Astrophysics Data System (ADS)

Olive, D. Michael

2011-03-01

Targeted fluorophore-labeled contrast agents are moving toward translation to human surgical use. To prepare for future clinical use, we examined the performance of potential ligands targeting the epidermal growth factor receptor, α5β3 integrins, and GLUT transporters for their suitability as directed contrast agents. Each agent was labeled with IRDye 800CW, and near-infrared dye with excitation/emission wavelengths of 789/805 nm, which we determined had favorable toxicity characteristics. The probe molecules examined consisted of Affibodies, nanobodies, peptides, and the sugar 2-deoxy-D-glucose. Each probe was tested for specific and non-specific binding in cell based assays. All probe types showed good performance in mouse models for detecting either spontaneous tumors or tumor xenografts in vivo. Each of the probes tested show promise for future human clinical studies.

Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy

PubMed Central

Zhou, Jiehua; Rossi, John J.

2014-01-01

One hundred years ago, Dr. Paul Ehrlich popularized the “magic bullet” concept for cancer therapy in which an ideal therapeutic agent would only kill the specific tumor cells it targeted. Since then, “targeted therapy” that specifically targets the molecular defects responsible for a patient's condition has become a long-standing goal for treating human disease. However, safe and efficient drug delivery during the treatment of cancer and infectious disease remains a major challenge for clinical translation and the development of new therapies. The advent of SELEX technology has inspired many groundbreaking studies that successfully adapted cell-specific aptamers for targeted delivery of active drug substances in both in vitro and in vivo models. By covalently linking or physically functionalizing the cell-specific aptamers with therapeutic agents, such as siRNA, microRNA, chemotherapeutics or toxins, or delivery vehicles, such as organic or inorganic nanocarriers, the targeted cells and tissues can be specifically recognized and the therapeutic compounds internalized, thereby improving the local concentration of the drug and its therapeutic efficacy. Currently, many cell-type-specific aptamers have been developed that can target distinct diseases or tissues in a cell-type-specific manner. In this review, we discuss recent advances in the use of cell-specific aptamers for targeted disease therapy, as well as conjugation strategies and challenges. PMID:24936916

Agent-Based Modeling in Molecular Systems Biology.

PubMed

Soheilypour, Mohammad; Mofrad, Mohammad R K

2018-07-01

Molecular systems orchestrating the biology of the cell typically involve a complex web of interactions among various components and span a vast range of spatial and temporal scales. Computational methods have advanced our understanding of the behavior of molecular systems by enabling us to test assumptions and hypotheses, explore the effect of different parameters on the outcome, and eventually guide experiments. While several different mathematical and computational methods are developed to study molecular systems at different spatiotemporal scales, there is still a need for methods that bridge the gap between spatially-detailed and computationally-efficient approaches. In this review, we summarize the capabilities of agent-based modeling (ABM) as an emerging molecular systems biology technique that provides researchers with a new tool in exploring the dynamics of molecular systems/pathways in health and disease. © 2018 WILEY Periodicals, Inc.

Species-Specific Detection of Mycosphaerella polygoni-cuspidati as a Biological Control Agent for Fallopia japonica by PCR Assay.

PubMed

Kurose, Daisuke; Furuya, Naruto; Saeki, Tetsuya; Tsuchiya, Kenichi; Tsushima, Seiya; Seier, Marion K

2016-10-01

The ascomycete fungus Mycosphaerella polygoni-cuspidati has been undergoing evaluation as a potential classical biological control agent for the invasive weed Fallopia japonica (Japanese knotweed), which has become troublesome in Europe and North America. In advance of the potential release of a biocontrol agent into a new environment, it is crucial to develop an effective monitoring system to enable the evaluation of agent establishment and dispersal within the target host population, as well as any potential attacks on non-target species. Therefore, a primer pair was designed for direct, rapid, and specific detection of the Japanese knotweed pathogen M. polygoni-cuspidati based on the sequences of the internal transcribed spacer regions including the 5.8S rDNA. A PCR product of approximately 298 bp was obtained only when the DNA extracted from mycelial fragments of M. polygoni-cuspidati was used. The lower limit of detection of the PCR method was 100 fg of genomic DNA. Using the specific primer pair, M. polygoni-cuspidati could be detected from both naturally and artificially infected Japanese knotweed plants. No amplification was observed for other Mycosphaerella spp. or fungal endophytes isolated from F. japonica. The designed primer pair is thus effective for the specific detection of M. polygoni-cuspidati in planta.

Biology and life history of Argopistes tsekooni (Coleoptera: Chrysomelidae) in China, a promising biological control agent of Chinese privet.

Treesearch

Y-Z Zhang; J. Sun; J.L. Hanula

2009-01-01

The biology and life history of Argopistes tsekooni Chen (Coleoptera: Chrysomelidae), a potential biological control agent of Chinese privet, Ligustrum sinense Lour., was studied under laboratory and outdoor conditions in Huangshan City of Anhui Province, China, in 2006. A. tsekooni larvae are leafminers that...

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

PubMed Central

Pasadhika, Sirichai; Rosenbaum, James T

2014-01-01

Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. PMID:24600203

Unbinding of targeted ultrasound contrast agent microbubbles by secondary acoustic forces.

PubMed

Garbin, Valeria; Overvelde, Marlies; Dollet, Benjamin; de Jong, Nico; Lohse, Detlef; Versluis, Michel

2011-10-07

Targeted molecular imaging with ultrasound contrast agent microbubbles is achieved by incorporating targeting ligands on the bubble coating and allows for specific imaging of tissues affected by diseases. Improved understanding of the interplay between the acoustic forces acting on the bubbles during insonation with ultrasound and other forces (e.g. shear due to blood flow, binding of targeting ligands to receptors on cell membranes) can help improve the efficacy of this technique. This work focuses on the effects of the secondary acoustic radiation force, which causes bubbles to attract each other and may affect the adhesion of targeted bubbles. First, we examine the translational dynamics of ultrasound contrast agent microbubbles in contact with (but not adherent to) a semi-rigid membrane due to the secondary acoustic radiation force. An equation of motion that effectively accounts for the proximity of the membrane is developed, and the predictions of the model are compared with experimental data extracted from optical recordings at 15 million frames per second. A time-averaged model is also proposed and validated. In the second part of the paper, initial results on the translation due to the secondary acoustic radiation force of targeted, adherent bubbles are presented. Adherent bubbles are also found to move due to secondary acoustic radiation force, and a restoring force is observed that brings them back to their initial positions. For increasing magnitude of the secondary acoustic radiation force, a threshold is reached above which the adhesion of targeted microbubbles is disrupted. This points to the fact that secondary acoustic radiation forces can cause adherent bubbles to detach and alter the spatial distribution of targeted contrast agents bound to tissues during activation with ultrasound. While the details of the rupture of intermolecular bonds remain elusive, this work motivates the use of the secondary acoustic radiation force to measure the strength

Application of chemical biology in target identification and drug discovery.

PubMed

Zhu, Yue; Xiao, Ting; Lei, Saifei; Zhou, Fulai; Wang, Ming-Wei

2015-09-01

Drug discovery and development is vital to the well-being of mankind and sustainability of the pharmaceutical industry. Using chemical biology approaches to discover drug leads has become a widely accepted path partially because of the completion of the Human Genome Project. Chemical biology mainly solves biological problems through searching previously unknown targets for pharmacologically active small molecules or finding ligands for well-defined drug targets. It is a powerful tool to study how these small molecules interact with their respective targets, as well as their roles in signal transduction, molecular recognition and cell functions. There have been an increasing number of new therapeutic targets being identified and subsequently validated as a result of advances in functional genomics, which in turn led to the discovery of numerous active small molecules via a variety of high-throughput screening initiatives. In this review, we highlight some applications of chemical biology in the context of drug discovery.

Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review.

PubMed

Mousavizadeh, Ali; Jabbari, Ali; Akrami, Mohammad; Bardania, Hassan

2017-10-01

Cell targeting peptides (CTP) are small peptides which have high affinity and specificity to a cell or tissue targets. They are typically identified by using phage display and chemical synthetic peptide library methods. CTPs have attracted considerable attention as a new class of ligands to delivery specifically therapeutic and diagnostic agents, because of the fact they have several advantages including easy synthesis, smaller physical sizes, lower immunogenicity and cytotoxicity and their simple and better conjugation to nano-carriers and therapeutic or diagnostic agents compared to conventional antibodies. In this systematic review, we will focus on the basic concepts concerning the use of cell-targeting peptides (CTPs), following the approaches of selecting them from peptide libraries. We discuss several developed strategies for cell-specific delivery of different cargos by CTPs, which are designed for drug delivery and diagnostic applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeted agents for patients with advanced/metastatic pancreatic cancer: A protocol for systematic review and network meta-analysis.

PubMed

Di, Baoshan; Pan, Bei; Ge, Long; Ma, Jichun; Wu, Yiting; Guo, Tiankang

2018-03-01

Pancreatic cancer (PC) is a devastating malignant tumor. Although surgical resection may offer a good prognosis and prolong survival, approximately 80% patients with PC are always diagnosed as unresectable tumor. National Comprehensive Cancer Network's (NCCN) recommended gemcitabine-based chemotherapy as efficient treatment. While, according to recent studies, targeted agents might be a better available option for advanced or metastatic pancreatic cancer patients. The aim of this systematic review and network meta-analysis will be to examine the differences of different targeted interventions for advanced/metastatic PC patients. We will conduct this systematic review and network meta-analysis using Bayesian method and according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. To identify relevant studies, 6 electronic databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of science, CNKI (Chinese National Knowledge Infrastructure), and CBM (Chinese Biological Medical Database) will be searched. The risk of bias in included randomized controlled trials (RCTs) will be assessed using the Cochrane Handbook version 5.1.0. And we will use GRADE approach to assess the quality of evidence from network meta-analysis. Data will be analyzed using R 3.4.1 software. To the best of our knowledge, this systematic review and network meta-analysis will firstly use both direct and indirect evidence to compare the differences of different targeted agents and targeted agents plus chemotherapy for advanced/metastatic pancreatic cancer patients. This is a protocol of systematic review and meta-analysis, so the ethical approval and patient consent are not required. We will disseminate the results of this review by submitting to a peer-reviewed journal.

Heterobivalent Imaging Agents Targeting Prostate Cancer Training

DTIC Science & Technology

2011-06-01

has been implicated as a salient player in the pathobiology of cancers of epithelial origin, e.g. prostate, cervix , ovarian, colon and...ANSI Std. Z39.18 W81XWH-10-1-0481 Heterobivalent Imaging Agents Targeting Prostate Cancer Training Aaron LeBeau University of California, San...Francisco San Francisco, CA 94103 Annual Summary 31 MAY 2010 - 1JUN 201101-06-2011 To determine the utility of imaging MT-SP1 in cancer , xenografts of

Multispectral photoacoustic decomposition with localized regularization for detecting targeted contrast agent

NASA Astrophysics Data System (ADS)

Tavakoli, Behnoosh; Chen, Ying; Guo, Xiaoyu; Kang, Hyun Jae; Pomper, Martin; Boctor, Emad M.

2015-03-01

Targeted contrast agents can improve the sensitivity of imaging systems for cancer detection and monitoring the treatment. In order to accurately detect contrast agent concentration from photoacoustic images, we developed a decomposition algorithm to separate photoacoustic absorption spectrum into components from individual absorbers. In this study, we evaluated novel prostate-specific membrane antigen (PSMA) targeted agents for imaging prostate cancer. Three agents were synthesized through conjugating PSMA-targeting urea with optical dyes ICG, IRDye800CW and ATTO740 respectively. In our preliminary PA study, dyes were injected in a thin wall plastic tube embedded in water tank. The tube was illuminated with pulsed laser light using a tunable Q-switch ND-YAG laser. PA signal along with the B-mode ultrasound images were detected with a diagnostic ultrasound probe in orthogonal mode. PA spectrums of each dye at 0.5 to 20 μM concentrations were estimated using the maximum PA signal extracted from images which are obtained at illumination wavelengths of 700nm-850nm. Subsequently, we developed nonnegative linear least square optimization method along with localized regularization to solve the spectral unmixing. The algorithm was tested by imaging mixture of those dyes. The concentration of each dye was estimated with about 20% error on average from almost all mixtures albeit the small separation between dyes spectrums.

PERMANENCE OF BIOLOGICAL AND CHEMICAL WARFARE AGENTS IN MUNICIPAL SOLID WASTE LANDFILL LEACHATES

EPA Science Inventory

The objective of this work is to permit EPA/ORD's National Homeland Security Research Center (NHSRC) and Edgewood Chemical Biological Center to collaborate together to test the permanence of biological and chemical warfare agents in municipal solid waste landfills. Research into ...

Development of Anti-Infectives Using Phage Display: Biological Agents against Bacteria, Viruses, and Parasites

PubMed Central

Huang, Johnny X.; Bishop-Hurley, Sharon L.

2012-01-01

The vast majority of anti-infective therapeutics on the market or in development are small molecules; however, there is now a nascent pipeline of biological agents in development. Until recently, phage display technologies were used mainly to produce monoclonal antibodies (MAbs) targeted against cancer or inflammatory disease targets. Patent disputes impeded broad use of these methods and contributed to the dearth of candidates in the clinic during the 1990s. Today, however, phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens, ranging from whole cells to proteins and lipid targets. In this review, we highlight research that exploits phage display technology as a means of discovering novel therapeutics against infectious diseases, with a focus on antimicrobial peptides and antibodies in clinical or preclinical development. We discuss the different strategies and methods used to derive, select, and develop anti-infectives from phage display libraries and then highlight case studies of drug candidates in the process of development and commercialization. Advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens. PMID:22664969

Development of anti-infectives using phage display: biological agents against bacteria, viruses, and parasites.

PubMed

Huang, Johnny X; Bishop-Hurley, Sharon L; Cooper, Matthew A

2012-09-01

The vast majority of anti-infective therapeutics on the market or in development are small molecules; however, there is now a nascent pipeline of biological agents in development. Until recently, phage display technologies were used mainly to produce monoclonal antibodies (MAbs) targeted against cancer or inflammatory disease targets. Patent disputes impeded broad use of these methods and contributed to the dearth of candidates in the clinic during the 1990s. Today, however, phage display is recognized as a powerful tool for selecting novel peptides and antibodies that can bind to a wide range of antigens, ranging from whole cells to proteins and lipid targets. In this review, we highlight research that exploits phage display technology as a means of discovering novel therapeutics against infectious diseases, with a focus on antimicrobial peptides and antibodies in clinical or preclinical development. We discuss the different strategies and methods used to derive, select, and develop anti-infectives from phage display libraries and then highlight case studies of drug candidates in the process of development and commercialization. Advances in screening, manufacturing, and humanization technologies now mean that phage display can make a significant contribution in the fight against clinically important pathogens.

Connexin 43-targeted T1 contrast agent for MRI diagnosis of glioma.

PubMed

Abakumova, Tatiana; Abakumov, Maxim; Shein, Sergey; Chelushkin, Pavel; Bychkov, Dmitry; Mukhin, Vladimir; Yusubalieva, Gaukhar; Grinenko, Nadezhda; Kabanov, Alexander; Nukolova, Natalia; Chekhonin, Vladimir

2016-01-01

Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T1 relaxivity (6.5 mM(-1) s(-1) at 7 T) than the commercial agent Magnevist® (3.4 mM(-1) s(-1)). Cellular uptake of Cx43-specific T1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI. Copyright © 2015 John Wiley & Sons, Ltd.

76 FR 3076 - Availability of an Environmental Assessment for a Biological Control Agent for Air Potato

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-19

...] Availability of an Environmental Assessment for a Biological Control Agent for Air Potato AGENCY: Animal and... environmental assessment (EA) relative to the control of air potato (Dioscorea bulbifera). The EA considers the... States for use as a biological control agent to reduce the severity of air potato infestations. We are...

Computation of the target state and feedback controls for time optimal consensus in multi-agent systems

NASA Astrophysics Data System (ADS)

Mulla, Ameer K.; Patil, Deepak U.; Chakraborty, Debraj

2018-02-01

N identical agents with bounded inputs aim to reach a common target state (consensus) in the minimum possible time. Algorithms for computing this time-optimal consensus point, the control law to be used by each agent and the time taken for the consensus to occur, are proposed. Two types of multi-agent systems are considered, namely (1) coupled single-integrator agents on a plane and, (2) double-integrator agents on a line. At the initial time instant, each agent is assumed to have access to the state information of all the other agents. An algorithm, using convexity of attainable sets and Helly's theorem, is proposed, to compute the final consensus target state and the minimum time to achieve this consensus. Further, parts of the computation are parallelised amongst the agents such that each agent has to perform computations of O(N2) run time complexity. Finally, local feedback time-optimal control laws are synthesised to drive each agent to the target point in minimum time. During this part of the operation, the controller for each agent uses measurements of only its own states and does not need to communicate with any neighbouring agents.

Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis.

PubMed

Mei, Wei-Qun; Hu, Hui-Zhen; Liu, Ying; Li, Zhi-Chen; Wang, Wei-Guo

2015-05-21

To compare the efficacy and safety of biological agents for the treatment of active ulcerative colitis (UC). PubMed, MEDLINE, EMBASE and the Cochrane library were searched to screen relevant articles from January 1996 to August 2014. The mixed treatment comparison meta-analysis within a Bayesian framework was performed using WinBUGS14 software. The proportions of patients reaching clinical response, clinical remission and mucosal healing in induction and maintenance phases were analyzed as efficacy indicators. Serious adverse events in maintenance phase were analyzed as safety indicators. The meta-analysis results showed that biological agents achieved better clinical response, clinical remission and mucosal healing than placebo. Indirect comparison indicated that in induction phase, infliximab was more effective than adalimumab in inducing clinical response (OR = 0.41, 95%CI: 0.29-0.57), clinical remission (OR = 0.33, 95%CI: 0.19-0.56) and mucosal healing (OR = 0.33, 95%CI: 0.19-0.56), and golimumab in inducing clinical response (OR = 0.66, 95%CI: 0.39-2.33) and mucosal healing (OR = 2.15, 95%CI: 1.18-4.22). No significant difference was found between placebo and biological agents regarding their safety. All biological agents were superior to placebo for UC treatment in both induction and maintenance phases with a similar safety profile, and infliximab had a better clinical effect than the other biological agents.

On-Demand Targeting: Investigating Biology with Proximity-Directed Chemistry.

PubMed

Long, Marcus J C; Poganik, Jesse R; Aye, Yimon

2016-03-23

Proximity enhancement is a central chemical tenet underpinning an exciting suite of small-molecule toolsets that have allowed us to unravel many biological complexities. The leitmotif of this opus is "tethering"-a strategy in which a multifunctional small molecule serves as a template to bring proteins/biomolecules together. Scaffolding approaches have been powerfully applied to control diverse biological outcomes such as protein-protein association, protein stability, activity, and improve imaging capabilities. A new twist on this strategy has recently appeared, in which the small-molecule probe is engineered to unleash controlled amounts of reactive chemical signals within the microenvironment of a target protein. Modification of a specific target elicits a precisely timed and spatially controlled gain-of-function (or dominant loss-of-function) signaling response. Presented herein is a unique personal outlook conceptualizing the powerful proximity-enhanced chemical biology toolsets into two paradigms: "multifunctional scaffolding" versus "on-demand targeting". By addressing the latest advances and challenges in the established yet constantly evolving multifunctional scaffolding strategies as well as in the emerging on-demand precision targeting (and related) systems, this Perspective is aimed at choosing when it is best to employ each of the two strategies, with an emphasis toward further promoting novel applications and discoveries stemming from these innovative chemical biology platforms.

Mode of Infection of Metarhizium spp. Fungus and Their Potential as Biological Control Agents

PubMed Central

Aw, Kimberly Moon San; Hue, Seow Mun

2017-01-01

Chemical insecticides have been commonly used to control agricultural pests, termites, and biological vectors such as mosquitoes and ticks. However, the harmful impacts of toxic chemical insecticides on the environment, the development of resistance in pests and vectors towards chemical insecticides, and public concern have driven extensive research for alternatives, especially biological control agents such as fungus and bacteria. In this review, the mode of infection of Metarhizium fungus on both terrestrial and aquatic insect larvae and how these interactions have been widely employed will be outlined. The potential uses of Metarhizium anisopliae and Metarhizium acridum biological control agents and molecular approaches to increase their virulence will be discussed. PMID:29371548

Bioterrorism and Biocrimes: The Illicit Use of Biological Agents Since 1900

DTIC Science & Technology

2001-02-01

to white supremacist groups, including the Aryan Nation and the Christian Identity movement, he 5 involve allegations of covert state activities ...toxin to poison livestock in what is now Kenya. The full extent of these activities is not known. Polish Resistance: Multiple reports suggest that...thorough reporting of Aum’s biological warfare activities . See page 47 for additional details. Table 1: Confirmed cases of illicit biological agent activity

Platinum-based anticancer agents: innovative design strategies and biological perspectives.

PubMed

Ho, Yee-Ping; Au-Yeung, Steve C F; To, Kenneth K W

2003-09-01

The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA-Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA-Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future. Copyright 2003 Wiley Periodicals, Inc.

Axinellamines as Broad-Spectrum Antibacterial Agents: Scalable Synthesis and Biology

PubMed Central

2015-01-01

Antibiotic-resistant bacteria present an ongoing challenge to both chemists and biologists as they seek novel compounds and modes of action to out-maneuver continually evolving resistance pathways, especially against Gram-negative strains. The dimeric pyrrole–imidazole alkaloids represent a unique marine natural product class with diverse primary biological activity and chemical architecture. This full account traces the strategy used to develop a second-generation route to key spirocycle 9, culminating in a practical synthesis of the axinellamines and enabling their discovery as broad-spectrum antibacterial agents, with promising activity against both Gram-positive and Gram-negative bacteria. While their detailed mode of antibacterial action remains unclear, the axinellamines appear to cause secondary membrane destabilization and impart an aberrant cellular morphology consistent with the inhibition of normal septum formation. This study serves as a rare example of a natural product initially reported to be devoid of biological activity surfacing as an active antibacterial agent with an intriguing mode of action. PMID:25328977

Selection of reference genes for RT-qPCR analysis in a predatory biological control agent, Coleomegilla maculata (Coleoptera: Coccinellidae).

PubMed

Yang, Chunxiao; Pan, Huipeng; Noland, Jeffrey Edward; Zhang, Deyong; Zhang, Zhanhong; Liu, Yong; Zhou, Xuguo

2015-12-10

Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable technique for quantifying gene expression across various biological processes, of which requires a set of suited reference genes to normalize the expression data. Coleomegilla maculata (Coleoptera: Coccinellidae), is one of the most extensively used biological control agents in the field to manage arthropod pest species. In this study, expression profiles of 16 housekeeping genes selected from C. maculata were cloned and investigated. The performance of these candidates as endogenous controls under specific experimental conditions was evaluated by dedicated algorithms, including geNorm, Normfinder, BestKeeper, and ΔCt method. In addition, RefFinder, a comprehensive platform integrating all the above-mentioned algorithms, ranked the overall stability of these candidate genes. As a result, various sets of suitable reference genes were recommended specifically for experiments involving different tissues, developmental stages, sex, and C. maculate larvae treated with dietary double stranded RNA. This study represents the critical first step to establish a standardized RT-qPCR protocol for the functional genomics research in a ladybeetle C. maculate. Furthermore, it lays the foundation for conducting ecological risk assessment of RNAi-based gene silencing biotechnologies on non-target organisms; in this case, a key predatory biological control agent.

Enhancement of biological control agents for use against forest insect pests and diseases through biotechnology

NASA Technical Reports Server (NTRS)

Slavicek, James M.

1991-01-01

Research and development efforts in our research group are focused on the generation of more efficacious biological control agents through the techniques of biotechnology for use against forest insect pests and diseases. Effective biological controls for the gypsy moth and for tree fungal wilt pathogens are under development. The successful use of Gypchek, a formulation of the Lymantria dispar nuclear polyhedrosis virus (LdNPV), in gypsy moth control programs has generated considerable interest in that agent. As a consequence of its specificity, LdPNV has negligible adverse ecological impacts compared to most gypsy moth control agents. However, LdNPV is not competitive with other control agents in terms of cost and efficacy. We are investigating several parameters of LdNPV replication and polyhedra production in order to enhance viral potency and efficacy thus mitigating the current disadvantages of LdNPV for gypsy moth control, and have identified LdNPV variants that will facilitate these efforts. Tree endophytic bacteria that synthesize antifungal compounds were identified and an antibiotic compound from one of these bacteria was characterized. The feasibility of developing tree endophytes as biological control agents for tree vascular fungal pathogens is being investigated.

Novel targeted therapies for eosinophilic disorders

PubMed Central

Wechsler, Michael E.; Fulkerson, Patricia C.; Bochner, Bruce S.; Gauvreau, Gail M.; Gleich, Gerald J.; Henkel, Tim; Kolbeck, Roland; Mathur, Sameer K.; Ortega, Hector; Patel, Jatin; Prussin, Calman; Renzi, Paolo; Rothenberg, Marc E.; Roufosse, Florence; Simon, Dagmar; Simon, Hans-Uwe; Wardlaw, Andrew; Weller, Peter F.; Klion, Amy D.

2013-01-01

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. PMID:22935585

Can we forecast the effects of climate change on entomophagous biological control agents?

PubMed

Aguilar-Fenollosa, Ernestina; Jacas, Josep A

2014-06-01

The worldwide climate has been changing rapidly over the past decades. Air temperatures have been increasing in most regions and will probably continue to rise for most of the present century, regardless of any mitigation policy put in place. Although increased herbivory from enhanced biomass production and changes in plant quality are generally accepted as a consequence of global warming, the eventual status of any pest species will mostly depend on the relative effects of climate change on its own versus its natural enemies' complex. Because a bottom-up amplification effect often occurs in trophic webs subjected to any kind of disturbance, natural enemies are expected to suffer the effects of climate change to a greater extent than their phytophagous hosts/preys. A deeper understanding of the genotypic diversity of the populations of natural enemies and their target pests will allow an informed reaction to climate change. New strategies for the selection of exotic natural enemies and their release and establishment will have to be adopted. Conservation biological control will probably become the keystone for the successful management of these biological control agents. © 2013 Society of Chemical Industry.

Specialty Tier-Level Cost Sharing and Biologic Agent Use in the Medicare Part D Initial Coverage Period Among Beneficiaries With Rheumatoid Arthritis.

PubMed

Doshi, Jalpa A; Hu, Tianyan; Li, Pengxiang; Pettit, Amy R; Yu, Xinyan; Blum, Marissa

2016-11-01

To examine associations between specialty tier-level cost sharing and use of biologic agents for rheumatoid arthritis (RA) during Medicare Part D's initial coverage period (ICP). This was a retrospective study using 2007-2010 5% sample Medicare files to examine RA patients with use of a Part D RA biologic agent in the prior year. Patients without low-income subsidies (non-LIS group), who faced specialty tier-level cost sharing, were compared to a control group of low-income subsidy patients (LIS group), who faced nominal out-of-pocket costs in the ICP. Outcomes included use of a Part D or Part B RA biologic agent during the ICP and presence of a ≥30-day continuous gap in treatment among Part D biologic agent users in the ICP. Risk-adjusted outcomes were estimated using logistic regressions, controlling for patient demographic, clinical, and Part D plan characteristics. On average, a 30-day Part D biologic agent supply cost the non-LIS group $484 out of pocket (29.9% cost sharing) versus $5 (0.3% cost sharing) for the LIS group. The non-LIS group was less likely to fill Part D biologic agents (61.2% versus 72.7%, odds ratio [OR] 0.58 [95% confidence interval (95% CI) 0.46-0.72]; P < 0.001), more than twice as likely to receive Part B biologic agents (9.9% versus 4.4%, OR 2.41 [95% CI 1.61-3.60]; P < 0.001), and less likely to use any biologic agent (70.1% versus 76.9%, OR 0.69 [95% CI 0.55-0.88]; P = 0.002). The non-LIS subgroup filling Part D biologic agents had approximately twice the odds of a gap in both Part D biologic agent and any biologic agent availability. Specialty tier-level cost sharing was associated with interruptions in RA biologic agent treatment among Medicare patients. © 2016, American College of Rheumatology.

Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis

PubMed Central

Mei, Wei-Qun; Hu, Hui-Zhen; Liu, Ying; Li, Zhi-Chen; Wang, Wei-Guo

2015-01-01

AIM: To compare the efficacy and safety of biological agents for the treatment of active ulcerative colitis (UC). METHODS: PubMed, MEDLINE, EMBASE and the Cochrane library were searched to screen relevant articles from January 1996 to August 2014. The mixed treatment comparison meta-analysis within a Bayesian framework was performed using WinBUGS14 software. The proportions of patients reaching clinical response, clinical remission and mucosal healing in induction and maintenance phases were analyzed as efficacy indicators. Serious adverse events in maintenance phase were analyzed as safety indicators. RESULTS: The meta-analysis results showed that biological agents achieved better clinical response, clinical remission and mucosal healing than placebo. Indirect comparison indicated that in induction phase, infliximab was more effective than adalimumab in inducing clinical response (OR = 0.41, 95%CI: 0.29-0.57), clinical remission (OR = 0.33, 95%CI: 0.19-0.56) and mucosal healing (OR = 0.33, 95%CI: 0.19-0.56), and golimumab in inducing clinical response (OR = 0.66, 95%CI: 0.39-2.33) and mucosal healing (OR = 2.15, 95%CI: 1.18-4.22). No significant difference was found between placebo and biological agents regarding their safety. CONCLUSION: All biological agents were superior to placebo for UC treatment in both induction and maintenance phases with a similar safety profile, and infliximab had a better clinical effect than the other biological agents. PMID:26019471

New era of biologic therapeutics in atopic dermatitis.

PubMed

Guttman-Yassky, Emma; Dhingra, Nikhil; Leung, Donald Y M

2013-04-01

Atopic dermatitis (AD) is a common inflammatory skin disease regulated by genetic and environmental factors. Both skin barrier defects and aberrant immune responses are believed to drive cutaneous inflammation in AD. Existing therapies rely largely on allergen avoidance, emollients and topical and systemic immune-suppressants, some with significant toxicity and transient efficacy; no specific targeted therapies are in clinical use today. As our specific understanding of the immune and molecular pathways that cause different subsets of AD increases, a variety of experimental agents, particularly biologic agents that target pathogenic molecules bring the promise of safe and effective therapeutics for long-term use. This paper discusses the molecular pathways characterizing AD, the contributions of barrier and immune abnormalities to its pathogenesis, and development of new treatments that target key molecules in these pathways. In this review, we will discuss a variety of biologic therapies that are in development or in clinical trials for AD, perhaps revolutionizing treatment of this disease. Biologic agents in moderate to severe AD offer promise for controlling a disease that currently lacks good and safe therapeutics posing a large unmet need. Unfortunately, existing treatments for AD aim to decrease cutaneous inflammation, but are not specific for the pathways driving this disease. An increasing understanding of the immune mechanisms underlying AD brings the promise of narrow targeted therapies as has occurred for psoriasis, another inflammatory skin disease, for which specific biologic agents have been demonstrated to both control the disease and prevent occurrence of new skin lesions. Although no biologic is yet approved for AD, these are exciting times for active therapeutic development in AD that might lead to revolutionary therapeutics for this disease.

Fluctuation-Enhanced Sensing for Biological Agent Detection and Identification

DTIC Science & Technology

2009-01-01

method for bacterium detection published earlier; sensing and evaluating the odors of microbes ; and spectral and amplitude distribution analysis of noise...REPORT TYPE 3. DATES COVERED 00-00-2009 to 00-00-2009 4. TITLE AND SUBTITLE Fluctuation-Enhanced Sensing for Biological Agent Detection and...evaluating the odors of microbes ; and spectral and amplitude distribution analysis of noise in light scattering to identify spores based on their

Biology and host range of Tecmessa elegans (Lepidoptera: Notodontidae), a leaf-feeding moth evaluated as a potential biological control agent for Schinus terebinthifolius (Sapindales: Anacardiaceae) in the United States.

PubMed

Oleiro, Marina; Mc Kay, Fernando; Wheeler, Gregory S

2011-06-01

During surveys for natural enemies that could be used as classical biological control agents of Schinus terebinthifolius Raddi (Brazilian pepper), the caterpillar, Tecmessa elegans Schaus (Lepidoptera: Notodontidae), was recorded feeding on the leaves of the shrub in South America. The biology and larval and adult host range of this species were examined to determine the insect's suitability for biological control of this invasive weed in North America and Hawaii. Biological observations indicate that the larvae have five instars. When disturbed, the late instar larvae emit formic acid from a prothoracic gland that may protect larvae from generalist predators. Larval host range tests conducted both in South and North America indicated that this species feeds and completes development primarily on members of the Anacardiaceae within the tribe Rhoeae. Oviposition tests indicated that when given a choice in large cages the adults will select the target weed over Pistacia spp. However, considering the many valued plant species in its host range, especially several North American natives, this species will not be considered further for biological control of S. terebinthifolius in North America.

Selective Targeting of Antiviral and Immunomodulating Agents in the Treatment of Arenavirus Infections

DTIC Science & Technology

1987-10-01

observed with free MTP-PE. In addition to our observations on peritoneal and alveolar macrophages, we also examined the effect of MTP-PE treatment on liver...Ir OIC FILE COPY C2 ILn 00 NM AD _____ N SELECTIVE TARGETING OF ANTIVIRAL AND IMMUNOMODULATING AGENTS IN THE TREATMENT OF ARENAVIRUS INFECTIONS "Kc...Selective Targeting of Antiviral and Immunomodulating Agents in the Treatment of Arenavirus Injections 12. PERSONAL AUTHOR(S) J. David Gangemi 13a. TYPE OF

Development of contrast agents targeted to macrophage scavenger receptors for MRI of vascular inflammation

PubMed Central

Gustafsson, Björn; Youens, Susan; Louie, Angelique Y.

2008-01-01

Atherosclerosis is a leading cause of death in the U.S. Because there is a potential to prevent coronary and arterial diseases through early diagnosis, there is a need for methods to image arteries in the sub-clinical stage as well as clinical stage using various non-invasive techniques, including Magnetic Resonance Imaging (MRI). We describe a development of a novel MRI contrast agent targeted to plaques that will allow imaging of lesion formation. The contrast agent is directed to macrophages, one of the earliest components of developing plaques. Macrophages are labeled through the macrophage scavenger receptor A, a macrophage specific cell surface protein, using an MRI contrast agent derived from scavenger receptor ligands. We have synthesized and characterized these contrast agents with a range of relaxivities. In vitro studies show that the targeted contrast agent accumulates in macrophages and solution studies indicate that micromolar concentrations are sufficient to produce contrast in an MR image. Cell toxicity and initial biodistribution studies indicate low toxicity, no detectable retention in normal blood vessels, and rapid clearance from blood. The promising performance of this contrast agent targeted towards vascular inflammation opens doors to tracking of other inflammatory diseases such as tumor immunotherapy and transplant acceptance using MRI. PMID:16536488

Method and apparatus for the gas phase decontamination of chemical and biological agents

DOEpatents

O'Neill, Hugh J.; Brubaker, Kenneth L.

2003-10-07

An apparatus and method for decontaminating chemical and biological agents using the reactive properties of both the single atomic oxygen and the hydroxyl radical for the decontamination of chemical and biological agents. The apparatus is self contained and portable and allows for the application of gas reactants directly at the required decontamination point. The system provides for the use of ultraviolet light of a specific spectral range to photolytically break down ozone into molecular oxygen and hydroxyl radicals where some of the molecular oxygen is in the first excited state. The excited molecular oxygen will combine with water vapor to produce two hydroxyl radicals.

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

PubMed Central

2018-01-01

Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids. PMID:29468872

Factors affecting the flight capacity of Tetrastichus planipennisi (Hymenoptera: Eulophidae), a classical biological control agent of Agrilus planipennis (Coleoptera: Buprestidae).

PubMed

Fahrner, Samuel J; Lelito, Jonathan P; Blaedow, Karen; Heimpel, George E; Aukema, Brian H

2014-12-01

The dispersal characteristics of a biological control agent can have direct implications on the ability of that agent to control populations of a target host. Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae) is a parasitic wasp native to eastern Asia that has been introduced into the United States as part of a classical biological control program against the emerald ash borer Agrilus planipennis Fairmaire (Coleoptera: Buprestidae). We used computer-monitored flight mills to investigate the role of age, feeding status, mating status, and size on the flight capacity of female T. planipennisi over a 24-h period. We also compared flight capacity between sexes. Flight distance of female T. planipennisi representative of populations released in the biological control program averaged 1.26 km in 24 h with a maximum flight of just over 7 km. Median flight distance, however, was 422 m. The flight capacity of females fed a honey-water solution was 41× that of females provided only water, who flew very little. Larger females were capable of flying farther distances, but age did not affect the flight capacity of females up to 70 d posteclosion. Females dispersed 6× farther than did their smaller, male counterparts. The implications of our findings to host-parasitoid interactions and release protocols for distributing T. planipennisi are discussed.

Biologic agents for anterior cruciate ligament healing: A systematic review

PubMed Central

Di Matteo, Berardo; Loibl, Markus; Andriolo, Luca; Filardo, Giuseppe; Zellner, Johannes; Koch, Matthias; Angele, Peter

2016-01-01

AIM To systematically review the currently available literature concerning the application of biologic agents such as platelet-rich plasma (PRP) and stem cells to promote anterior cruciate ligament (ACL) healing. METHODS A systematic review of the literature was performed on the use of biologic agents (i.e., PRP or stem cells) to favor ACL healing during reconstruction or repair. The following inclusion criteria for relevant articles were used: Clinical reports of any level of evidence, written in English language, on the use of PRP or stem cells during ACL reconstruction/repair. Exclusion criteria were articles written in other languages, reviews, or studies analyzing other applications of PRP/stem cells in knee surgery not related to promoting ACL healing. RESULTS The database search identified 394 records that were screened. A total of 23 studies were included in the final analysis: In one paper stem cells were applied for ACL healing, in one paper there was a concomitant application of PRP and stem cells, whereas in the remaining 21 papers PRP was used. Based on the ACL injury pattern, two papers investigated biologic agents in ACL partial tears whereas 21 papers in ACL reconstruction. Looking at the quality of the available literature, 17 out of 21 studies dealing with ACL reconstruction were randomized controlled trials. Both studies on ACL repair were case series. CONCLUSION There is a paucity of clinical trials investigating the role of stem cells in promoting ACL healing both in case of partial and complete tears. The role of PRP is still controversial and the only advantage emerging from the literature is related to a better graft maturation over time, without documenting beneficial effects in terms of clinical outcome, bone-graft integration and prevention of bony tunnel enlargement. PMID:27672573

Biocompatible Nanocomplexes for Molecular Targeted MRI Contrast Agent

NASA Astrophysics Data System (ADS)

Chen, Zhijin; Yu, Dexin; Wang, Shaojie; Zhang, Na; Ma, Chunhong; Lu, Zaijun

2009-07-01

Accurate diagnosis in early stage is vital for the treatment of Hepatocellular carcinoma. The aim of this study was to investigate the potential of poly lactic acid-polyethylene glycol/gadolinium-diethylenetriamine-pentaacetic acid (PLA-PEG/Gd-DTPA) nanocomplexes using as biocompatible molecular magnetic resonance imaging (MRI) contrast agent. The PLA-PEG/Gd-DTPA nanocomplexes were obtained using self-assembly nanotechnology by incubation of PLA-PEG nanoparticles and the commercial contrast agent, Gd-DTPA. The physicochemical properties of nanocomplexes were measured by atomic force microscopy and photon correlation spectroscopy. The T1-weighted MR images of the nanocomplexes were obtained in a 3.0 T clinical MR imager. The stability study was carried out in human plasma and the distribution in vivo was investigated in rats. The mean size of the PLA-PEG/Gd-DTPA nanocomplexes was 187.9 ± 2.30 nm, and the polydispersity index was 0.108, and the zeta potential was -12.36 ± 3.58 mV. The results of MRI test confirmed that the PLA-PEG/Gd-DTPA nanocomplexes possessed the ability of MRI, and the direct correlation between the MRI imaging intensities and the nano-complex concentrations was observed ( r = 0.987). The signal intensity was still stable within 2 h after incubation of the nanocomplexes in human plasma. The nanocomplexes gave much better image contrast effects and longer stagnation time than that of commercial contrast agent in rat liver. A dose of 0.04 mmol of gadolinium per kilogram of body weight was sufficient to increase the MRI imaging intensities in rat livers by five-fold compared with the commercial Gd-DTPA. PLA-PEG/Gd-DTPA nanocomplexes could be prepared easily with small particle sizes. The nanocomplexes had high plasma stability, better image contrast effect, and liver targeting property. These results indicated that the PLA-PEG/Gd-DTPA nanocomplexes might be potential as molecular targeted imaging contrast agent.

Plasma flame for mass purification of contaminated air with chemical and biological warfare agents

NASA Astrophysics Data System (ADS)

Uhm, Han S.; Shin, Dong H.; Hong, Yong C.

2006-09-01

An elimination of airborne simulated chemical and biological warfare agents was carried out by making use of a plasma flame made of atmospheric plasma and a fuel-burning flame, which can purify the interior air of a large volume in isolated spaces such as buildings, public transportation systems, and military vehicles. The plasma flame generator consists of a microwave plasma torch connected in series to a fuel injector and a reaction chamber. For example, a reaction chamber, with the dimensions of a 22cm diameter and 30cm length, purifies an airflow rate of 5000lpm contaminated with toluene (the simulated chemical agent) and soot from a diesel engine (the simulated aerosol for biological agents). Large volumes of purification by the plasma flame will free mankind from the threat of airborne warfare agents. The plasma flame may also effectively purify air that is contaminated with volatile organic compounds, in addition to eliminating soot from diesel engines as an environmental application.

Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

PubMed Central

Zhang, Yilong; Jain, Rajul K.; Zhu, Min

2015-01-01

The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed. PMID:28536405

Imaging efficacy of a targeted imaging agent for fluorescence endoscopy

NASA Astrophysics Data System (ADS)

Healey, A. J.; Bendiksen, R.; Attramadal, T.; Bjerke, R.; Waagene, S.; Hvoslef, A. M.; Johannesen, E.

2008-02-01

Colorectal cancer is a major cause of cancer death. A significant unmet clinical need exists in the area of screening for earlier and more accurate diagnosis and treatment. We have identified a fluorescence imaging agent targeted to an early stage molecular marker for colorectal cancer. The agent is administered intravenously and imaged in a far red imaging channel as an adjunct to white light endoscopy. There is experimental evidence of preclinical proof of mechanism for the agent. In order to assess potential clinical efficacy, imaging was performed with a prototype fluorescence endoscope system designed to produce clinically relevant images. A clinical laparoscope system was modified for fluorescence imaging. The system was optimised for sensitivity. Images were recorded at settings matching those expected with a clinical endoscope implementation (at video frame rate operation). The animal model was comprised of a HCT-15 xenograft tumour expressing the target at concentration levels expected in early stage colorectal cancer. Tumours were grown subcutaneously. The imaging agent was administered intravenously at a dose of 50nmol/kg body weight. The animals were killed 2 hours post administration and prepared for imaging. A 3-4mm diameter, 1.6mm thick slice of viable tumour was placed over the opened colon and imaged with the laparoscope system. A receiver operator characteristic analysis was applied to imaging results. An area under the curve of 0.98 and a sensitivity of 87% [73, 96] and specificity of 100% [93, 100] were obtained.

Near infrared spectral polarization imaging of prostate cancer tissues using Cybesin: a receptor-targeted contrast agent

NASA Astrophysics Data System (ADS)

Pu, Yang; Wang, W. B.; Tang, G. C.; Liang, Kexian; Achilefu, S.; Alfano, R. R.

2013-03-01

Cybesin, a smart contrast agent to target cancer cells, was investigated using a near infrared (NIR) spectral polarization imaging technique for prostate cancer detection. The approach relies on applying a contrast agent that can target cancer cells. Cybesin, as a small ICG-derivative dye-peptide, emit fluorescence between 750 nm and 900 nm, which is in the "tissue optical window". Cybesin was reported targeting the over-expressed bombesin receptors in cancer cells in animal model and the human prostate cancers over-expressing bombesin receptors. The NIR spectral polarization imaging study reported here demonstrated that Cybesin can be used as a smart optical biomarker and as a prostate cancer receptor targeted contrast agent.

Diverse Molecular Targets for Chalcones with Varied Bioactivities

PubMed Central

Zhou, Bo; Xing, Chengguo

2015-01-01

Natural or synthetic chalcones with different substituents have revealed a variety of biological activities that may benefit human health. The underlying mechanisms of action, particularly with respect to the direct cellular targets and the modes of interaction with the targets, have not been rigorously characterized, which imposes challenges to structure-guided rational development of therapeutic agents or chemical probes with acceptable target-selectivity profile. This review summarizes literature evidence on chalcones’ direct molecular targets in the context of their biological activities. PMID:26798565

Biological Warfare Agents, Toxins, Vectors and Pests as Biological Terrorism Agents

DTIC Science & Technology

2003-07-01

number of positive answers. According to criterion, no effective prophylaxis or therapy, positive answer signifies the absence of effective ...likelihood that the agent will be used. There are not effective prophylaxis and therapy against for the bulk of enlisted agents and toxins if used as...difficult to imagine how it would be looked like mass- vaccination often maybe simultaneously against more than one disease. Toxins are effective and

A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent.

PubMed

Xiong, Fei; Hu, Ke; Yu, Haoli; Zhou, Lijun; Song, Lina; Zhang, Yu; Shan, Xiuhong; Liu, Jianping; Gu, Ning

2017-08-01

Tumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent. In this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe 3 O 4 @OA NPs. The stability and anti phagocytosis of Fe 3 O 4 @OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo. These functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose. The DG can validly enhance the tumor-targetting effect of Fe 3 O 4 @OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

Mobile Robot Enabled Detection of Explosives and Biological Agents

DTIC Science & Technology

2006-11-01

Detection of Explosives and Biological Agents 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) 5d. PROJECT NUMBER 5e...TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) Wayne State University, SSIM Program, Detroit, Michigan 48202 8...PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME( S ) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM( S ) 11. SPONSOR

Systems biology approaches and tools for analysis of interactomes and multi-target drugs.

PubMed

Schrattenholz, André; Groebe, Karlfried; Soskic, Vukic

2010-01-01

diseases" remains a most pressing medical need. Currently, a change of paradigm can be observed with regard to a new interest in agents that modulate multiple targets simultaneously, essentially "dirty drugs." Targeting cellular function as a system rather than on the level of the single target, significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data. But the key is the extraction of relevant molecular information from biological systems by implementing rigid statistical procedures to differential proteomic analytics.

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

PubMed

Islam, Tania; Rahman, Rezanur; Gov, Esra; Turanli, Beste; Gulfidan, Gizem; Haque, Anwarul; Arga, Kazım Yalçın; Haque Mollah, Nurul

2018-06-01

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Current and emerging biologics for ulcerative colitis.

PubMed

Park, Sung Chul; Jeen, Yoon Tae

2015-01-01

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are be-ing used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.

Current and Emerging Biologics for Ulcerative Colitis

PubMed Central

Park, Sung Chul; Jeen, Yoon Tae

2015-01-01

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are being investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are being used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage. PMID:25547087

Transferrin receptors and the targeted delivery of therapeutic agents against cancer

PubMed Central

Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

2012-01-01

Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

Short-term efficacy and safety of new biological agents targeting the interleukin-23-T helper 17 pathway for moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis.

PubMed

Gómez-García, F; Epstein, D; Isla-Tejera, B; Lorente, A; Vélez García-Nieto, A; Ruano, J

2017-03-01

A new generation of biologics targeting the interleukin-23-T helper 17 pathway has been developed. This study aimed to assess the short-term effectiveness and safety of these new agents using a network meta-analysis. Twenty-seven randomized clinical trials (10 629 patients) were identified by a comprehensive systematic literature review (PROSPERO 2015: CRD42015025472). Quality of evidence was assessed following Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations approach. Efficacy and safety outcomes at weeks 10-16 were compared using a random-effects network meta-analysis within a frequentist framework to estimate pooled odds ratios (ORs) of direct and indirect comparisons among the therapeutic options. There were six direct drug-to-drug comparisons in the network, with a high degree of consistency between the direct and indirect evidence. From the available evidence, infliximab 5 mg kg -1 every 8 weeks [OR 118·89, 95% confidence interval (CI) 60·91-232·04] and secukinumab 300 mg every 4 weeks (OR 87·07, 95% CI 55·01-137·82) are shown to be among the most effective short-term treatments, but are ranked as the biologics most likely to produce any adverse event or an infectious adverse event, respectively. Ustekinumab 90 mg every 12 weeks, the third most efficacious treatment (OR 73·67, 95% CI 46·97-115·56), was the only agent that did not show increased risk of adverse events compared with placebo. Treatment recommendations should also consider long-term outcomes and costs. © 2016 British Association of Dermatologists.

Tumor Vessel Development and Expansion in Ewing's Sarcoma: A Review of the Vasculogenesis Process and Clinical Trials with Vascular-Targeting Agents

PubMed Central

Stewart, Keri S.; Kleinerman, Eugenie S.

2011-01-01

Ewing's sarcoma accounts for a disproportionately high portion of the overall pediatric mortality rate compared to its rare incidence in the pediatric population. Little progress has been made since the introduction of traditional chemotherapies, and understanding the biology of the tumor is critical for developing new therapies. Ewing's sarcomas rely on a functional vascular supply, which is formed by a combination of angiogenesis and vasculogenesis. Recent insights into the molecular regulation of bone marrow (BM) cell participation in vascular development have identified VEGF, SDF-1α, and DLL4 as critical players in the vasculogenesis process. Clinical trials using vascular targeting agents, specifically targeting VEGF or DLL4, are underway. PMID:21785569

Ultrasonic Analysis of Peptide- and Antibody-Targeted Microbubble Contrast Agents for Molecular Imaging of αvβ3-Expressing Cells

PubMed Central

Dayton, Paul A.; Pearson, David; Clark, Jarrod; Simon, Scott; Schumann, Patricia A.; Zutshi, Reena; Matsunaga, Terry O.; Ferrara, Katherine W.

2008-01-01

The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. In this manuscript, three distinct contrast agents targeted to the αvβ3 integrin are examined. The αvβ3 integrin has been shown to be highly expressed on metastatic tumors and endothelial cells during neovascularization, and its expression has been shown to correlate with tumor grade. Specific adhesion of these contrast agents to αvβ3-expressing cell monolayers is demonstrated in vitro, and compared with that of nontargeted agents. Acoustic studies illustrate a backscatter amplitude increase from monolayers exposed to the targeted contrast agents of up to 13-fold (22 dB) relative to enhancement due to control bubbles. A linear dependence between the echo amplitude and bubble concentration was observed for bound agents. The decorrelation of the echo from adherent targeted agents is observed over successive pulses as a function of acoustic pressure and bubble density. Frequency–domain analysis demonstrates that adherent targeted bubbles exhibit high-amplitude narrowband echo components, in contrast to the primarily wideband response from free microbubbles. Results suggest that adherent targeted contrast agents are differentiable from free-floating microbubbles, that targeted contrast agents provide higher sensitivity in the detection of angiogenesis, and that conventional ultrasound imaging techniques such as signal subtraction or decorrelation detection can be used to detect integrin-expressing vasculature with sufficient signal-to-noise. PMID:15296677

Target-specific contrast agents for magnetic resonance microscopy

PubMed Central

Blackwell, Megan L.; Farrar, Christian T.; Fischl, Bruce; Rosen, Bruce R.

2009-01-01

High-resolution ex vivo magnetic resonance (MR) imaging can be used to delineate prominent architectonic features in the human brain, but increased contrast is required to visualize more subtle distinctions. To aid MR sensitivity to cell density and myelination, we have begun the development of target-specific paramagnetic contrast agents. This work details the first application of luxol fast blue (LFB), an optical stain for myelin, as a white matter-selective MR contrast agent for human ex vivo brain tissue. Formalin-fixed human visual cortex was imaged with an isotropic resolution between 80 and 150 μm at 4.7 and 14 T before and after en bloc staining with LFB. Longitudinal (R1) and transverse (R2) relaxation rates in LFB-stained tissue increased proportionally with myelination at both field strengths. Changes in R1 resulted in larger contrast-to-noise ratios (CNR), per unit time, on T1-weighted images between more myelinated cortical layers (IV–VI) and adjacent, superficial layers (I–III) at both field strengths. Specifically, CNR for LFB-treated samples increased by 229±13% at 4.7 T and 269±25% at 14 T when compared to controls. Also, additional cortical layers (IVca, IVd, and Va) were resolvable in 14T-MR images of LFB-treated samples but not in control samples. After imaging, samples were sliced in 40-micron sections, mounted, and photographed. Both the macroscopic and microscopic distributions of LFB were found to mimic those of traditional histological preparations. Our results suggest target-specific contrast agents will enable more detailed MR images with applications in imaging pathological ex vivo samples and constructing better MR atlases from ex vivo brains. PMID:19385012

Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs.

PubMed

St-Pierre, Gabrielle; Pal, Sudip; Østergaard, Michael E; Zhou, Tianyuan; Yu, Jinghua; Tanowitz, Michael; Seth, Punit P; Hanessian, Stephen

2016-06-01

Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biologic Therapy for HLA-B27-associated Ocular Disorders.

PubMed

Gueudry, Julie; Thorne, Jennifer E; Bansie, Rakesh; Braun, Juergen; van Hagen, P Martin; Bodaghi, Bahram

2017-04-01

The treatment of articular and extra-articular manifestations associated with HLA-B27 has undergone dramatic changes over the past two decades, mainly as a consequence of the introduction of biologic agents and in particular anti-tumor necrosis factor α (anti-TNFα) agents. Uveitis is known to be the most frequent extra-articular feature in HLA-B27-associated spondyloarthritides. Topical corticosteroids and cycloplegic agents remain the cornerstones of treatment. However, biologic therapy may be effective in the management of refractory or recurrent forms of uveitis. This review gives an update on the management of HLA-B27-associated ocular disorders with biologics, including anti-TNFα agents and non-anti-TNFα biologic modifier drugs. There is an emerging role for newer biologics targeting interleukin-12/23 and interleukin-17 for the treatment of spondyloarthritides but data on their efficacy on anterior uveitis are sparse.

On-Demand Targeting: Investigating Biology with Proximity-Directed Chemistry

PubMed Central

2016-01-01

Proximity enhancement is a central chemical tenet underpinning an exciting suite of small-molecule toolsets that have allowed us to unravel many biological complexities. The leitmotif of this opus is “tethering”—a strategy in which a multifunctional small molecule serves as a template to bring proteins/biomolecules together. Scaffolding approaches have been powerfully applied to control diverse biological outcomes such as protein–protein association, protein stability, activity, and improve imaging capabilities. A new twist on this strategy has recently appeared, in which the small-molecule probe is engineered to unleash controlled amounts of reactive chemical signals within the microenvironment of a target protein. Modification of a specific target elicits a precisely timed and spatially controlled gain-of-function (or dominant loss-of-function) signaling response. Presented herein is a unique personal outlook conceptualizing the powerful proximity-enhanced chemical biology toolsets into two paradigms: “multifunctional scaffolding” versus “on-demand targeting”. By addressing the latest advances and challenges in the established yet constantly evolving multifunctional scaffolding strategies as well as in the emerging on-demand precision targeting (and related) systems, this Perspective is aimed at choosing when it is best to employ each of the two strategies, with an emphasis toward further promoting novel applications and discoveries stemming from these innovative chemical biology platforms. PMID:26907082

Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice.

PubMed

Fazio, N; Scarpa, A; Falconi, M

2014-01-01

Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

Emerging biological therapies for the treatment of myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Stahl, Maximilian; Komrokji, Rami

2016-09-01

No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure. This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche. Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.

Development of biosensors for the detection of biological warfare agents: its issues and challenges.

PubMed

Kumar, Harish; Rani, Renu

2013-01-01

This review discusses current development in biosensors for the detection of biological warfare agents (BWAs). BWAs include bacteria, virus and toxins that are added deliberately into air water and food to spread terrorism and cause disease or death. The rapid and unambiguous detection and identification of BWAs with early warning signals for detecting possible biological attack is a major challenge for government agencies particularly military and health. The detection devices--biosensors--can be classified (according to their physicochemical transducers) into four types: electrochemical, nucleic acid, optical and piezoelectric. Advantages and limitations of biosensors are discussed in this review followed by an assessment of the current state of development of different types of biosensors. The research and development in biosensors for biological warfare agent detection is of great interest for the public as well as for governments.

Gadolinium-conjugated PLA-PEG nanoparticles as liver targeted molecular MRI contrast agent.

PubMed

Chen, Zhijin; Yu, Dexin; Liu, Chunxi; Yang, Xiaoyan; Zhang, Na; Ma, Chunhong; Song, Jibin; Lu, Zaijun

2011-09-01

A nanoparticle magnetic resonance imaging (MRI) contrast agent targeted to liver was developed by conjugation of gadolinium (Gd) chelate groups onto the biocompatible poly(l-lactide)-block-poly (ethylene glycol) (PLA-PEG) nanoparticles. PLA-PEG conjugated with diethylenetriaminopentaacetic acid (DTPA) was used to formulate PLA-PEG-DTPA nanoparticles by solvent diffusion method, and then Gd was loaded onto the nanoparticles by chelated with the unfolding DTPA on the surface of the PLA-PEG-DTPA nanoparticles. The mean size of the nanoparticles was 265.9 ± 6.7 nm. The relaxivity of the Gd-labeled nanoparticles was measured, and the distribution in vivo was evaluated in rats. Compared with conventional contrast agent (Magnevist), the Gd-labeled PLA-PEG nanoparticles showed significant enhancement both on liver targeting ability and imaging signal intensity. The T(1) and T(2) relaxivities per [Gd] of the Gd-labeled nanoparticles was 18.865 mM(-1) s(-1) and 24.863 mM(-1) s(-1) at 3 T, respectively. In addition, the signal intensity in vivo was stronger comparing with the Gd-DTPA and the T(1) weight time was lasting for 4.5 h. The liver targeting efficiency of the Gd-labeled PLA-PEG nanoparticles in rats was 14.57 comparing with Magnevist injection. Therefore, the Gd-labeled nanoparticles showed the potential as targeting molecular MRI contrast agent for further clinical utilization.

Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier.

PubMed

Lajoie, Jason M; Shusta, Eric V

2015-01-01

Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo.

Insect-gene-activity detection system for chemical and biological warfare agents and toxic industrial chemicals

NASA Astrophysics Data System (ADS)

Mackie, Ryan S.; Schilling, Amanda S.; Lopez, Arturo M.; Rayms-Keller, Alfredo

2002-02-01

Detection of multiple chemical and biological weapons (CBW) agents and/or complex mixtures of toxic industrial chemicals (TIC) is imperative for both the commercial and military sectors. In a military scenario, a multi-CBW attack would create confusion, thereby delaying decontamination and therapeutic efforts. In the commercial sector, polluted sites invariably contain a mixture of TIC. Novel detection systems capable of detecting CBW and TIC are sorely needed. While it may be impossible to build a detector capable of discriminating all the possible combinations of CBW, a detection system capable of statistically predicting the most likely composition of a given mixture is within the reach of current emerging technologies. Aquatic insect-gene activity may prove to be a sensitive, discriminating, and elegant paradigm for the detection of CBW and TIC. We propose to systematically establish the expression patterns of selected protein markers in insects exposed to specific mixtures of chemical and biological warfare agents to generate a library of biosignatures of exposure. The predicting capabilities of an operational library of biosignatures of exposures will allow the detection of emerging novel or genetically engineered agents, as well as complex mixtures of chemical and biological weapons agents. CBW and TIC are discussed in the context of war, terrorism, and pollution.

Collaborative filtering on a family of biological targets.

PubMed

Erhan, Dumitru; L'heureux, Pierre-Jean; Yue, Shi Yi; Bengio, Yoshua

2006-01-01

Building a QSAR model of a new biological target for which few screening data are available is a statistical challenge. However, the new target may be part of a bigger family, for which we have more screening data. Collaborative filtering or, more generally, multi-task learning, is a machine learning approach that improves the generalization performance of an algorithm by using information from related tasks as an inductive bias. We use collaborative filtering techniques for building predictive models that link multiple targets to multiple examples. The more commonalities between the targets, the better the multi-target model that can be built. We show an example of a multi-target neural network that can use family information to produce a predictive model of an undersampled target. We evaluate JRank, a kernel-based method designed for collaborative filtering. We show their performance on compound prioritization for an HTS campaign and the underlying shared representation between targets. JRank outperformed the neural network both in the single- and multi-target models.

Personal protection during resuscitation of casualties contaminated with chemical or biological warfare agents--a survey of medical first responders.

PubMed

Brinker, Andrea; Prior, Kate; Schumacher, Jan

2009-01-01

The threat of mass casualties caused by an unconventional terrorist attack is a challenge for the public health system, with special implications for emergency medicine, anesthesia, and intensive care. Advanced life support of patients injured by chemical or biological warfare agents requires an adequate level of personal protection. The aim of this study was to evaluate the personal protection knowledge of emergency physicians and anesthetists who would be at the frontline of the initial health response to a chemical/biological warfare agent incident. After institutional review board approval, knowledge of personal protection measures among emergency medicine (n = 28) and anesthetics (n = 47) specialty registrars in the South Thames Region of the United Kingdom was surveyed using a standardized questionnaire. Participants were asked for the recommended level of personal protection if a chemical/biological warfare agent(s) casualty required advanced life support in the designated hospital resuscitation area. The best awareness within both groups was regarding severe acute respiratory syndrome, and fair knowledge was found regarding anthrax, plague, Ebola, and smallpox. In both groups, knowledge about personal protection requirements against chemical warfare agents was limited. Knowledge about personal protection measures for biological agents was acceptable, but was limited for chemical warfare agents. The results highlight the need to improve training and education regarding personal protection measures for medical first receivers.

Assessing Probabilistic Risk Assessment Approaches for Insect Biological Control Introductions.

PubMed

Kaufman, Leyla V; Wright, Mark G

2017-07-07

The introduction of biological control agents to new environments requires host specificity tests to estimate potential non-target impacts of a prospective agent. Currently, the approach is conservative, and is based on physiological host ranges determined under captive rearing conditions, without consideration for ecological factors that may influence realized host range. We use historical data and current field data from introduced parasitoids that attack an endemic Lepidoptera species in Hawaii to validate a probabilistic risk assessment (PRA) procedure for non-target impacts. We use data on known host range and habitat use in the place of origin of the parasitoids to determine whether contemporary levels of non-target parasitism could have been predicted using PRA. Our results show that reasonable predictions of potential non-target impacts may be made if comprehensive data are available from places of origin of biological control agents, but scant data produce poor predictions. Using apparent mortality data rather than marginal attack rate estimates in PRA resulted in over-estimates of predicted non-target impact. Incorporating ecological data into PRA models improved the predictive power of the risk assessments.

Synthesis and biological activity of imidazopyridine anticoccidial agents: part I.

PubMed

Scribner, Andrew; Dennis, Richard; Hong, Jean; Lee, Shuliang; McIntyre, Donald; Perrey, David; Feng, Dennis; Fisher, Michael; Wyvratt, Matthew; Leavitt, Penny; Liberator, Paul; Gurnett, Anne; Brown, Chris; Mathew, John; Thompson, Donald; Schmatz, Dennis; Biftu, Tesfaye

2007-01-01

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.

Photoactivatable Lipid-based Nanoparticles as a Vehicle for Dual Agent Delivery | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the National Cancer Institute (NCI) RNA Biology Laboratory have developed nanoparticles that can deliver an agent (i.e., therapeutic or imaging) and release the agent upon targeted photoactivation allowing for controlled temporal and localized release of the agent.

Canada thistle biological control agents on two South Dakota wildlife refuges

USGS Publications Warehouse

Reed, C.C.; Larson, D.L.; Larson, J.L.

2006-01-01

We monitored populations of Canada thistle biocontrol agents Cassida rubiginosa, Ceutorhynchus litura, Larinus (= Hadroplantus) planus, Urophora cardui, Orellia (= Terellia) ruficauda, and Rhinocyllus conicus on Canada thistle (Cirsium arvense) at two national wildlife refuges in South Dakota from 1999 through 2003. C. litura, U. cardui, O. ruficauda, and R. conicus were present on both refuges. Agent populations were low except for C. litura, which was present in up to 90% of stems in some plots. C. litura infestation did not reduce thistle flowering, stem length, or over-winter survival. There was no change in thistle stem numbers over the study period and no difference in stem numbers in areas of high C. litura populations compared to areas of low C. litura populations. Our results suggest that insect biological control agents are inadequate for reduction of Canada thistle in southern South Dakota.

Modeling Co-evolution of Speech and Biology.

PubMed

de Boer, Bart

2016-04-01

Two computer simulations are investigated that model interaction of cultural evolution of language and biological evolution of adaptations to language. Both are agent-based models in which a population of agents imitates each other using realistic vowels. The agents evolve under selective pressure for good imitation. In one model, the evolution of the vocal tract is modeled; in the other, a cognitive mechanism for perceiving speech accurately is modeled. In both cases, biological adaptations to using and learning speech evolve, even though the system of speech sounds itself changes at a more rapid time scale than biological evolution. However, the fact that the available acoustic space is used maximally (a self-organized result of cultural evolution) is constant, and therefore biological evolution does have a stable target. This work shows that when cultural and biological traits are continuous, their co-evolution may lead to cognitive adaptations that are strong enough to detect empirically. Copyright © 2016 Cognitive Science Society, Inc.

Deciphering endophyte behaviour: the link between endophyte biology and efficacious biological control agents.

PubMed

Card, Stuart; Johnson, Linda; Teasdale, Suliana; Caradus, John

2016-08-01

Endophytes associate with the majority of plant species found in natural and managed ecosystems. They are regarded as extremely important plant partners that provide improved stress tolerance to the host compared with plants that lack this symbiosis. Fossil records of endophytes date back more than 400 million years, implicating these microorganisms in host plant adaptation to habitat transitions. However, it is only recently that endophytes, and their bioactive products, have received meaningful attention from the scientific community. The benefits some endophytes can confer on their hosts include plant growth promotion and survival through the inhibition of pathogenic microorganisms and invertebrate pests, the removal of soil contaminants, improved tolerance of low fertility soils, and increased tolerance of extreme temperatures and low water availability. Endophytes are extremely diverse and can exhibit many different biological behaviours. Not all endophyte technologies have been successfully commercialised. Of interest in the development of the next generation of plant protection products is how much of this is due to the biology of the particular endophytic microorganism. In this review, we highlight selected case studies of endophytes and discuss their lifestyles and behavioural traits, and discuss how these factors contribute towards their effectiveness as biological control agents. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies.

PubMed

Zarschler, K; Prapainop, K; Mahon, E; Rocks, L; Bramini, M; Kelly, P M; Stephan, H; Dawson, K A

2014-06-07

For effective localization of functionalized nanoparticles at diseased tissues such as solid tumours or metastases through biorecognition, appropriate targeting vectors directed against selected tumour biomarkers are a key prerequisite. The diversity of such vector molecules ranges from proteins, including antibodies and fragments thereof, through aptamers and glycans to short peptides and small molecules. Here, we analyse the specific nanoparticle targeting capabilities of two previously suggested peptides (D4 and GE11) and a small camelid single-domain antibody (sdAb), representing potential recognition agents for the epidermal growth factor receptor (EGFR). We investigate specificity by way of receptor RNA silencing techniques and look at increasing complexity in vitro by introducing increasing concentrations of human or bovine serum. Peptides D4 and GE11 proved problematic to employ and conjugation resulted in non-receptor specific uptake into cells. Our results show that sdAb-functionalized particles can effectively target the EGFR, even in more complex bovine and human serum conditions where targeting specificity is largely conserved for increasing serum concentration. In human serum however, an inhibition of overall nanoparticle uptake is observed with increasing protein concentration. For highly affine targeting ligands such as sdAbs, targeting a receptor such as EGFR with low serum competitor abundance, receptor recognition function can still be partially realised in complex conditions. Here, we stress the value of evaluating the targeting efficiency of nanoparticle constructs in realistic biological milieu, prior to more extensive in vivo studies.

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents.

PubMed

Galluzzi, Lorenzo; Buqué, Aitziber; Kepp, Oliver; Zitvogel, Laurence; Kroemer, Guido

2015-12-14

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

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

Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long

2011-10-22

Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor.more » These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.« less

Guidelines for Managing Suspected Chemical and Biological Agent Incidents in Rail Tunnel Systems

DOT National Transportation Integrated Search

2002-03-01

These emergency management guidelines are designed to help transit managers (1) prepare and implement standard operating procedures (SOPs) for handling potential and actual chemical or biological agent attacks in their rail tunnel system and (2) unde...

Simulations of population dynamics of hemlock woolly adelgid and potential impact of biological control agents

Treesearch

Joseph S. Elkinton; Robert T. Trotter; Ann F. Paradis

2011-01-01

The hemlock woolly adelgid (Adelges tsugae) is a small invasive Hemipteran herbivore that threatens the continued presence and abundance of hemlock in eastern North America. Efforts to control the adelgid have focused on the introduction of classical biological control agents. These biological controls include six different species of predatory...

Design Principles of Nanoparticles as Contrast Agents for Magnetic Resonance Imaging

NASA Astrophysics Data System (ADS)

Shan, Liang; Gu, Xinbin; Wang, Paul

2013-09-01

Molecular imaging is an emerging field that introduces molecular agents into traditional imaging techniques, enabling visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. The promise of molecular imaging lies in its potential for selective potency by targeting biomarkers or molecular targets and the imaging agents serve as reporters for the selectivity of targeting. Development of an efficient molecular imaging agent depends on well-controlled high-quality experiment design involving target selection, agent synthesis, in vitro characterization, and in vivo animal characterization before it is applied in humans. According to the analysis from the Molecular Imaging and Contrast Agent Database (MICAD, ), more than 6000 molecular imaging agents with sufficient preclinical evaluation have been reported to date in the literature and this number increases by 250-300 novel agents each year. The majority of these agents are radionuclides, which are developed for positron emission tomography (PET) and single photon emission computed tomography (SPECT). Contrast agents for magnetic resonance imaging (MRI) account for only a small part. This is largely due to the fact that MRI is currently not a fully quantitative imaging technique and is less sensitive than PET and SPECT. However, because of the superior ability to simultaneously extract molecular and anatomic information, molecular MRI is attracting significant interest and various targeted nanoparticle contrast agents have been synthesized for MRI. The first and one of the most critical steps in developing a targeted nanoparticle contrast agent is target selection, which plays the central role and forms the basis for success of molecular imaging. This chapter discusses the design principles of targeted contrast agents in the emerging frontiers of molecular MRI.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents).

PubMed

Baddley, J W; Cantini, F; Goletti, D; Gómez-Reino, J J; Mylonakis, E; San-Juan, R; Fernández-Ruiz, M; Torre-Cisneros, J

2018-06-01

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Market uptake of biologic and small-molecule--targeted oncology drugs in Europe.

PubMed

Obradovic, Marko; Mrhar, Ales; Kos, Mitja

2009-12-01

The aim of this study was to investigate the market uptake of biologic and small-molecule-targeted oncology drugs in Europe. Targeted oncology drugs that were used in one of the selected European countries before the end of 2007 were eligible for inclusion in the analysis. The following European countries were included: Austria, Croatia, France, Germany, Hungary, Italy, Slovenia, and the United Kingdom. Monetary market uptake of targeted oncology drugs was assessed by using sales data (in euros) obtained from 2 large data- bases for the period 1997-2007. Market uptake was assessed in terms of expenditures for specific drugs in euros per capita and in market shares. The monetary market uptake of targeted oncology drugs had an exponential growth from 1997 to 2007 in all comparison countries and reached 40% of the total oncology drug market in 2007. Although the various European countries allocate substantially different amounts of resources per capita for oncology drugs, the share of expenditures attributed to targeted oncology drugs did not differ substantially among the countries. Biologic molecules were used in clinical practice before the small-molecule-targeted oncology drugs. Targeted oncology drugs that were introduced first to clinical practice in most of the comparison countries (ie, rituximab, trastuzumab, imatinib mesylate) maintained the leading positions on the market throughout the period of the analysis. In 2007, approximately 25% of all expenditures for oncology drugs were attributed to biologic oncology drugs, and approximately 15% were spent on small-molecule-targeted oncology drugs. Expenditures on targeted oncology drugs have been increasing exponentially in Europe throughout the past decade and have reached a 40% share of the oncology drug market. As of 2007, the market share of biologic oncology drugs was higher than the market share of small-molecule-targeted oncology drugs. Copyright 2009 Excerpta Medica Inc. All rights reserved.

Novel receptor-targeted contrast agents for optical imaging of tumors

NASA Astrophysics Data System (ADS)

Becker, Andreas; Hessenius, Carsten; Bhargava, Sarah; Ebert, Bernd; Sukowski, Uwe; Rinneberg, Herbert H.; Wiedenmann, Bertram; Semmler, Wolfhard; Licha, Kai

2000-04-01

Many gastroenteropancreatic tumors express receptors for somatostatin (SST) and/or vasoactive intestinal peptide (VIP). These receptors can be used as molecular targets for the delivery of contrast agents for tumor diagnostics. We have synthesized conjugates consisting of a cyanine dye and an SST analogue or VIP for use as contrast agents in optical imaging. Receptor binding and internalization of these compounds were examined with optical methods in transfected RIN38 tumor cells expressing the SST2 receptor or a GFP- labeled VIP (VPAC1) receptor. Furthermore, biodistribution of the conjugates was examined by laser-induced fluorescence imaging in nude mice bearing SST2 or VPAC1 receptor- expressing tumors. After incubation of RIN38 SSTR2 cells in the presence of 100 nM indotricarbocyanine-SST analogue, cell-associated fluorescence increased, whereas no increase was observed when receptor-medicated endocytosis was inhibited. Indodicarbocyanine-VIP accumulated in RIN38 VPAC1 cells and co-localization with the GFP-labeled VPAC1 receptor was observed. After injection of indotricarbocyanine-SST analogue into tumor-bearing nude mice, SST2 receptor-positive tumors could be visualized for a time period from 10 min to at least 48 h. After application of indodicarbocyanine-VIP, a fluorescence signal in VIP1 receptor-expressing tumors was only detected during the first hour. We conclude that cyanine dye-labeled VIP and SST analogue are novel, targeted contrast agents for the optical imaging of tumors expressing the relevant receptor.

Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents.

PubMed

Ding, S; Bierbach, U

2016-08-16

A versatile and efficient modular synthetic platform was developed for assembling multifunctional conjugates and targeted forms of platinum-(benz)acridines, a class of highly cytotoxic DNA-targeted hybrid agents. The synthetic strategy involved amide coupling between succinyl ester-modified platinum compounds (P1, P2) and a set of 11 biologically relevant primary and secondary amines (N1-N11). To demonstrate the feasibility and versatility of the approach, a structurally and functionally diverse range of amines was introduced. These include biologically active molecules, such as rucaparib (a PARP inhibitor), E/Z-endoxifen (an estrogen receptor antagonist), and a quinazoline-based tyrosine kinase inhibitor. Micro-scale reactions in Eppendorf tubes or on 96-well plates were used to screen for optimal coupling conditions in DMF solution with carbodiimide-, uronium-, and phosphonium-based compounds, as well as other common coupling reagents. Reactions with the phosphonium-based coupling reagent PyBOP produced the highest yields and gave the cleanest conversions. Furthermore, it was demonstrated that the chemistry can also be performed in aqueous media and is amenable to parallel synthesis based on multiple consecutive reactions in DMF in a "one-tube" format. In-line LC-MS was used to assess the stability of the conjugates in physiologically relevant buffers. Hydrolysis of the conjugates occurs at the ester moiety and is facilitated by the aquated metal moiety under low-chloride ion conditions. The rate of ester cleavage greatly depends on the nature of the amine component. Potential applications of the linker technology are discussed.

Molecular targeted therapies for solid tumors: management of side effects.

PubMed

Grünwald, Viktor; Soltau, Jens; Ivanyi, Philipp; Rentschler, Jochen; Reuter, Christoph; Drevs, Joachim

2009-03-01

This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and mammalian target of rapamycin (mTOR) signaling in the treatment of solid tumors. Such targeted agents can be divided into monoclonal antibodies, tyrosine kinase inhibitors, multitargeted tyrosine kinase inhibitors and serine/threonine kinase inhibitors. Molecular targeted therapies are generally well tolerated, but inhibitory effects on the biological function of the targets in healthy tissue can result in specific treatment-related side effects, particularly with multitargeted agents. We offer some guidance on how to manage adverse events in cancer patients based on the range of options currently available. Copyright 2009 S. Karger AG, Basel.

Combination Antimicrobial Nanocomposite Materials for Neutralization of Biological Threat Agents (PREPRINT)

DTIC Science & Technology

2008-09-01

AFRL-RX-TY-TP-2008-4601 PREPRINT COMBINATION ANTIMICROBIAL NANOCOMPOSITE MATERIALS FOR NEUTRALIZATION OF BIOLOGICAL THREAT AGENTS...AIRBASE TECHNOLOGIES DIVISION MATERIALS AND MANUFACTURING DIRECTORATE AIR FORCE RESEARCH LABORATORY AIR FORCE MATERIEL COMMAND 139 BARNES DRIVE, SUITE 2...a composite material that combines the protein and inorganic components. The process can be mimicked in vitro to some degree, providing methods for

Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications.

PubMed

Chadha, Navriti; Silakari, Om

2017-09-01

Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc. The hit molecules were duly synthesized and biochemical estimation of these molecules against aldose reductase (ALR2), protein kinase Cβ (PKCβ) and poly (ADP-ribose) polymerase 1 (PARP-1) led to identification of compound 2 that showed good potency against PARP-1 and ALR2 enzymes. These positive results support the progress of a low cost multi-targeted agent with putative roles in diabetic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

Biology, behavior, and larval morphology of Salbia lotanalis (Lepidoptera: Crambidae), a potential biological control agent of Miconia calvescens (Myrtales: Melastomataceae) from Costa Rica

Treesearch

Alexander Castillo; M. Tracy Johnson; Francisco R. Badenes-Pérez

2014-01-01

The leaf roller Salbia lotanalis Druce (Lepidoptera: Crambidae), a potential biological control agent of Miconia calvescens de Candolle (Melastomataceae), was studied in Costa Rica. Larvae were collected from a field site near San Jose and the insect was reared in the laboratory to study its biology and behavior. Chaetotaxy and...

A support vector machine approach to the automatic identification of fluorescence spectra emitted by biological agents

NASA Astrophysics Data System (ADS)

Gelfusa, M.; Murari, A.; Lungaroni, M.; Malizia, A.; Parracino, S.; Peluso, E.; Cenciarelli, O.; Carestia, M.; Pizzoferrato, R.; Vega, J.; Gaudio, P.

2016-10-01

Two of the major new concerns of modern societies are biosecurity and biosafety. Several biological agents (BAs) such as toxins, bacteria, viruses, fungi and parasites are able to cause damage to living systems either humans, animals or plants. Optical techniques, in particular LIght Detection And Ranging (LIDAR), based on the transmission of laser pulses and analysis of the return signals, can be successfully applied to monitoring the release of biological agents into the atmosphere. It is well known that most of biological agents tend to emit specific fluorescence spectra, which in principle allow their detection and identification, if excited by light of the appropriate wavelength. For these reasons, the detection of the UVLight Induced Fluorescence (UV-LIF) emitted by BAs is particularly promising. On the other hand, the stand-off detection of BAs poses a series of challenging issues; one of the most severe is the automatic discrimination between various agents which emit very similar fluorescence spectra. In this paper, a new data analysis method, based on a combination of advanced filtering techniques and Support Vector Machines, is described. The proposed approach covers all the aspects of the data analysis process, from filtering and denoising to automatic recognition of the agents. A systematic series of numerical tests has been performed to assess the potential and limits of the proposed methodology. The first investigations of experimental data have already given very encouraging results.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

Survey of rheumatologists on the use of the Philippine Guidelines on the Screening for Tuberculosis prior to use of Biologic Agents.

PubMed

Aquino-Villamin, Melissa; Tankeh-Torres, Sandra; Lichauco, Juan Javier

2016-11-01

The use of biologic agents has become an important option in treating patients with rheumatoid arthritis. However, these drugs have been associated with an increased risk of tuberculosis (TB) reactivation. Local guidelines for TB screening prior to the use of biologic agents were developed to address this issue. This study is a survey describing the compliance of Filipino rheumatologists to these guidelines. Eighty-seven rheumatologists in the Philippines were given the questionnaire and responses from 61 rheumatologists were included in the analysis. All respondents agree that patients should be screened prior to giving the biologic agents. Local guidelines recommend screening with tuberculin skin test (TST) and chest radiograph. However, cut-off values considered for a positive TST and timing of initiation of biologic agents after starting TB prophylaxis and treatment varied among respondents. In addition, screening of close household contacts were only performed by 41 (69.5%) respondents. There were 11 respondents who reported 16 patients developing TB during or after receiving biologic agents, despite adherence to the guidelines. This survey describes the compliance rate of Filipino rheumatologists in applying current local recommendations for TB screening prior to initiating biologic agents. The incidence of new TB cases despite the current guidelines emphasizes the importance of compliance and the need to revise the guidelines based on updated existing literature. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Microarray Analysis and Mutagenesis of the Biological Control Agent Pseudomonas fluorescens Pf-5

USDA-ARS?s Scientific Manuscript database

The biological control agent Pseudomonas fluorescens Pf-5 suppresses seedling emergence diseases caused by soilborne fungi and Oomycetes. Pf-5 produces at least ten secondary metabolites. These include hydrogen cyanide, pyrrolnitrin, pyoluteorin and 2,4-diacetylphloroglucinol, which have known funct...

MIDAS: A Practical Bayesian Design for Platform Trials with Molecularly Targeted Agents

PubMed Central

Yuan, Ying; Guo, Beibei; Munsell, Mark; Lu, Karen; Jazaeri, Amir

2016-01-01

Recent success of immunotherapy and other targeted therapies in cancer treatment has led to an unprecedented surge in the number of novel therapeutic agents that need to be evaluated in clinical trials. Traditional phase II clinical trial designs were developed for evaluating one candidate treatment at a time, and thus not efficient for this task. We propose a Bayesian phase II platform design, the Multi-candidate Iterative Design with Adaptive Selection (MIDAS), which allows investigators to continuously screen a large number of candidate agents in an efficient and seamless fashion. MIDAS consists of one control arm, which contains a standard therapy as the control, and several experimental arms, which contain the experimental agents. Patients are adaptively randomized to the control and experimental agents based on their estimated efficacy. During the trial, we adaptively drop inefficacious or overly toxic agents and “graduate” the promising agents from the trial to the next stage of development. Whenever an experimental agent graduates or is dropped, the corresponding arm opens immediately for testing the next available new agent. Simulation studies show that MIDAS substantially outperforms the conventional approach. The proposed design yields a significantly higher probability for identifying the promising agents and dropping the futile agents. In addition, MIDAS requires only one master protocol, which streamlines trial conduct and substantially decreases the overhead burden. PMID:27112322

Development of RNAi technology for targeted therapy--a track of siRNA based agents to RNAi therapeutics.

PubMed

Zhou, Yinjian; Zhang, Chunling; Liang, Wei

2014-11-10

RNA interference (RNAi) was intensively studied in the past decades due to its potential in therapy of diseases. The target specificity and universal treatment spectrum endowed siRNA advantages over traditional small molecules and protein drugs. However, barriers exist in the blood circulation system and the diseased tissues blocked the actualization of RNAi effect, which raised function versatility requirements to siRNA therapeutic agents. Appropriate functionalization of siRNAs is necessary to break through these barriers and target diseased tissues in local or systemic targeted application. In this review, we summarized that barriers exist in the delivery process and popular functionalized technologies for siRNA such as chemical modification and physical encapsulation. Preclinical targeted siRNA delivery and the current status of siRNA based RNAi therapeutic agents in clinical trial were reviewed and finally the future of siRNA delivery was proposed. The valuable experience from the siRNA agent delivery study and the RNAi therapeutic agents in clinical trial paved ways for practical RNAi therapeutics to emerge early. Copyright © 2014 Elsevier B.V. All rights reserved.

How Long Does the Benefit of Biologics Last? An Update on Time To Relapse and Potential for Rebound of Biologic Agents for Psoriasis.

PubMed

Kamaria, Monique; Liao, Wilson; Koo, J Y

2010-01-01

The biologic agents vary considerably in terms of their long-term duration of effect. Using the definitions provided by the National Psoriasis Foundation Medical Board, the objective of this review was to compare all biologic agents with respect to time to relapse and potential for rebound. Overall, alefacept had the longest off-treatment benefit (29.9 weeks in Psoriasis Area and Severity Index [PASI] 75 responders), followed by ustekinumab (22 weeks), infliximab (19.5 weeks), adalimumab (18 weeks), etanercept (12.1 weeks in PASI 50 responders), and, lastly, efalizumab (9.6 weeks). Rebound was reported commonly for efalizumab (14%) and, extremely rarely, for etanercept (0.002%).

From Here to Autonomicity: Self-Managing Agents and the Biological Metaphors that Inspire Them

NASA Technical Reports Server (NTRS)

Sterritt, Roy; Hinchey, Mike

2005-01-01

We seek inspiration for self-managing systems from (obviously, pre-existing) biological mechanisms. Autonomic Computing (AC), a self-managing systems initiative based on the biological metaphor of the autonomic nervous system, is increasingly gaining momentum as the way forward for integrating and designing reliable systems, while agent technologies have been identified as a key enabler for engineering autonomicity in systems. This paper looks at other biological metaphors such as reflex and healing, heart- beat monitors, pulse monitors and apoptosis for assisting in the realization of autonomicity.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2017-04-29

Sturge-Weber Syndrome (SWS) is among the neurocutaneous diseases, which has several clinical manifestations of ocular (glaucoma), cutaneous (port-wine stain), neurological (seizures) and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for the SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against this syndrome. Development of such platforms of bioassay can bring along the implementation of high throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of biological targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholine esterase, alkaline phosphatase, gamma-aminobutyricacidergic, Hypoxia-Inducible Factor (HIF) -1α and 2α are suggested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Assessing Probabilistic Risk Assessment Approaches for Insect Biological Control Introductions

PubMed Central

Kaufman, Leyla V.; Wright, Mark G.

2017-01-01

The introduction of biological control agents to new environments requires host specificity tests to estimate potential non-target impacts of a prospective agent. Currently, the approach is conservative, and is based on physiological host ranges determined under captive rearing conditions, without consideration for ecological factors that may influence realized host range. We use historical data and current field data from introduced parasitoids that attack an endemic Lepidoptera species in Hawaii to validate a probabilistic risk assessment (PRA) procedure for non-target impacts. We use data on known host range and habitat use in the place of origin of the parasitoids to determine whether contemporary levels of non-target parasitism could have been predicted using PRA. Our results show that reasonable predictions of potential non-target impacts may be made if comprehensive data are available from places of origin of biological control agents, but scant data produce poor predictions. Using apparent mortality data rather than marginal attack rate estimates in PRA resulted in over-estimates of predicted non-target impact. Incorporating ecological data into PRA models improved the predictive power of the risk assessments. PMID:28686180

Biological nitric oxide signalling: chemistry and terminology

PubMed Central

Heinrich, Tassiele A; da Silva, Roberto S; Miranda, Katrina M; Switzer, Christopher H; Wink, David A; Fukuto, Jon M

2013-01-01

Biological nitrogen oxide signalling and stress is an area of extreme clinical, pharmacological, toxicological, biochemical and chemical research interest. The utility of nitric oxide and derived species as signalling agents is due to their novel and vast chemical interactions with a variety of biological targets. Herein, the chemistry associated with the interaction of the biologically relevant nitrogen oxide species with fundamental biochemical targets is discussed. Specifically, the chemical interactions of nitrogen oxides with nucleophiles (e.g. thiols), metals (e.g. hemeproteins) and paramagnetic species (e.g. dioxygen and superoxide) are addressed. Importantly, the terms associated with the mechanisms by which NO (and derived species) react with their respective biological targets have been defined by numerous past chemical studies. Thus, in order to assist researchers in referring to chemical processes associated with nitrogen oxide biology, the vernacular associated with these chemical interactions is addressed. PMID:23617570

Leveraging culture collections for the discovery and development of microbial biological control agents

USDA-ARS?s Scientific Manuscript database

The incorporation of living microbial biological control agents into integrated pest management programs is highly desirable because it reduces the use of chemical insecticides harmful to livestock, humans and the environment. In addition, it provides an alternative means to combat resistance to che...

Changes in Renal Function of Patients with Metastatic Renal Cell Carcinoma During Treatment with Molecular-Targeted Agents.

PubMed

Miyake, Hideaki; Muramaki, Mototsugu; Imai, Satoshi; Harada, Ken-Ichi; Fujisawa, Masato

2016-06-01

Impairment of renal function is a serious issue that should be considered in patients undergoing treatment with molecular-targeted agents for metastatic renal cell carcinoma (mRCC). The objective of this study was to assess the impact of molecular-targeted therapy on changes in renal function among patients with mRCC. The study included 408 mRCC patients treated with sunitinib, sorafenib, axitinib, everolimus and/or temsirolimus. Among these, 185, 128 and 95 received molecular-targeted agents as first-line (group 1), second-line (group 2) and third-line (group 3) therapy, respectively. No significant differences between the estimated glomerular filtration rate (eGFR) at baseline and that at the end of molecular-targeted therapy were noted among the three groups of patients. In addition, there were no significant differences between eGFR prior to the introduction of molecular-targeted therapy and that at the end of therapy across agents and lines of targeted therapy, with the exception of patients treated with axitinib and everolimus in second-line and third-line therapy, respectively. In group 1, a reduction in eGFR of >10 % from baseline was independently associated with performance status, hypertension and treatment duration, while in groups 2 and 3, only treatment duration was independently related to a reduction in eGFR of >10 %. It appears that renal function in patients with mRCC is not markedly impaired by molecular-targeted therapies, irrespective of the specific agents introduced; however, it may be necessary to pay special attention to deterioration in renal function when molecular-targeted therapy is continued for longer periods.

Engineered plant biomass particles coated with biological agents

DOEpatents

Dooley, James H.; Lanning, David N.

2014-06-24

Plant biomass particles coated with a biological agent such as a bacterium or seed, characterized by a length dimension (L) aligned substantially parallel to a grain direction and defining a substantially uniform distance along the grain, a width dimension (W) normal to L and aligned cross grain, and a height dimension (H) normal to W and L. In particular, the L.times.H dimensions define a pair of substantially parallel side surfaces characterized by substantially intact longitudinally arrayed fibers, the W.times.H dimensions define a pair of substantially parallel end surfaces characterized by crosscut fibers and end checking between fibers, and the L.times.W dimensions define a pair of substantially parallel top and bottom surfaces.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2018-02-01

Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. © 2017 John Wiley & Sons A/S.

75 FR 69396 - Availability of an Environmental Assessment for a Biological Control Agent for Arundo donax

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-12

... infestations. The proposed biological control agent, Arundo scale, is one of the most damaging insects to A... feeding on cells that carry out photosynthesis and cellular respiration, resulting over time in gradual... donacis (Hemiptera: Diaspididae), an Insect for Biological Control of Arundo donax (Poaceae) in the...

Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore.

PubMed

Szałaj, Natalia; Bajda, Marek; Dudek, Katarzyna; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

2015-08-01

Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50  = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

PubMed

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

PubMed Central

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs. PMID:26356639

Evaluation of Nipah Virus as a Human and Animal Biological Terrorism and Warfare Agent

DTIC Science & Technology

2001-09-01

UNCLASSIFIED Defense Technical Information Center Compilation Part Notice ADP013384 TITLE: Evaluation of Nipah Virus as a Human and Animal Biological...following component part numbers comprise the compilation report: ADP013371 thru ADP013468 UNCLASSIFIED 14. EVALUATION OF NIPAH VIRUS AS A HUMAN AND ANIMAL...of BTWC proposed including Nipah virus in the list of animal pathogens. This paper describes an evaluation of Nipah virus as a biological agent for

Performance of Traditional and Molecular Methods for Detecting Biological Agents in Drinking Water

EPA Science Inventory

USGS Report - To reduce the impact from a possible bioterrorist attack on drinking-water supplies, analytical methods are needed to rapidly detect the presence of biological agents in water. To this end, 13 drinking-water samples were collected at 9 water-treatment plants in Ohio...

MIDAS: a practical Bayesian design for platform trials with molecularly targeted agents.

PubMed

Yuan, Ying; Guo, Beibei; Munsell, Mark; Lu, Karen; Jazaeri, Amir

2016-09-30

Recent success of immunotherapy and other targeted therapies in cancer treatment has led to an unprecedented surge in the number of novel therapeutic agents that need to be evaluated in clinical trials. Traditional phase II clinical trial designs were developed for evaluating one candidate treatment at a time and thus not efficient for this task. We propose a Bayesian phase II platform design, the multi-candidate iterative design with adaptive selection (MIDAS), which allows investigators to continuously screen a large number of candidate agents in an efficient and seamless fashion. MIDAS consists of one control arm, which contains a standard therapy as the control, and several experimental arms, which contain the experimental agents. Patients are adaptively randomized to the control and experimental agents based on their estimated efficacy. During the trial, we adaptively drop inefficacious or overly toxic agents and 'graduate' the promising agents from the trial to the next stage of development. Whenever an experimental agent graduates or is dropped, the corresponding arm opens immediately for testing the next available new agent. Simulation studies show that MIDAS substantially outperforms the conventional approach. The proposed design yields a significantly higher probability for identifying the promising agents and dropping the futile agents. In addition, MIDAS requires only one master protocol, which streamlines trial conduct and substantially decreases the overhead burden. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.

PubMed

Gibiansky, Leonid; Gibiansky, Ekaterina

2018-02-01

The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation.

Effects of Immunomodulators and Biologic Agents on Sexual Health in Patients With Inflammatory Bowel Disease.

PubMed

Kanar, Ozdemir; Berry, Andrew C; Nakshabendi, Rahman; Lee, Ann Joo; Aldridge, Petra; Myers, Travis; Eid, Emely

2017-01-01

Although much knowledge has been gained regarding the medical and surgical management of inflammatory bowel disease (IBD), a paucity of information is available on the psychosexual issues related to IBD. The aim of this study was to evaluate the sexual health of patients with IBD who were taking immunomodulators and/or biologic agents vs patients with IBD who were not on that medication regimen. All study participants completed a validated sexual health questionnaire, the Female Sexual Function Index or the International Index of Erectile Function, to assess their subjective perception of the effect of IBD on the different domains of sexual function during the prior 1-month time period. No statistically significant differences in any baseline demographic variables were found for either sex between the group taking immunomodulators/biologic agents and the nontreatment group. Among females and males, individual question responses, domain scores, and total scores showed no statistically significant differences between the 2 treatment groups. Our data suggest that the use of immunomodulators or biologic agents does not affect female or male sexual health. However, treatment of patients with IBD must be individualized based on the aggressive nature of the disease, treatment goals, and the tolerability of various medications.

Indirect ecological effects in invaded landscapes: Spillover and spillback from biological control agents to native analogues

USDA-ARS?s Scientific Manuscript database

Biological control remains an effective option for managing large-scale weed problems in natural areas. The predation or parasitism of biological control agents by other species present in the introduced range (biotic resistance) is well studied and is often cited as the cause for a lack of establis...

Nanostructured thermites based on iodine pentoxide for bio agent defeat systems.

NASA Astrophysics Data System (ADS)

Hobosyan, Mkhitar; Kazansky, Alexander; Martirosyan, Karen

2011-10-01

The risk for bioterrorist events involving the intentional airborne release of contagious agents has led to development of new approaches for bio agent defeat technologies both indoors and outdoors. Novel approaches to defeat harmful biological agents have generated a strong demand for new active materials. The preferred solutions are to neutralize the biological agents within the immediate target area by using aerosolized biocidal substances released in situ by high energetic reactions. By using nano-thermite reactions, with energy release up to 25 kJ/cc, based on I2O5/Al nanoparticles we intend to generate high quantity of vaporized iodine for spatial deposition onto harmful bacteria for their destruction. In this report, the effect of reaction product on growth and survival of Escherichia coli (E-coli) expressing GFP (Green Fluorescent Protein) was investigated. Moreover, we developed an approach to increase sensitivity of the detection. The study has shown that I2O5/Al nanosystem is extremely effective to disinfect harmful biological agents such (E-coli) bacteria in seconds.

Biological Targets and Mechanisms of Action of Natural Products from Marine Cyanobacteria

PubMed Central

Salvador-Reyes, Lilibeth A.

2015-01-01

Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial. PMID:25571978

Potential of Neoactinolaimus as a biological control agent of root-knot and reniform nematodes

USDA-ARS?s Scientific Manuscript database

The predatory nematode Neoactinolaimus spp. (family Actinolaimidae) was examined as a potential biological control agent against root-knot (Meloidogyne spp.) and reniform (Rotylenchulus reniformis) nematodes in laboratory conditions. Neoactinolaimus possesses a large odontostylet to puncture the cu...

Amplification of biological targets via on-chip culture for biosensing

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

Harper, Jason C.; Edwards, Thayne L.; Carson, Bryan

The present invention, in part, relates to methods and apparatuses for on-chip amplification and/or detection of various targets, including biological targets and any amplifiable targets. In some examples, the microculture apparatus includes a single-use, normally-closed fluidic valve that is initially maintained in the closed position by a valve element bonded to an adhesive coating. The valve is opened using a magnetic force. The valve element includes a magnetic material or metal. Such apparatuses and methods are useful for in-field or real-time detection of targets, especially in limited resource settings.

Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

PubMed Central

2011-01-01

Introduction The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice. Methods The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents. Results A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection

Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

PubMed Central

Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

2015-01-01

Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

Comparison of traditional and molecular analytical methods for detecting biological agents in raw and drinking water following ultrafiltration

USGS Publications Warehouse

Francy, D.S.; Bushon, R.N.; Brady, A.M.G.; Bertke, E.E.; Kephart, C.M.; Likirdopulos, C.A.; Mailot, B.E.; Schaefer, F. W.; Lindquist, H.D. Alan

2009-01-01

Aims: To compare the performance of traditional methods to quantitative polymerase chain reaction (qPCR) for detecting five biological agents in large-volume drinking-water samples concentrated by ultrafiltration (UF). Methods and Results: Drinking-water samples (100 l) were seeded with Bacillus anthracis, Cryptospordium parvum, Francisella tularensis, Salmonella Typhi, and Vibrio cholerae and concentrated by UF. Recoveries by traditional methods were variable between samples and between some replicates; recoveries were not determined by qPCR. Francisella tularensis and V. cholerae were detected in all 14 samples after UF, B. anthracis was detected in 13, and C. parvum was detected in 9 out of 14 samples. Numbers found by qPCR after UF were significantly or nearly related to those found by traditional methods for all organisms except for C. parvum. A qPCR assay for S. Typhi was not available. Conclusions: qPCR can be used to rapidly detect biological agents after UF as well as traditional methods, but additional work is needed to improve qPCR assays for several biological agents, determine recoveries by qPCR, and expand the study to other areas. Significance and Impact of the Study: To our knowledge, this is the first study to compare the use of traditional and qPCR methods to detect biological agents in large-volume drinking-water samples. ?? 2009 The Society for Applied Microbiology.

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

A Novel Isoquinoline Derivative Anticancer Agent and Its Targeted Delivery to Tumor Cells Using Transferrin-Conjugated Liposomes

PubMed Central

Yang, Xuewei; Yang, Shuang; Chai, Hongyu; Yang, Zhaogang; Lee, Robert J.; Liao, Weiwei; Teng, Lesheng

2015-01-01

We have screened 11 isoquinoline derivatives and α-methylene-γ-butyrolactones using the 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay in HeLa and HEK-293T cells. Compound 2 was identified as potential anticancer agent. To further improve its therapeutic potential, this agent was incorporated into transferrin (Tf)-conjugated liposomes (LPs) for targeted delivery to tumor cells. We have demonstrated Tf-LP-Compound 2 have superior antitumor activity compared to non-targeted controls and the free drug. These data show Tf-LP-Compound 2 to be a promising agent that warrants further evaluation. PMID:26309138

Adverse effects of anticancer agents that target the VEGF pathway.

PubMed

Chen, Helen X; Cleck, Jessica N

2009-08-01

Antiangiogenesis agents that target the VEGF/VEGF receptor pathway have become an important part of standard therapy in multiple cancer indications. With expanded clinical experience with this class of agents has come the increasing recognition of the diverse adverse effects related to disturbance of VEGF-dependent physiological functions and homeostasis in the cardiovascular and renal systems, as well as wound healing and tissue repair. Although most adverse effects of VEGF inhibitors are modest and manageable, some are associated with serious and life-threatening consequences, particularly in high-risk patients and in certain clinical settings. This Review examines the toxicity profiles of anti-VEGF antibodies and small-molecule inhibitors. The potential mechanisms of the adverse effects, risk factors, and the implications for selection of patients and management are discussed.

Surveys for Biological Control Agents of Hydrilla verticillata in the People’s Republic of China in 2013

DTIC Science & Technology

2017-03-01

Hydrilla was rare at this site and only male plants were collected at 0.5-1 m from shore and a depth of 0.5-1m. The lake/wetlands were explored by boat...ER D C/ EL T R- 17 -3 Aquatic Plant Control Research Program Surveys for Biological Control Agents of Hydrilla verticillata in the...acwc.sdp.sirsi.net/client/default. Aquatic Plant Control Research Program ERDC/EL TR-17-3 March 2017 Surveys for Biological Control Agents of

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - March 2010 update.

PubMed

Fonseca, João Eurico; Canhão, Helena; Reis, Paulo; Santos, Maria José; Branco, Jaime; Quintal, Alberto; Malcata, Armando; Araújo, Domingos; Ventura, Francisco; Figueiredo, Guilherme; da Silva, José Canas; Patto, José Vaz; de Queiroz, Mário Viana; Santos, Rui André; Neto, Adriano José; de Matos, Alves de; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Godinho, Fátima; Cunha, Inês; Costa, José António; Gomes, José António Melo; Pinto, José António Araújo; da Silva, J A Pereira; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Bernardes, Miguel; Bogas, Mónica; Araújo, Paula; Machado, Pedro; Pinto, Patrícia; de Melo, Rui Gomes; Cortes, Sara; Alcino, Sérgio; Capela, Susana

2010-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of rheumatoid arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of non-responders. Biological treatment should be considered in RA patients with a disease activity score 28 (DAS 28) superior to 3.2 despite treatment with 20mg/week of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 6 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, characterized by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of 0.6 in the DAS28 score. After 6 months of treatment response criteria is defined as a decrease of more than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Towards the implementation of a spectral database for the detection of biological warfare agents

NASA Astrophysics Data System (ADS)

Carestia, M.; Pizzoferrato, R.; Gelfusa, M.; Cenciarelli, O.; D'Amico, F.; Malizia, A.; Scarpellini, D.; Murari, A.; Vega, J.; Gaudio, P.

2014-10-01

The deliberate use of biological warfare agents (BWA) and other pathogens can jeopardize the safety of population, fauna and flora, and represents a concrete concern from the military and civil perspective. At present, the only commercially available tools for fast warning of a biological attack can perform point detection and require active or passive sampling collection. The development of a stand-off detection system would be extremely valuable to minimize the risk and the possible consequences of the release of biological aerosols in the atmosphere. Biological samples can be analyzed by means of several optical techniques, covering a broad region of the electromagnetic spectrum. Strong evidence proved that the informative content of fluorescence spectra could provide good preliminary discrimination among those agents and it can also be obtained through stand-off measurements. Such a system necessitates a database and a mathematical method for the discrimination of the spectral signatures. In this work, we collected fluorescence emission spectra of the main BWA simulants, to implement a spectral signature database and apply the Universal Multi Event Locator (UMEL) statistical method. Our preliminary analysis, conducted in laboratory conditions with a standard UV lamp source, considers the main experimental setups influencing the fluorescence signature of some of the most commonly used BWA simulants. Our work represents a first step towards the implementation of a spectral database and a laser-based biological stand-off detection and identification technique.

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

Novel dual-mode nanobubbles as potential targeted contrast agents for female tumors exploration.

PubMed

Yang, Hengli; Zhou, Tian; Cai, Wenbin; Yi, Xiaomin; Liu, Xi; Wang, Yixiao; Zhang, Li; Duan, Yunyou

2016-10-01

The purpose of this study was to prepare tumor-specific dual-mode nanobubbles as both ultrasound contrast agents (UCAs) and near-infrared fluorescence (NIRF) imaging agents for female tumors. Recent studies have demonstrated the conjugation of anti-tumor ligands on the surface of nanobubbles for use as molecule-targeting ultrasound contrast agents for tumor visualization. However, this complicated procedure has also posed a challenge to nanobubble stability. Thus, in the present study, we combined the fluorescent dye, NIRF IR-780 iodide, which has lipid solubility and tumor-targeting characteristics, with the phospholipid film of nanobubbles that we constructed. We then characterized the physical features of the IR-780-nanobubbles, observed their tumor-targeting capacity in multiple female tumor cell types in vitro, and verified their capability for use in tumor-specific ultrasound contrast imaging and NIRF imaging in vivo. The results showed that the new IR-780-nanobubbles had a uniform nano-size (442.5 ± 48.6 nm) and stability and that they were safe and effective at NIRF imaging and ultrasound imaging in vitro. The IR-780-nanobubbles were found to automatically accumulate on different female tumor cells in vitro with a considerable targeting rate (close to 40 %) but did not accumulate on cardiac muscle cells used as a negative control. Importantly, the IR-780-nanobubbles can detect female tumors precisely via dual-mode imaging in vivo. In conclusion, the new dual-mode IR-780-nanobubbles are stable and have potential advantages in non-invasive tumor-specific detection for female tumors via contrast-enhanced ultrasound and NIRF imaging.

Effects of biological control agents and exotic plant invasion on deer mouse populations

Treesearch

Yvette K. Ortega; Dean E. Pearson; Kevin S. McKelvey

2004-01-01

Exotic insects are commonly introduced as biological control agents to reduce densities of invasive exotic plants. Although current biocontrol programs for weeds take precautions to minimize ecological risks, little attention is paid to the potential nontarget effects of introduced food subsidies on native consumers. Previous research demonstrated that two gall flies (...

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.

Interfacial Stacks of Polymeric Nanofilms on Soft Biological Surfaces that Release Multiple Agents.

PubMed

Herron, Maggie; Schurr, Michael J; Murphy, Christopher J; McAnulty, Jonathan F; Czuprynski, Charles J; Abbott, Nicholas L

2016-10-03

We report a general and facile method that permits the transfer (stacking) of multiple independently fabricated and nanoscopically thin polymeric films, each containing a distinct bioactive agent, onto soft biomedically relevant surfaces (e.g., collagen-based wound dressings). By using polyelectrolyte multilayer films (PEMs) formed from poly(allyl amine hydrochloride) and poly(acrylic acid) as representative polymeric nanofilms and micrometer-thick water-soluble poly(vinyl alcohol) sacrificial films to stack the PEMs, we demonstrate that it is possible to create stacked polymeric constructs containing multiple bioactive agents (e.g., antimicrobial and antibiofilm agents) on soft and chemically complex surfaces onto which PEMs cannot be routinely transferred by stamping. We illustrate the characteristics and merits of the approach by fabricating stacks of Ga 3+ (antibiofilm agent)- and Ag + (antimicrobial agent)-loaded PEMs as prototypical examples of agent-containing PEMs and demonstrate that the stacked PEMs incorporate precise loadings of the agents and provide flexibility in terms of tuning release rates. Specifically, we show that simultaneous release of Ga 3+ and Ag + from the stacked PEMs on collagen-based wound dressings can lead to synergistic effects on bacteria, killing and dispersing biofilms formed by Pseudomonas aeruginosa (two strains: ATCC 27853 and MPAO1) at sufficiently low loadings of agents such that cytotoxic effects on mammalian cells are avoided. The approach is general (a wide range of bioactive agents other than Ga 3+ and Ag + can be incorporated into PEMs), and the modular nature of the approach potentially allows end-user functionalization of soft biological surfaces for programmed release of multiple bioactive agents.

Synthesis and biological activity of imidazopyridine anticoccidial agents: Part II.

PubMed

Scribner, Andrew; Dennis, Richard; Lee, Shuliang; Ouvry, Gilles; Perrey, David; Fisher, Michael; Wyvratt, Matthew; Leavitt, Penny; Liberator, Paul; Gurnett, Anne; Brown, Chris; Mathew, John; Thompson, Donald; Schmatz, Dennis; Biftu, Tesfaye

2008-06-01

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.

Synthesis, Biological Evaluation and Molecular Docking of New Benzenesulfonylhydrazone as Potential anti-Trypanosoma cruzi Agents.

PubMed

Elizondo-Jimenez, Silvia; Moreno-Herrera, Antonio; Reyes-Olivares, Rogelio; Dorantes-Gonzalez, Edith; Nogueda-Torres, Benjamín; Oliveira, Eduardo A Gamosa de; Romeiro, Nelilma C; Lima, Lidia M; Palos, Isidro; Rivera, Gildardo

2017-01-01

Chagas disease is a public health problem caused by Trypanosoma cruzi. Cruzain is a pharmacological target for designing a new drug against this parasite. Hydrazone and Nacylhydrazone derivatives have been traditionally associated as potential Cruzain inhibitors. Additionally, benzenesulfonyl derivatives show trypanocidal activity. Therefore, in this study, the combination of both structures has been taken into account for drug design. Seven benzenesulfonylhydrazone (BS-H) and seven N-propionyl benzenesulfonylhydrazone (BS-NAH) derivatives were synthetized and elucidated by infrared spectroscopy, nuclear magnetic resonance, and elemental analysis. All compounds were evaluated biologically in vitro against two strains of Trypanosoma cruzi (NINOA and INC-5), which are endemic in Mexico, and compared with the reference drugs nifurtimox and benznidazole. In order to gain insight into the putative molecular origin of the trypanocidal properties of these derivatives, docking studies were carried out with Cruzain. Compounds 4 and 6 (BS-H) and 10, 12-14 (BS-NAH) showed the best biological activity against NINOA and INC-5 strains, respectively. Compound 13 was the most potent trypanocidal compound showing a LC50 of 0.06 µM against INC-5 strain. However, compound 4 showed the best activity against both strains (LC50 <30 µM). Theoretical binding modes obtained suggested covalent binding that could explain their biological activity. Benzenesulfonyl and N-propionyl benzenesulfonyl hydrazone derivatives are good options for developing new trypanocidal agents. Particularly, compound 4 could be considered a lead compound. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Establishment of the armored scale, Rhizaspidiotus donacis, a biological control agent of Arundo donax

USDA-ARS?s Scientific Manuscript database

The armored scale biological control agent, Rhizaspidiotus donacis (Leonardi) (Hemiptera; Diaspididae) has established populations on the invasive weed, Arundo donax L. (Poaceae; Arundinoideae) in Del Rio (Val Verde, Co.) and in field plots at the USDA-APHIS-PPQ-Moore Airbase, Edinburg (Hidalgo Co.)...

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI

NASA Astrophysics Data System (ADS)

Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing; Yang, Jenny J.

2016-06-01

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 × 10-22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM-1 s-1 and r2 of 37.9 mM-1 s-1 per Gd (55.2 and 75.8 mM-1 s-1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM-1 s-1 per Gd (188.0 mM-1 s-1 per molecule) and r1 of 18.6 mM-1 s-1 per Gd (37.2 mM-1 s-1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high

Sensor Systems for Biological Agent Attacks: Protecting Buildings and Military Bases

DTIC Science & Technology

2004-01-01

simple aerosol detectors, to those that identify an agent based on its genetic, structural, or chemical properties , to so- called "functional...Cytometry, 122 Target Binding That Changes Detectable Properties of Smart Sensor Surfaces, 124 Colorimetric Detection, 124 Fluorescence Detection, 125 One...microscopy. In addition to particles directly derived from living organisms, other particles in air may also share properties with the bioaerosols

Aggressive treatment of early rheumatoid arthritis: recognizing the window of opportunity and treating to target goals.

PubMed

Resman-Targoff, Beth H; Cicero, Marco P

2010-11-01

Evidence supports the use of aggressive therapy for patients with early rheumatoid arthritis (RA). Clinical outcomes in patients with early RA can improve with a treat-to-target approach that sets the goal at disease remission. The current selection of antirheumatic therapies, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), has made disease remission a realistic target for patients with early RA. The challenge is selecting the optimal antirheumatic drug or combination of drugs for initial and subsequent therapy to balance the clinical benefits, risks, and economic considerations. In some cases, the use of biologic agents as part of the treatment regimen has shown superior results compared with conventional DMARDs alone in halting the progression of disease, especially in reducing radiographic damage. However, the use of biologic agents as initial therapy is challenged by cost-effectiveness analyses, which favor the use of conventional DMARDs. The use of biologic agents may be justified in certain patients with poor prognostic factors or those who experience an inadequate response to conventional DMARDs as a means to slow or halt disease progression and its associated disability. In these cases, the higher cost of treatment with biologic agents may be offset by decreased societal costs, such as lost work productivity, and increased health-related quality of life. Further research is needed to understand optimal strategies for balancing costs, benefits, and risks of antirheumatic drugs. Some key questions are (1) when biologic agents are appropriate for initial therapy, and (2) when to conclude that response to conventional DMARDs is inadequate and biologic agents should be initiated.

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

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

Park, Ji-Ae, E-mail: jpark@kirams.re.kr; Lee, Yong Jin; Ko, In Ok

2014-12-12

Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyKmore » peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.« less

[Biosafety provision on handling pathogenic biological agents on the concept of biorisk assessment and management].

PubMed

Dobrokhotskiĭ, O N; Kolombet, L V

2010-01-01

The paper shows it urgent to realize the concept of biological risk assessment and management on handling pathogenic biological agents (PBA). It gives a number of objective reasons that impede development of a methodology to assess laboratory biological risks. A concept of continuous improvement (a process approach) is proposed for use as a biorisk management tool for biosafety assurance when handling PBA. It is demonstrated that development of international cooperation urgently requires that national concepts and standards be harmonized with international regulatory documents on biosafety assurance on handling PBA.

Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases.

PubMed

Fragoulis, George E; Siebert, Stefan; McInnes, Iain B

2016-01-01

The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.

Biology, host specificity tests, and risk assessment of the sawfly Heteroperreyia hubrichi, a potential biological control agent of Schinus terebinthifolius in Hawaii

USDA-ARS?s Scientific Manuscript database

Abstract. Heteroperreyia hubrichi Malaise (Hymenoptera: Pergidae), a foliage feeding sawfly of Schinus terebinthifolius Raddi (Sapindales: Anacardiaceae), was studied to assess its suitability as a classical biological control agent of this invasive weed in Hawaii. Nochoice host-specificity tests we...

Interaction of Herbal Compounds with Biological Targets: A Case Study with Berberine

PubMed Central

Chen, Xiao-Wu; Di, Yuan Ming; Zhang, Jian; Zhou, Zhi-Wei; Li, Chun Guang; Zhou, Shu-Feng

2012-01-01

Berberine is one of the main alkaloids found in the Chinese herb Huang lian (Rhizoma Coptidis), which has been reported to have multiple pharmacological activities. This study aimed to analyze the molecular targets of berberine based on literature data followed by a pathway analysis using the PANTHER program. PANTHER analysis of berberine targets showed that the most classes of molecular functions include receptor binding, kinase activity, protein binding, transcription activity, DNA binding, and kinase regulator activity. Based on the biological process classification of in vitro berberine targets, those targets related to signal transduction, intracellular signalling cascade, cell surface receptor-linked signal transduction, cell motion, cell cycle control, immunity system process, and protein metabolic process are most frequently involved. In addition, berberine was found to interact with a mixture of biological pathways, such as Alzheimer's disease-presenilin and -secretase pathways, angiogenesis, apoptosis signalling pathway, FAS signalling pathway, Hungtington disease, inflammation mediated by chemokine and cytokine signalling pathways, interleukin signalling pathway, and p53 pathways. We also explored the possible mechanism of action for the anti-diabetic effect of berberine. Further studies are warranted to elucidate the mechanisms of action of berberine using systems biology approach. PMID:23213296

Whole-body multicolor spectrally resolved fluorescence imaging for development of target-specific optical contrast agents using genetically engineered probes

NASA Astrophysics Data System (ADS)

Kobayashi, Hisataka; Hama, Yukihiro; Koyama, Yoshinori; Barrett, Tristan; Urano, Yasuteru; Choyke, Peter L.

2007-02-01

Target-specific contrast agents are being developed for the molecular imaging of cancer. Optically detectable target-specific agents are promising for clinical applications because of their high sensitivity and specificity. Pre clinical testing is needed, however, to validate the actual sensitivity and specificity of these agents in animal models, and involves both conventional histology and immunohistochemistry, which requires large numbers of animals and samples with costly handling. However, a superior validation tool takes advantage of genetic engineering technology whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra thus, identifying them as cancer cells. Multicolor fluorescence imaging of these genetically engineered probes can provide rapid validation of newly developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not-express specific cell surface receptors. Various antibody-based or receptor ligand-based optical contrast agents with either green or near infrared fluorophores were developed to concurrently target and validate cancer cells and their positive and negative controls, such as β-D-galactose receptor, HER1 and HER2 in a single animal/organ. Spectrally resolved fluorescence multicolor imaging was used to detect separate fluorescent emission spectra from the exogenous agents and RFP. Therefore, using this in vivo imaging technique, we were able to demonstrate the sensitivity and specificity of the target-specific optical contrast agents, thus reducing the number of animals needed to conduct these experiments.

Target and Agent Prioritization for the Children's Oncology Group-National Cancer Institute Pediatric MATCH Trial.

PubMed

Allen, Carl E; Laetsch, Theodore W; Mody, Rajen; Irwin, Meredith S; Lim, Megan S; Adamson, Peter C; Seibel, Nita L; Parsons, D Williams; Cho, Y Jae; Janeway, Katherine

2017-05-01

Over the past decades, outcomes for children with cancer have improved dramatically through serial clinical trials based in large measure on dose intensification of cytotoxic chemotherapy for children with high-risk malignancies. Progress made through such dose intensification, in general, is no longer yielding further improvements in outcome. With the revolution in sequencing technologies and rapid development of drugs that block specific proteins and pathways, there is now an opportunity to improve outcomes for pediatric cancer patients through mutation-based targeted therapeutic strategies. The Children's Oncology Group (COG), in partnership with the National Cancer Institute (NCI), is planning a trial entitled the COG-NCI Pediatric Molecular Analysis for Therapeutic Choice (Pediatric MATCH) protocol utilizing an umbrella design. This protocol will have centralized infrastructure and will consist of a biomarker profiling protocol and multiple single-arm phase II trials of targeted therapies. Pediatric patients with recurrent or refractory solid tumors, lymphomas, or histiocytoses with measurable disease will be eligible. The Pediatric MATCH Target and Agent Prioritization (TAP) committee includes membership representing COG disease committees, the Food and Drug Administration, and the NCI. The TAP Committee systematically reviewed target and agent pairs for inclusion in the Pediatric MATCH trial. Fifteen drug-target pairs were reviewed by the TAP Committee, with seven recommended for further development as initial arms of the Pediatric MATCH trial. The current evidence for availability, efficacy, and safety of targeted agents in children for each class of mutation considered for inclusion in the Pediatric MATCH trial is discussed in this review. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Potential biological control agents for management of cogongrass (Cyperales: Poaceae) in the southeastern USA

USDA-ARS?s Scientific Manuscript database

Cogongrass, Imperata cylindrica (L.) Palisot de Beauvois (Cyperales: Poaceae), is a noxious invasive weed in the southeastern USA. Surveys for potential biological control agents of cogongrass were conducted in Asia and East Africa from 2013 to 2016. Several insect herbivores were found that may hav...

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - October 2011 update.

PubMed

Fonseca, João Eurico; Bernardes, Miguel; Canhão, Helena; Santos, Maria José; Quintal, Alberto; Malcata, Armando; Neto, Adriano; Cordeiro, Ana; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Duarte, Cátia; Araújo, Domingos; Nour, Dolores; Sousa, Elsa; Simões, Eugénia; Godinho, Fátima; Brandão, Filipe; Ventura, Francisco; Sequeira, Graça; Figueiredo, Guilherme; Cunha, Inês; Matos, J Alves; Branco, Jaime; Ramos, João; Costa, José António; Gomes, José António; Pinto, José; Silva, José Canas; Silva, J A; Patto, José Vaz; Costa, Lúcia; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Queiroz, Mário Viana; Bogas, Mónica; Araújo, Paula; Reis, Paulo; Abreu, Pedro; Machado, Pedro; Pinto, Patrícia; André, Rui; Melo, Rui; Garcês, Sandra; Cortes, Sara; Alcino, Sérgio; Ramiro, Sofia; Capela, Susana

2011-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of Rheumatoid Arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of nonresponders. Biological treatment (with a tumour necrosis factor antagonist, abatacept or tocilizumab) should be considered in RA patients with a disease activity score 28 (DAS 28) equal to or greater than 3.2 despite treatment with at least 20mg-weekly-dose of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 3 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, defined by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of at least 0.6 in the DAS28 score. After 6 months of treatment res­ponse criteria is defined as a decrease greater than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist’s clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Antibody-based Biologics and Their Promise to Combat Staphylococcus aureus Infections

PubMed Central

Sause, William E.; Buckley, Peter T.; Strohl, William R.; Lynch, Anthony S.; Torres, Victor J.

2015-01-01

The growing incidence of serious infections mediated by methicillin-resistant Staphylococcus aureus (MRSA) strains poses a significant risk to public health. This risk is exacerbated by a prolonged void in the discovery and development of truly novel antibiotics and the absence of a vaccine. These gaps have created renewed interest in the use of biologics in the prevention and treatment of serious staphylococcal infections. This review focuses on efforts towards the discovery and development of antibody-based biologic agents and their potential as clinical agents in the management of serious S. aureus infections. Recent promising data for monoclonal antibodies (mAbs) targeting anthrax and Ebola highlight the potential of antibody-based biologics as therapeutic agents for serious infections. PMID:26719219

Portable Raman instrument for rapid biological agent detection and identification

NASA Astrophysics Data System (ADS)

Lesaicherre, Marie L.; Paxon, Tracy L.; Mondello, Frank J.; Burrell, Michael C.; Linsebigler, Amy

2009-05-01

The rapid and sensitive identification of biological species is a critical need for the 1st responder and military communities. Raman spectroscopy is a powerful tool for substance identification that has gained popularity with the respective communities due to the increasing availability of portable Raman spectrometers. Attempts to use Raman spectroscopy for the direct identification of biological pathogens has been hindered by the complexity of the generated Raman spectrum. We report here the use of a sandwich immunoassay containing antibody modified magnetic beads to capture and concentrate target analytes in solution and Surface Enhanced Raman Spectroscopy (SERS) tags conjugated with these same antibodies for specific detection. Using this approach, the biological complexity of a microorganism can be translated into chemical simplicity and Raman can be used for the identification of biological pathogens. The developed assay has a low limit of detection due to the SERS effect, robust to commonly found white powders interferants, and stable at room temperature over extended period of time. This assay is being implemented into a user-friendly interface to be used in conjunction with the GE Homeland Protection StreetLab MobileTM Raman instrument for rapid, field deployable chemical and biological identification.

Anti-EpCAM scFv gadolinium chelate: a novel targeted MRI contrast agent for imaging of colorectal cancer.

PubMed

Khantasup, Kannika; Saiviroonporn, Pairash; Jarussophon, Suwatchai; Chantima, Warangkana; Dharakul, Tararaj

2018-05-08

The development of targeted contrast agents for magnetic resonance imaging (MRI) facilitates enhanced cancer imaging and more accurate diagnosis. In the present study, a novel contrast agent was developed by conjugating anti-EpCAM humanized scFv with gadolinium chelate to achieve target specificity. The material design strategy involved site-specific conjugation of the chelating agent to scFv. The scFv monomer was linked to maleimide-DTPA via unpaired cysteine at the scFv C-terminus, followed by chelation with gadolinium (Gd). Successful scFv-DTPA conjugation was achieved at 1:10 molar ratio of scFv to maleimide-DTPA at pH 6.5. The developed anti-EpCAM-Gd-DTPA MRI contrast agent was evaluated for cell targeting ability, in vitro serum stability, cell cytotoxicity, relaxivity, and MR contrast enhancement. A high level of targeting efficacy of anti-EpCAM-Gd-DTPA to an EpCAM-overexpressing HT29 colorectal cell was demonstrated by confocal microscopy. Good stability of the contrast agent was obtained and no cytotoxicity was observed in HT29 cells after 48 h incubation with 25-100 µM of Gd. Favorable imaging was obtained using anti-EpCAM-Gd-DTPA, including 1.8-fold enhanced relaxivity compared with Gd-DTPA, and MR contrast enhancement observed after binding to HT29. The potential benefit of this contrast agent for in vivo MR imaging of colorectal cancer, as well as other EpCAM positive cancers, is suggested and warrants further investigation.

Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology

PubMed Central

Galdeano, Carles; Ciulli, Alessio

2017-01-01

Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity. PMID:27193077

Peptide-based pharmacomodulation of a cancer-targeted optical imaging and photodynamic therapy agent

PubMed Central

Stefflova, Klara; Li, Hui; Chen, Juan; Zheng, Gang

2008-01-01

We designed and synthesized a folate receptor-targeted, water soluble, and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is comprised of three components: 1) Pyropheophorbide a (Pyro) as an imaging and therapeutic agent, 2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and 3) Folate as a homing molecule targeting FR-expressing cancer cells. We observed an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs. HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was observed in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro’s own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe – a process we attributed to a possible peptide-based pharmacomodulation – as was demonstrated by a 50-fold reduction in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted molecular imaging and photodynamic therapy agents. PMID:17298029

Decontamination of biological agents from drinking water infrastructure: a literature review and summary.

PubMed

Szabo, Jeff; Minamyer, Scott

2014-11-01

This report summarizes the current state of knowledge on the persistence of biological agents on drinking water infrastructure (such as pipes) along with information on decontamination should persistence occur. Decontamination options for drinking water infrastructure have been explored for some biological agents, but data gaps remain. Data on bacterial spore persistence on common water infrastructure materials such as iron and cement-mortar lined iron show that spores can be persistent for weeks after contamination. Decontamination data show that common disinfectants such as free chlorine have limited effectiveness. Decontamination results with germinant and alternate disinfectants such as chlorine dioxide are more promising. Persistence and decontamination data were collected on vegetative bacteria, such as coliforms, Legionella and Salmonella. Vegetative bacteria are less persistent than spores and more susceptible to disinfection, but the surfaces and water quality conditions in many studies were only marginally related to drinking water systems. However, results of real-world case studies on accidental contamination of water systems with E. coli and Salmonella contamination show that flushing and chlorination can help return a water system to service. Some viral persistence data were found, but decontamination data were lacking. Future research suggestions focus on expanding the available biological persistence data to other common infrastructure materials. Further exploration of non-traditional drinking water disinfectants is recommended for future studies. Published by Elsevier Ltd.

Classifying transcription factor targets and discovering relevant biological features

PubMed Central

Holloway, Dustin T; Kon, Mark; DeLisi, Charles

2008-01-01

Background An important goal in post-genomic research is discovering the network of interactions between transcription factors (TFs) and the genes they regulate. We have previously reported the development of a supervised-learning approach to TF target identification, and used it to predict targets of 104 transcription factors in yeast. We now include a new sequence conservation measure, expand our predictions to include 59 new TFs, introduce a web-server, and implement an improved ranking method to reveal the biological features contributing to regulation. The classifiers combine 8 genomic datasets covering a broad range of measurements including sequence conservation, sequence overrepresentation, gene expression, and DNA structural properties. Principal Findings (1) Application of the method yields an amplification of information about yeast regulators. The ratio of total targets to previously known targets is greater than 2 for 11 TFs, with several having larger gains: Ash1(4), Ino2(2.6), Yaf1(2.4), and Yap6(2.4). (2) Many predicted targets for TFs match well with the known biology of their regulators. As a case study we discuss the regulator Swi6, presenting evidence that it may be important in the DNA damage response, and that the previously uncharacterized gene YMR279C plays a role in DNA damage response and perhaps in cell-cycle progression. (3) A procedure based on recursive-feature-elimination is able to uncover from the large initial data sets those features that best distinguish targets for any TF, providing clues relevant to its biology. An analysis of Swi6 suggests a possible role in lipid metabolism, and more specifically in metabolism of ceramide, a bioactive lipid currently being investigated for anti-cancer properties. (4) An analysis of global network properties highlights the transcriptional network hubs; the factors which control the most genes and the genes which are bound by the largest set of regulators. Cell-cycle and growth related

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.

Highlights from the 2015 WIN Symposium: novel targets, innovative agents, and advanced technologies-a WINning strategy?

PubMed

Schilsky, Richard L

2015-01-01

The worldwide innovative networking (WIN) consortium comprises a global alliance of 28 academic and clinical cancer centres, 11 pharmaceutical and technology companies and five charitable or health payer organisations. Since its inception the consortium has striven to provide a forum for all of its members to network, share information and experience, and perform clinical trials with the overarching goal of advancing the care of patients with cancer through the use of precision medicine. The annual 2-day WIN Symposium is the most visible output of the consortium and provides an opportunity for around 400 experts and other delegates to meet and discuss the latest research and initiatives in personalised cancer medicine. The seventh WIN Symposium, held in Paris, France, 29-30 June 2015, consisted of nine plenary and eight poster sessions that covered the overarching theme of novel targets, innovative agents, and advanced technologies being a winning strategy. Highlights included discussions of immune mechanisms and ways to target the cancer immunome and systems biology approaches to supporting personalised cancer. The latest data from the BATTLE-2 and WINther trials were discussed, and round table discussions were held that focused on how best to design the next generation of clinical trials, which included SPRING, SUMMER, and BOOSTER being initiated by the WIN Consortium.

Direct-acting Antivirals and Host-targeting Agents against the Hepatitis A Virus

PubMed Central

Kanda, Tatsuo; Nakamoto, Shingo; Wu, Shuang; Nakamura, Masato; Jiang, Xia; Haga, Yuki; Sasaki, Reina; Yokosuka, Osamu

2015-01-01

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries. Although effective vaccines for HAV are available, the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists, such as Japan. There are two forms of antiviral agents against HAV: direct-acting antivirals (DAAs) and host-targeting agents (HTAs). Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection. Among the HTAs, amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication. Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication. Based on this review, both DAAs and HTAs may be needed to control effectively HAV infection, and their use should continue to be explored. PMID:26623267

Use of pupal parasitoids as biological control agents of filth flies on equine facilities

USDA-ARS?s Scientific Manuscript database

House flies, Musca domestica L., and stable flies, Stomoxys calcitrans (L.), (Diptera: Muscidae), are common pests on horse farms. The use of pupal parasitoids as biological control agents for filth flies is becoming more popular on equine facilities; however, there is a lack of information on the e...

Near-Infrared Fluorescent Materials for Sensing of Biological Targets

PubMed Central

Amiot, Carrie L.; Xu, Shuping; Liang, Song; Pan, Lingyun; Zhao, Julia Xiaojun

2008-01-01

Near-infrared fluorescent (NIRF) materials are promising labeling reagents for sensitive determination and imaging of biological targets. In the near-infrared region biological samples have low background fluorescence signals, providing high signal to noise ratio. Meanwhile, near-infrared radiation can penetrate into sample matrices deeply due to low light scattering. Thus, in vivo and in vitro imaging of biological samples can be achieved by employing the NIRF probes. To take full advantage of NIRF materials in the biological and biomedical field, one of the key issues is to develop intense and biocompatible NIRF probes. In this review, a number of NIRF materials are discussed including traditional NIRF dye molecules, newly developed NIRF quantum dots and single-walled carbon nanotubes, as well as rare earth metal compounds. The use of some NIRF materials in various nanostructures is illustrated. The enhancement of NIRF using metal nanostructures is covered as well. The fluorescence mechanism and bioapplications of each type of the NIRF materials are discussed in details. PMID:27879867

A theranostic dental pulp capping agent with improved MRI and CT contrast and biological properties.

PubMed

Mastrogiacomo, S; Güvener, N; Dou, W; Alghamdi, H S; Camargo, W A; Cremers, J G O; Borm, P J A; Heerschap, A; Oosterwijk, E; Jansen, J A; Walboomers, X F

2017-10-15

Different materials have been used for vital dental pulp treatment. Preferably a pulp capping agent should show appropriate biological performance, excellent handling properties, and a good imaging contrast. These features can be delivered into a single material through the combination of therapeutic and diagnostic agents (i.e. theranostic). Calcium phosphate based composites (CPCs) are potentially ideal candidate for pulp treatment, although poor imaging contrast and poor dentino-inductive properties are limiting their clinical use. In this study, a theranostic dental pulp capping agent was developed. First, imaging properties of the CPC were improved by using a core-shell structured dual contrast agent (csDCA) consisting of superparamagnetic iron oxide (SPIO) and colloidal gold, as MRI and CT contrast agent respectively. Second, biological properties were implemented by using a dentinogenic factor (i.e. bone morphogenetic protein 2, BMP-2). The obtained CPC/csDCA/BMP-2 composite was tested in vivo, as direct pulp capping agent, in a male Habsi goat incisor model. Our outcomes showed no relevant alteration of the handling and mechanical properties (e.g. setting time, injectability, and compressive strength) by the incorporation of csDCA particles. In vivo results proved MRI contrast enhancement up to 7weeks. Incisors treated with BMP-2 showed improved tertiary dentin deposition as well as faster cement degradation as measured by µCT assessment. In conclusion, the presented theranostic agent matches the imaging and regenerative requirements for pulp capping applications. In this study, we combined diagnostic and therapeutic agents in order to developed a theranostic pulp capping agent with enhanced MRI and CT contrast and improved dentin regeneration ability. In our study we cover all the steps from material preparation, mechanical and in vitro characterization, to in vivo study in a goat dental model. To the best of our knowledge, this is the first time that a

Cytokine-targeting biologics for allergic diseases.

PubMed

Lawrence, Monica G; Steinke, John W; Borish, Larry

2018-04-01

Asthma and allergic diseases continue to increase in prevalence, creating a financial burden on the health care system and affecting the quality of life for those who have these diseases. Many intrinsic and extrinsic factors are involved in the initiation and maintenance of the allergic response. Cytokines are proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses. clinicaltrials.gov and PubMed. Relevant clinical trials and recent basic science studies were chosen for discussion. Many cytokines have been implicated in the development and perpetuation of the allergic response. Biologics have been and are continuing to be developed that target these molecules for use in patients with asthma and atopic dermatitis where standard treatment options fail. The current state of cytokine-targeting therapies is discussed. This review focused on cytokines involved in the allergic response with an emphasis on those for which therapies are being or have been developed. Copyright © 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals.

PubMed

Li, Changzhao; Srivastava, Ritesh K; Athar, Mohammad

2016-08-01

Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. On the basis of these observations, and considering the low cost and simple methods of their bulk syntheses, these agents were thought to be appropriate for chemical warfare. Among these, the best-known agent that was synthesized and weaponized during World War I (WWI) is Lewisite. Exposure to Lewisite causes painful inflammatory and blistering responses in the skin, lung, and eye. These chemicals also manifest systemic tissue injury following their cutaneous exposure. Although largely discontinued after WWI, stockpiles are still known to exist in the former Soviet Union, Germany, Italy, the United States, and Asia. Thus, access by terrorists or accidental exposure could be highly dangerous for humans and the environment. This review summarizes studies that describe the biological, pathophysiological, toxicological, and environmental effects of exposure to arsenicals, with a major focus on cutaneous injury. Studies related to the development of novel molecular pathobiology-based antidotes against these agents are also described. © 2016 New York Academy of Sciences.

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals

PubMed Central

Li, Changzhao; Srivastava, Ritesh K.; Athar, Mohammad

2016-01-01

Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. Based on these observations, and considering the low cost and simple methods of their bulk syntheses, these agents were thought to be appropriate for chemical warfare. Among these, the most known agent synthesized and weaponized during World War I (WWI) is Lewisite. Exposure to Lewisite causes painful inflammatory and blistering responses in the skin, lung, and eye. These chemicals also manifest systemic tissue injury following their cutaneous exposure. Although largely discontinued after WWI, their stockpiles are still known to exist in the former Soviet Union, Germany, Italy, the United States, and Asia. Thus, their access by terrorists or accidental exposure could be highly dangerous for humans and the environment. This review summarizes studies which describe the biological, pathophysiological, toxicological, and environmental effects of exposure to arsenicals, with a major focus on cutaneous injury. Studies related to the development of novel molecular pathobiology–based antidotes against these agents are also described. PMID:27636894

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy.

PubMed

Ganapathy-Kanniappan, S; Vali, M; Kunjithapatham, R; Buijs, M; Syed, L H; Rao, P P; Ota, S; Kwak, B K; Loffroy, R; Geschwind, J F

2010-08-01

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3-bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3-bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

Laboratory evaluation of two native fishes from tropical North Queensland as biological control agents of subterranean Aedes aegypti.

PubMed

Russell, B M; Wang, J; Williams, Y; Hearnden, M N; Kay, B H

2001-06-01

The ability of 2 freshwater fishes, eastern rainbow fish Melanotaenia splendida splendida and fly-specked hardyhead Craterocephalus stercusmuscarum stercusmuscarum, native to North Queensland to prey on immature Aedes aegypti was evaluated under laboratory conditions. The predation efficiency of the 2 species was compared to the exotic guppy, Poecilia reticulata, which is commonly used as a biological control agent of mosquito larvae. Of the 3 fish species tested, M. s. splendida was shown to be the most promising agent for the biological control of Ae. aegypti that breed in wells. Melanotaenia s. splendida consumed significantly greater numbers of immature Ae. aegypti than P. reticulata, irrespective of developmental stage or light conditions. Unlike C s. stercusmuscarum, M. s. splendida could be handled, transported, and kept in captivity for extended periods with negligible mortality. However, M. s. splendida was also an efficient predator of Litoria caerulea tadpoles, a species of native frog found in wells during the dry season. This result may limit the usefulness of M. s. splendida as a biological control agent of well-breeding Ae. aegypti and suggests that predacious copepods, Mesocyclops spp., are more suitable. However, the use of M. s. splendida as a mosquito control agent in containers that are unlikely to support frog populations (e.g., aquaculture tanks and drinking troughs) should be given serious consideration.

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.

Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme.

PubMed

Julián, Esther; Baelo, Aida; Gavaldà, Joan; Torrents, Eduard

2015-01-01

The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme.

Methyl-Hydroxylamine as an Efficacious Antibacterial Agent That Targets the Ribonucleotide Reductase Enzyme

PubMed Central

Julián, Esther; Baelo, Aida; Gavaldà, Joan; Torrents, Eduard

2015-01-01

The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme. PMID:25782003

Identification of biological agents using surface enhanced Raman scattering

NASA Astrophysics Data System (ADS)

Paxon, Tracy L.; Duthie, R. Scott; Renko, Casey; Burns, Andrew A.; Lesaicherre, Marie L.; Mondello, Frank J.

2011-05-01

GE Global Research Center, in collaboration with Morpho Detection, Inc. has developed an assay scheme for the identification of biological agents using Surface Enhanced Raman Scattering (SERS). Specifically, unique spectroscopic signatures are generated using SERS tags consisting of individual glass-encapsulated gold nanoparticles and surfacebound reporter molecules. These SERS tags are modified with a capture moiety specific to the antigen of interest, and serve as a spectroscopic label in a bead-based sandwich assay. Assays are being developed for a variety of pathogens and this paper will focus on aspects of assay development, optimization, stabilization and validation. Results on the development of an assay to detect Ricin toxin will be presented, and preliminary feasibility studies for the detection of additional pathogens will be discussed.

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI†

PubMed Central

Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing

2017-01-01

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 ± 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 ± 0.1 × 10−22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM−1 s−1 and r2 of 37.9 mM−1 s−1 per Gd (55.2 and 75.8 mM−1 s−1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM−1 s−1 per Gd (188.0 mM−1 s−1 per molecule) and r1 of 18.6 mM−1 s−1 per Gd (37.2 mM−1 s−1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI. PMID:26961235

"Design characteristics of the CORRONA CERTAIN study: a comparative effectiveness study of biologic agents for rheumatoid arthritis patients".

PubMed

Pappas, Dimitrios A; Kremer, Joel M; Reed, George; Greenberg, Jeffrey D; Curtis, Jeffrey R

2014-04-01

Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA). CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-α inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naïve and biologic experienced). The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA.

A proposed CT contrast agent using carboxybetaine zwitterionic tantalum oxide nanoparticles: Imaging, biological, and physicochemical performance

PubMed Central

FitzGerald, Paul F.; Butts, Matthew D.; Roberts, Jeannette C.; Colborn, Robert E.; Torres, Andrew S.; Lee, Brian D.; Yeh, Benjamin M.; Bonitatibus, Peter J.

2016-01-01

Objectives To produce and evaluate a proposed computed tomography (CT) contrast agent based on carboxybetaine zwitterionic (CZ) coated soluble tantalum oxide nanoparticles (CZ-TaO NPs). We chose tantalum to provide superior imaging performance compared to current iodine-based clinical CT contrast agents. We developed the CZ coating to provide biological and physical performance similar to that of current iodinated contrast agents. The aim of this study was to evaluate the imaging, biological, and physicochemical performance of this proposed contrast agent compared to clinically-used iodinated agents. Materials and Methods We evaluated CT imaging performance of our CZ-TaO NPs compared to an iodinated agent in live rats, imaged centrally-located within a tissue-equivalent plastic phantom that simulated a large patient. To evaluate vascular contrast enhancement, we scanned the rats’ great vessels at high temporal resolution during and following contrast agent injection. We performed several in vivo CZ-TaO NP studies in healthy rats to evaluate tolerability. These studies included injecting the agent at the anticipated clinical dose (ACD) and at 3 times and 6 times the ACD, followed by longitudinal hematology to assess impact to blood cells and organ function (from 4 hours to 1 week). Kidney histological analysis was performed 48 hours after injection at 3 times the ACD. We measured the elimination half-life of CZ-TaO NPs from blood, and we monitored acute kidney injury biomarkers with a kidney injury assay using urine collected from 4 hours to 1 week. We measured tantalum retention in individual organs and in the whole carcass 48 hours after injection at ACD. CZ-TaO NPs were synthesized and analyzed in detail. We used multi-dimensional nuclear magnetic resonance (NMR) to determine surface functionality of the nanoparticles. We measured nanoparticle size and solution properties (osmolality and viscosity) of the agent over a range of tantalum concentrations, including

Principles of antidote pharmacology: an update on prophylaxis, post-exposure treatment recommendations and research initiatives for biological agents

PubMed Central

Ramasamy, S; Liu, CQ; Tran, H; Gubala, A; Gauci, P; McAllister, J; Vo, T

2010-01-01

The use of biological agents has generally been confined to military-led conflicts. However, there has been an increase in non-state-based terrorism, including the use of asymmetric warfare, such as biological agents in the past few decades. Thus, it is becoming increasingly important to consider strategies for preventing and preparing for attacks by insurgents, such as the development of pre- and post-exposure medical countermeasures. There are a wide range of prophylactics and treatments being investigated to combat the effects of biological agents. These include antibiotics (for both conventional and unconventional use), antibodies, anti-virals, immunomodulators, nucleic acids (analogues, antisense, ribozymes and DNAzymes), bacteriophage therapy and micro-encapsulation. While vaccines are commercially available for the prevention of anthrax, cholera, plague, Q fever and smallpox, there are no licensed vaccines available for use in the case of botulinum toxins, viral encephalitis, melioidosis or ricin. Antibiotics are still recommended as the mainstay treatment following exposure to anthrax, plague, Q fever and melioidosis. Anti-toxin therapy and anti-virals may be used in the case of botulinum toxins or smallpox respectively. However, supportive care is the only, or mainstay, post-exposure treatment for cholera, viral encephalitis and ricin – a recommendation that has not changed in decades. Indeed, with the difficulty that antibiotic resistance poses, the development and further evaluation of techniques and atypical pharmaceuticals are fundamental to the development of prophylaxis and post-exposure treatment options. The aim of this review is to present an update on prophylaxis and post-exposure treatment recommendations and research initiatives for biological agents in the open literature from 2007 to 2009. PMID:20860656

Integrative biology approach identifies cytokine targeting strategies for psoriasis.

PubMed

Perera, Gayathri K; Ainali, Chrysanthi; Semenova, Ekaterina; Hundhausen, Christian; Barinaga, Guillermo; Kassen, Deepika; Williams, Andrew E; Mirza, Muddassar M; Balazs, Mercedesz; Wang, Xiaoting; Rodriguez, Robert Sanchez; Alendar, Andrej; Barker, Jonathan; Tsoka, Sophia; Ouyang, Wenjun; Nestle, Frank O

2014-02-12

Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic. We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap. We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti-IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti-IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes. Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis. Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

Silicon Nanoparticles as Hyperpolarized Magnetic Resonance Imaging Agents

PubMed Central

Aptekar, Jacob W.; Cassidy, Maja C.; Johnson, Alexander C.; Barton, Robert A.; Lee, Menyoung; Ogier, Alexander C.; Vo, Chinh; Anahtar, Melis N.; Ren, Yin; Bhatia, Sangeeta N.; Ramanathan, Chandrasekhar; Cory, David G.; Hill, Alison L.; Mair, Ross W.; Rosen, Matthew S.; Walsworth, Ronald L.

2014-01-01

Magnetic resonance imaging of hyperpolarized nuclei provides high image contrast with little or no background signal. To date, in-vivo applications of pre-hyperpolarized materials have been limited by relatively short nuclear spin relaxation times. Here, we investigate silicon nanoparticles as a new type of hyperpolarized magnetic resonance imaging agent. Nuclear spin relaxation times for a variety of Si nanoparticles are found to be remarkably long, ranging from many minutes to hours at room temperature, allowing hyperpolarized nanoparticles to be transported, administered, and imaged on practical time scales. Additionally, we demonstrate that Si nanoparticles can be surface functionalized using techniques common to other biologically targeted nanoparticle systems. These results suggest that Si nanoparticles can be used as a targetable, hyperpolarized magnetic resonance imaging agent with a large range of potential applications. PMID:19950973

Silicon nanoparticles as hyperpolarized magnetic resonance imaging agents.

PubMed

Aptekar, Jacob W; Cassidy, Maja C; Johnson, Alexander C; Barton, Robert A; Lee, Menyoung; Ogier, Alexander C; Vo, Chinh; Anahtar, Melis N; Ren, Yin; Bhatia, Sangeeta N; Ramanathan, Chandrasekhar; Cory, David G; Hill, Alison L; Mair, Ross W; Rosen, Matthew S; Walsworth, Ronald L; Marcus, Charles M

2009-12-22

Magnetic resonance imaging of hyperpolarized nuclei provides high image contrast with little or no background signal. To date, in vivo applications of prehyperpolarized materials have been limited by relatively short nuclear spin relaxation times. Here, we investigate silicon nanoparticles as a new type of hyperpolarized magnetic resonance imaging agent. Nuclear spin relaxation times for a variety of Si nanoparticles are found to be remarkably long, ranging from many minutes to hours at room temperature, allowing hyperpolarized nanoparticles to be transported, administered, and imaged on practical time scales. Additionally, we demonstrate that Si nanoparticles can be surface functionalized using techniques common to other biologically targeted nanoparticle systems. These results suggest that Si nanoparticles can be used as a targetable, hyperpolarized magnetic resonance imaging agent with a large range of potential applications.

Molecular Docking, Synthesis And Biological Evaluation Of Sulphonylureas/Guanidine Derivatives As Promising Antidiabetics Agent.

PubMed

Panchal, Ishan; Sen, Dhrubo Jyoti; Patel, Ashish D; Shah, Umang; Patel, Mehul; Navle, Archana; Bhavsar, Vashisth

2017-10-02

A series of novel sulphonylureas/guanidine derivatives were designed, synthesized, and evaluated for the treatment of diabetes mellitus. In this study, the designed compounds were docked with AKR1C1 complexes by using glide docking program and docking calculations were performed to predict the binding affinity of the designed compounds with the binding pocket of protein 4YVP and QikProp program was used to predict the ADME/T properties of the analogues. All the targeted derivatives were synthesized and purified by recrystallization. Synthesize compounds were characterized by various physicochemical and various spectroscopic techniques like melting point, thin layer chromatography, infrared spectroscopy (KBr pellets), mass spectroscopy(m/z), 1H NMR (DMSO-d6), and 13C NMR. The synthesized compounds were further studied for biological evolution by alloxan (150 mg/dl, intraperitonial) induced diabetic rat model for in-vivo studies. Among all the synthesized derivatives, 5c and 5d were most potent as per binding energy. Compound 5i have shown a better plasma glucose reduction compared to glibenclamide. Hence, it will further use as a lead compound to develop a more such kind of agent. The docking study revealed that in all designed sulphonylureas/guanidine series of compounds 5c and 5d were found to be most potent compounds as per the binding energy compared to glibenclamide. With the help of details study of in vivo biological activity we observed that compound 5i gives better result compared to glibenclamide as standard. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Photoacoustic imaging of tumor targeting with biotin conjugated nanostructured phthalocyanine assemblies

NASA Astrophysics Data System (ADS)

Lee, Seunghyun; Li, Xingshu; Lee, Dayoung; Yoon, Juyoung; Kim, Chulhong

2018-02-01

Visualizing biological markers and delivering bioactive agents to living organisms are important to biological research. In recent decades, photoacoustic imaging (PAI) has been significantly improved in the area of molecular imaging, which provides high-resolution volume imaging with high optical absorption contrast. To demonstrate the ability of nanoprobes to target tumors using PAI, we synthesize convertible nanostructured agents with strong photothermal and photoacoustic properties and linked the nanoprobe with biotin to target tumors in small animal model. Interestingly, these nanoprobes allow partial to disassemble in the presence of targeted proteins that switchable photoactivity, thus the nanoprobes provides a fluorescent-cancer imaging with high signal-to-background ratios. The proposed nanoprobe produce a much stronger PA signal compared to the same concentration of methylene blue (MB), which is widely used in clinical study and contrast agent for PAI. The biotin conjugated nanoprobe has high selectivity for biotin receptor positive cancer cells such as A549 (human lung cancer). Then we subsequently examined the PA properties of the nanoprobe that are inherently suitable for in vivo PAI. After injecting of the nanoprobe via intravenous method, we observed the mice's whole body by PA imaging and acquired the PA signal near the cancer. The PA signal increased linearly with time after injection and the fluorescence signal near the cancer was confirmed by fluorescence imaging. The ability to target a specific cancer of the nanoprobe was well verified by PA imaging. This study provides valuable perspective on the advancement of clinical translations and in the design of tumor-targeting phototheranostic agents that could act as new nanomedicines.

Susceptibility of non-target invertebrates to Brazilian microbial pest control agents.

PubMed

Oliveira-Filho, Eduardo Cyrino; Muniz, Daphne Heloisa Freitas; Freire, Ingrid Souza; Ramos, Felipe Rosa; Alves, Roberto Teixeira; Jonsson, Claudio Martin; Grisolia, Cesar Koppe; Monnerat, Rose Gomes

2011-08-01

Microbial pest control agents or entomopathogens have been considered an interesting alternative to use instead of chemical insecticides. Knowledge of ecotoxicity data is very important to predict the hazard of any product released in the environment and subsidize the regulation of these products by governmental agencies. In the present study four new Brazilian strains of Bacillus and one fungus were tested to evaluate their acute toxicity to the microcrustacean Daphnia similis, the snail Biomphalaria glabrata and the dung beetle Digitonthophagus gazella. The microcrustaceans and the snails were exposed to entomopathogens in synthetic softwater and the beetles were exposed directly in cattle dung. Obtained data reveal low susceptibility of the non-target species to tested microorganisms, with lethal concentrations being observed only at much higher concentrations than that effective against target insects. These results show that the tested strains are selective in their action mode and seem to be non-hazardous to non-target species.

Trichogramma spp. (Hymenoptera: Trichogrammatidae) as biological control agents in the Philippines: history and current practice

USDA-ARS?s Scientific Manuscript database

Trichogramma parasitoids have long been recognized as important and viable biological control agents against lepidopteran pests of rice, corn and sugarcane in the Philippines. We describe the history of research and use of Trichogramma spp. in the Philippines in three main areas: 1) field surveys – ...

Suprafenacine, an Indazole-Hydrazide Agent, Targets Cancer Cells Through Microtubule Destabilization

PubMed Central

Choi, Bo-Hwa; Chattopadhaya, Souvik; Thanh, Le Nguyen; Feng, Lin; Nguyen, Quoc Toan; Lim, Chuan Bian; Harikishore, Amaravadhi; Nanga, Ravi Prakash Reddy; Bharatham, Nagakumar; Zhao, Yan; Liu, Xuewei; Yoon, Ho Sup

2014-01-01

Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule - 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK - mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents. PMID:25354194

A proposal for the classification of biological weapons sensu lato.

PubMed

Rozsa, Lajos

2014-12-01

Due to historical and legislation reasons, the category of bioweapons is rather poorly defined. Authors often disagree on involving or excluding agents like hormones, psychochemicals, certain plants and animals (such as weeds or pests) or synthetic organisms. Applying a wide definition apparently threatens by eroding the regime of international legislation, while narrow definitions abandon several important issues. Therefore, I propose a category of 'biological weapons sensu lato' (BWsl) that is defined here as any tool of human aggression whose acting principle is based on disciplines of biology including particularly microbiology, epidemiology, medical biology, physiology, psychology, pharmacology and ecology, but excluding those based on inorganic agents. Synthetically produced equivalents (not necessarily exact copies) and mock weapons are also included. This definition does not involve any claim to subject all these weapons to international legislation but serves a purely scholarly purpose. BWsl may be properly categorized on the base of the magnitude of the human population potentially targeted (4 levels: individuals, towns, countries, global) and the biological nature of the weapons' intended effects (4 levels: agricultural-ecological agents, and non-pathogenic, pathogenic, or lethal agents against humans).

Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting

NASA Astrophysics Data System (ADS)

Sykes, Edward Alexander

Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. . Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano

Development of a Biological Control Program for Eurasian Watermilfoil (Myriophyllum Spicatum)

DTIC Science & Technology

2006-12-22

spicatum). Pakistan Station Commonwealth Institute of Biological Control, Rawalpindi. 16 Gleason, H.A., Cronquist , A . 1991. Manual of Vascular Plants of...Development of a biological control program for Eurasian watermilfoil (Myriophyllum spicatum...control agents have not considered potential impact on non target indigenous species. A phased programme to address these gaps is put forward. List of

Development of a matrix to evaluate the threat of biological agents used for bioterrorism.

PubMed

Tegnell, A; Van Loock, F; Baka, A; Wallyn, S; Hendriks, J; Werner, A; Gouvras, G

2006-10-01

Adequate public health preparedness for bioterrorism includes the elaboration of an agreed list of biological and chemical agents that might be used in an attack or as threats of deliberate release. In the absence of counterterrorism intelligence information, public health authorities can also base their preparedness on the agents for which the national health structures would be most vulnerable. This article aims to describe a logical method and the characteristics of the variables to be brought in a weighing process to reach a priority list for preparedness. The European Union, in the aftermath of the anthrax events of October 2001 in the United States, set up a task force of experts from multiple member states to elaborate and implement a health security programme. One of the first tasks of this task force was to come up with a list of priority threats. The model, presented here, allows Web-based updates for newly identified agents and for the changes occurring in preventive measures for agents already listed. The same model also allows the identification of priority protection action areas.

Spectroscopic characterization of biological agents using FTIR, normal Raman and surface-enhanced Raman spectroscopies

NASA Astrophysics Data System (ADS)

Luna-Pineda, Tatiana; Soto-Feliciano, Kristina; De La Cruz-Montoya, Edwin; Pacheco Londoño, Leonardo C.; Ríos-Velázquez, Carlos; Hernández-Rivera, Samuel P.

2007-04-01

FTIR, Raman spectroscopy and Surface Enhanced Raman Scattering (SERS) requires a minimum of sample allows fast identification of microorganisms. The use of this technique for characterizing the spectroscopic signatures of these agents and their stimulants has recently gained considerable attention due to the fact that these techniques can be easily adapted for standoff detection from considerable distances. The techniques also show high sensitivity and selectivity and offer near real time detection duty cycles. This research focuses in laying the grounds for the spectroscopic differentiation of Staphylococcus spp., Pseudomonas spp., Bacillus spp., Salmonella spp., Enterobacter aerogenes, Proteus mirabilis, Klebsiella pneumoniae, and E. coli, together with identification of their subspecies. In order to achieve the proponed objective, protocols to handle, cultivate and analyze the strains have been developed. Spectroscopic similarities and marked differences have been found for Spontaneous or Normal Raman spectra and for SERS using silver nanoparticles have been found. The use of principal component analysis (PCA), discriminate factor analysis (DFA) and a cluster analysis were used to evaluate the efficacy of identifying potential threat bacterial from their spectra collected on single bacteria. The DFA from the bacteria Raman spectra show a little discrimination between the diverse bacterial species however the results obtained from the SERS demonstrate to be high discrimination technique. The spectroscopic study will be extended to examine the spores produced by selected strains since these are more prone to be used as Biological Warfare Agents due to their increased mobility and possibility of airborne transport. Micro infrared spectroscopy as well as fiber coupled FTIR will also be used as possible sensors of target compounds.

Fatty acid synthase - Modern tumor cell biology insights into a classical oncology target.

PubMed

Buckley, Douglas; Duke, Gregory; Heuer, Timothy S; O'Farrell, Marie; Wagman, Allan S; McCulloch, William; Kemble, George

2017-09-01

Decades of preclinical and natural history studies have highlighted the potential of fatty acid synthase (FASN) as a bona fide drug target for oncology. This review will highlight the foundational concepts upon which this perspective is built. Published studies have shown that high levels of FASN in patient tumor tissues are present at later stages of disease and this overexpression predicts poor prognosis. Preclinical studies have shown that experimental overexpression of FASN in previously normal cells leads to changes that are critical for establishing a tumor phenotype. Once the tumor phenotype is established, FASN elicits several changes to the tumor cell and becomes intertwined with its survival. The product of FASN, palmitate, changes the biophysical nature of the tumor cell membrane; membrane microdomains enable the efficient assembly of signaling complexes required for continued tumor cell proliferation and survival. Membranes densely packed with phospholipids containing saturated fatty acids become resistant to the action of other chemotherapeutic agents. Inhibiting FASN leads to tumor cell death while sparing normal cells, which do not have the dependence of this enzyme for normal functions, and restores membrane architecture to more normal properties thereby resensitizing tumors to killing by chemotherapies. One compound has recently reached clinical studies in solid tumor patients and highlights the need for continued evaluation of the role of FASN in tumor cell biology. Significant advances have been made and much remains to be done to optimally apply this class of pharmacological agents for the treatment of specific cancers. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer.

PubMed

Grundy, Megan; Coussios, Constantin; Carlisle, Robert

2016-07-01

The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities. This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by 'passively' and 'actively' targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of 'biologics', antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated. Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.

Agent-based re-engineering of ErbB signaling: a modeling pipeline for integrative systems biology.

PubMed

Das, Arya A; Ajayakumar Darsana, T; Jacob, Elizabeth

2017-03-01

Experiments in systems biology are generally supported by a computational model which quantitatively estimates the parameters of the system by finding the best fit to the experiment. Mathematical models have proved to be successful in reverse engineering the system. The data generated is interpreted to understand the dynamics of the underlying phenomena. The question we have sought to answer is that - is it possible to use an agent-based approach to re-engineer a biological process, making use of the available knowledge from experimental and modelling efforts? Can the bottom-up approach benefit from the top-down exercise so as to create an integrated modelling formalism for systems biology? We propose a modelling pipeline that learns from the data given by reverse engineering, and uses it for re-engineering the system, to carry out in-silico experiments. A mathematical model that quantitatively predicts co-expression of EGFR-HER2 receptors in activation and trafficking has been taken for this study. The pipeline architecture takes cues from the population model that gives the rates of biochemical reactions, to formulate knowledge-based rules for the particle model. Agent-based simulations using these rules, support the existing facts on EGFR-HER2 dynamics. We conclude that, re-engineering models, built using the results of reverse engineering, opens up the possibility of harnessing the power pack of data which now lies scattered in literature. Virtual experiments could then become more realistic when empowered with the findings of empirical cell biology and modelling studies. Implemented on the Agent Modelling Framework developed in-house. C ++ code templates available in Supplementary material . liz.csir@gmail.com. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Early indicators of exposure to biological threat agents using host gene profiles in peripheral blood mononuclear cells

PubMed Central

Das, Rina; Hammamieh, Rasha; Neill, Roger; Ludwig, George V; Eker, Steven; Lincoln, Patrick; Ramamoorthy, Preveen; Dhokalia, Apsara; Mani, Sachin; Mendis, Chanaka; Cummings, Christiano; Kearney, Brian; Royaee, Atabak; Huang, Xiao-Zhe; Paranavitana, Chrysanthi; Smith, Leonard; Peel, Sheila; Kanesa-Thasan, Niranjan; Hoover, David; Lindler, Luther E; Yang, David; Henchal, Erik; Jett, Marti

2008-01-01

Background Effective prophylaxis and treatment for infections caused by biological threat agents (BTA) rely upon early diagnosis and rapid initiation of therapy. Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs. Methods To detect exposures to the various pathogens more rapidly, especially during these early stages, we evaluated a suite of host responses to biological threat agents using global gene expression profiling on complementary DNA arrays. Results We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness. Nonhuman primates were exposed to some pathogens and the in vitro and in vivo findings were compared. We found major gene expression changes at the earliest times tested post exposure to aerosolized B. anthracis spores and 30 min post exposure to a bacterial toxin. Conclusion Host gene expression patterns have the potential to serve as diagnostic markers or predict the course of impending illness and may lead to new stage-appropriate therapeutic strategies to ameliorate the devastating effects of exposure to biothreat agents. PMID:18667072

Principles of antidote pharmacology: an update on prophylaxis, post-exposure treatment recommendations and research initiatives for biological agents.

PubMed

Ramasamy, S; Liu, C Q; Tran, H; Gubala, A; Gauci, P; McAllister, J; Vo, T

2010-10-01

The use of biological agents has generally been confined to military-led conflicts. However, there has been an increase in non-state-based terrorism, including the use of asymmetric warfare, such as biological agents in the past few decades. Thus, it is becoming increasingly important to consider strategies for preventing and preparing for attacks by insurgents, such as the development of pre- and post-exposure medical countermeasures. There are a wide range of prophylactics and treatments being investigated to combat the effects of biological agents. These include antibiotics (for both conventional and unconventional use), antibodies, anti-virals, immunomodulators, nucleic acids (analogues, antisense, ribozymes and DNAzymes), bacteriophage therapy and micro-encapsulation. While vaccines are commercially available for the prevention of anthrax, cholera, plague, Q fever and smallpox, there are no licensed vaccines available for use in the case of botulinum toxins, viral encephalitis, melioidosis or ricin. Antibiotics are still recommended as the mainstay treatment following exposure to anthrax, plague, Q fever and melioidosis. Anti-toxin therapy and anti-virals may be used in the case of botulinum toxins or smallpox respectively. However, supportive care is the only, or mainstay, post-exposure treatment for cholera, viral encephalitis and ricin - a recommendation that has not changed in decades. Indeed, with the difficulty that antibiotic resistance poses, the development and further evaluation of techniques and atypical pharmaceuticals are fundamental to the development of prophylaxis and post-exposure treatment options. The aim of this review is to present an update on prophylaxis and post-exposure treatment recommendations and research initiatives for biological agents in the open literature from 2007 to 2009. © 2010 The Commonwealth of Australia. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Molecular targeted therapy for advanced gastric cancer.

PubMed

Kim, Jong Gwang

2013-03-01

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy.

PubMed

Shi, Yunli; Liu, Shengnan; Ahmad, Shabir; Gao, Qingzhi

2018-05-22

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents

PubMed Central

Husain, Asif; Ahmad, Aftab; Khan, Shah Alam; Asif, Mohd; Bhutani, Rubina; Al-Abbasi, Fahad A.

2015-01-01

The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives (3a–k) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives (3a–k) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine (3g), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine (3i) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine (3j) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number (3i) emerged as a potential candidate for further research as it obeyed Lipinski’s rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening. PMID:26903774

Fluorescent ampicillin analogues as multifunctional disguising agents against opsonization

NASA Astrophysics Data System (ADS)

Kotagiri, Nalinikanth; Sakon, Joshua; Han, Haewook; Zharov, Vladimir P.; Kim, Jin-Woo

2016-06-01

Cancer nanomedicines are opening new paradigms in cancer management and recent research points to how they can vastly improve imaging and therapy through multimodality and multifunctionality. However, challenges to achieving optimal efficacy are manifold starting from processing materials and evaluating their intended effectiveness on biological tissue, to developing new strategies aimed at improving transport of these materials through the biological milieu to the target tissue. Here, we report a fluorescent derivative of a beta-lactam antibiotic, ampicillin (termed iAmp) and its multifunctional physicobiochemical characteristics and potential as a biocompatible shielding agent and an effective dispersant. Carbon nanotubes (CNTs) were chosen to demonstrate the efficacy of iAmp. CNTs are known for their versatility and have been used extensively for cancer theranostics as photothermal and photoacoustic agents, but have limited solubility in water and biocompatibility. Traditional dispersants are associated with imaging artifacts and are not fully biocompatible. The chemical structure of iAmp is consistent with a deamination product of ampicillin. Although the four-membered lactam ring is intact, it does not retain the antibiotic properties. The iAmp is an effective dispersant and simultaneously serves as a fluorescent label for single-walled CNTs (SWNTs) with minimal photobleaching. The iAmp also enables bioconjugation of SWNTs to bio-ligands such as antibodies through functional carboxyl groups. Viability tests show that iAmp-coated SWNTs have minimal toxicity. Bio-stability tests under physiological conditions reveal that iAmp coating not only remains stable in a biologically relevant environment with high protein and salt concentrations, but also renders SWNTs transparent against nonspecific protein adsorption, also known as protein corona. Mammalian tissue culture studies with macrophages and opsonins validate that iAmp coating affords immunological resistance

Advancing cancer drug discovery towards more agile development of targeted combination therapies.

PubMed

Carragher, Neil O; Unciti-Broceta, Asier; Cameron, David A

2012-01-01

Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.

Drug discovery in tuberculosis. New drug targets and antimycobacterial agents.

PubMed

Campaniço, André; Moreira, Rui; Lopes, Francisca

2018-04-25

Tuberculosis (TB) remains a major health problem worldwide. The infectious agent, Mycobacterium tuberculosis, has a unique ability to survive within the host, alternating between active and latent disease states, and escaping the immune system defences. The extended duration of anti-TB regimens and the increasing prevalence of multidrug- (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have created an urgent need for new antibiotics active against drug-resistant organisms and that can shorten standard therapy. However, despite success in identifying active compounds through phenotypic screens, the conversion of hits into novel chemical series and ultimately into clinical candidates is hampered by the poor efficacy in eliminating M. tuberculosis within different host compartments, including macrophages, as well as a lack of knowledge about the specific target(s) inhibited and/or upregulated. The current status of anti-TB lead generation has much improved over the last decade, as exemplified by the recent approval of bedaquiline and delamanid to treat MDR-TB and XDR-TB. This review provides a critical analysis on the strategies used to progress hit compounds into viable lead candidates, and how emerging targets may play a role in TB drug discovery in the near future. Four new relevant targets are addressed: the enoyl-acyl carrier protein reductase, InhA; the transmembrane transport protein large, MmpL3; the decaprenylphospho-beta-d-ribofuranose 2-oxidase, DprE1; and the ubiquinol-cytochrome C reductase, QcrB. Validated hit compounds for each target are presented and explored, and the medicinal chemistry strategies to expand SAR around novel chemotypes analyzed. In addition, very recent emerging targets are also discussed. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

75 FR 28232 - Availability of an Environmental Assessment for a Biological Control Agent for Hemlock Woolly...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-20

... conditions. Existing HWA management options include chemical control and silvicultural control, which, in...] Availability of an Environmental Assessment for a Biological Control Agent for Hemlock Woolly Adelgid AGENCY... environmental assessment relative to the control of hemlock woolly adelgid (Adelges tsugae). The environmental...

Renal toxicity of anticancer agents targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs).

PubMed

Cosmai, Laura; Gallieni, Maurizio; Liguigli, Wanda; Porta, Camillo

2017-04-01

Since angiogenesis plays a key role in tumor growth, progression and metastasization, anti-vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) agents have been developed over the years as anticancer agents, and have changed, for the better, the natural history of a number of cancer types. In the present review, the renal safety profile of presently available agents targeting either VEGF or VEGFRs will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, renal toxicity (especially, but not exclusively, hypertension and proteinuria) are quite commonly observed with these agents, and may be increased by the concomitant use of cytoxic chemotherapeutics. Despite all the above, kidney impairment or dialysis must not be regarded di per se as reasons not to administer or to stop an active anticancer treatment, especially considering the possibility of a significant survival improvement in many cancer patients treated with these agents.

Surface Functionalization and Targeting Strategies of Liposomes in Solid Tumor Therapy: A Review

PubMed Central

Riaz, Muhammad Kashif; Riaz, Muhammad Adil; Zhang, Xue; Lin, Congcong; Wong, Ka Hong; Chen, Xiaoyu; Lu, Aiping

2018-01-01

Surface functionalization of liposomes can play a key role in overcoming the current limitations of nanocarriers to treat solid tumors, i.e., biological barriers and physiological factors. The phospholipid vesicles (liposomes) containing anticancer agents produce fewer side effects than non-liposomal anticancer formulations, and can effectively target the solid tumors. This article reviews information about the strategies for targeting of liposomes to solid tumors along with the possible targets in cancer cells, i.e., extracellular and intracellular targets and targets in tumor microenvironment or vasculature. Targeting ligands for functionalization of liposomes with relevant surface engineering techniques have been described. Stimuli strategies for enhanced delivery of anticancer agents at requisite location using stimuli-responsive functionalized liposomes have been discussed. Recent approaches for enhanced delivery of anticancer agents at tumor site with relevant surface functionalization techniques have been reviewed. Finally, current challenges of functionalized liposomes and future perspective of smart functionalized liposomes have been discussed. PMID:29315231

Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.

PubMed

Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan; Ho, Chi-Lee C; Retterer, Cary; Gharaibeh, Dima; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A; Clubb, Robert T; Cohen, Stanley N; Gupta, Vivek; Martchenko, Mikhail

2015-08-27

A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.

Integrin Targeted MR Imaging

PubMed Central

Tan, Mingqian; Lu, Zheng-Rong

2011-01-01

Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution. Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize. There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T1, T2, chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents. Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions. The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging. Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent. Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging. An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging. An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging. By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models. PMID:21547154

A Proposed Computed Tomography Contrast Agent Using Carboxybetaine Zwitterionic Tantalum Oxide Nanoparticles: Imaging, Biological, and Physicochemical Performance.

PubMed

FitzGerald, Paul F; Butts, Matthew D; Roberts, Jeannette C; Colborn, Robert E; Torres, Andrew S; Lee, Brian D; Yeh, Benjamin M; Bonitatibus, Peter J

2016-12-01

The aim of this study was to produce and evaluate a proposed computed tomography (CT) contrast agent based on carboxybetaine zwitterionic (CZ)-coated soluble tantalum oxide (TaO) nanoparticles (NPs). We chose tantalum to provide superior imaging performance compared with current iodine-based clinical CT contrast agents. We developed the CZ coating to provide biological and physical performance similar to that of current iodinated contrast agents. In addition, the aim of this study was to evaluate the imaging, biological, and physicochemical performance of this proposed contrast agent compared with clinically used iodinated agents. We evaluated CT imaging performance of our CZ-TaO NPs compared with that of an iodinated agent in live rats, imaged centrally located within a tissue-equivalent plastic phantom that simulated a large patient. To evaluate vascular contrast enhancement, we scanned the rats' great vessels at high temporal resolution during and after contrast agent injection. We performed several in vivo CZ-TaO NP studies in healthy rats to evaluate tolerability. These studies included injecting the agent at the anticipated clinical dose (ACD) and at 3 times and 6 times the ACD, followed by longitudinal hematology to assess impact to blood cells and organ function (from 4 hours to 1 week). Kidney histological analysis was performed 48 hours after injection at 3 times the ACD. We measured the elimination half-life of CZ-TaO NPs from blood, and we monitored acute kidney injury biomarkers with a kidney injury assay using urine collected from 4 hours to 1 week. We measured tantalum retention in individual organs and in the whole carcass 48 hours after injection at ACD. Carboxybetaine zwitterionic TaO NPs were synthesized and analyzed in detail. We used multidimensional nuclear magnetic resonance to determine surface functionality of the NPs. We measured NP size and solution properties (osmolality and viscosity) of the agent over a range of tantalum concentrations

Mass spectrometry for the detection of bioterrorism agents: from environmental to clinical applications.

PubMed

Duriez, Elodie; Armengaud, Jean; Fenaille, François; Ezan, Eric

2016-03-01

In the current context of international conflicts and localized terrorist actions, there is unfortunately a permanent threat of attacks with unconventional warfare agents. Among these, biological agents such as toxins, microorganisms, and viruses deserve particular attention owing to their ease of production and dissemination. Mass spectrometry (MS)-based techniques for the detection and quantification of biological agents have a decisive role to play for countermeasures in a scenario of biological attacks. The application of MS to every field of both organic and macromolecular species has in recent years been revolutionized by the development of soft ionization techniques (MALDI and ESI), and by the continuous development of MS technologies (high resolution, accurate mass HR/AM instruments, novel analyzers, hybrid configurations). New possibilities have emerged for exquisite specific and sensitive detection of biological warfare agents. MS-based strategies for clinical application can now address a wide range of analytical questions mainly including issues related to the complexity of biological samples and their available volume. Multiplexed toxin detection, discovery of new markers through omics approaches, and identification of untargeted microbiological or of novel molecular targets are examples of applications. In this paper, we will present these technological advances along with the novel perspectives offered by omics approaches to clinical detection and follow-up. Copyright © 2016 John Wiley & Sons, Ltd.

Hepatocellular Carcinoma: Molecular Biology and Therapy

PubMed Central

Abou-Alfa, Ghassan

2007-01-01

Advanced and metastatic hepatocellular carcinomas (HCC) are challenging to treat, and no cytotoxic agents have impacted survival. The underlying liver cirrhosis that commonly accompanies HCC provides an additional challenge; indeed, functional scoring of cirrhosis and HCC is a critical component of patient evaluation. Currently, the molecular biology and pathogenesis of HCC are being increasingly investigated, which may lead to better understanding of the evolution of the disease, especially differing etiologies and identification of survival genes that may affect outcome. Early studies of targeted therapies in HCC have shown disease stabilization, and an increased understanding of the mechanism(s) of these novel agents combined with correlative studies may lead to the identification of an active agent or combination of agents that impacts the natural history of HCC. PMID:17178294

MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA

PubMed Central

Liu, Xiaoli; Madhankumar, Achuthamangalam B.; Miller, Patti A.; Duck, Kari A.; Hafenstein, Susan; Rizk, Elias; Slagle-Webb, Becky; Sheehan, Jonas M.; Connor, James R.; Yang, Qing X.

2016-01-01

Background Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety. We hypothesized that liposomes conjugated with IL-13 and encapsulating MRI contrast agent are capable of passing through an intact BBB and producing MRI contrast with greater sensitivity. Methods The targeted MRI contrast agent was created by encapsulating Magnevist (Gd-DTPA) into liposomes conjugated with IL-13 and characterized by particle size distribution, cytotoxicity, and MRI relaxivity. MR image intensity was evaluated in the brain in normal mice post injection of Gd-DTPA and IL-13-liposome-Gd-DTPA one day apart. The specificity for glioma detection by IL-13-liposome-Gd-DTPA was demonstrated in an intracranial glioma mouse model and validated histologically. Results The average size of IL-13-liposome-Gd-DTPA was 137 ± 43 nm with relaxivity of 4.0 ± 0.4 L/mmole-s at 7 Tesla. No significant cytotoxicity was observed with MTS assay and serum chemistry in mice. The MRI signal intensity was enhanced up to 15% post injection of IL-13-liposome-Gd-DTPA in normal brain tissue following a similar time course as that for the pituitary gland outside of the BBB. MRI enhanced by IL-13-liposome-Gd-DTPA detected small tumor masses in addition to those seen with Magnevist-enhanced MRI. Conclusions IL-13-liposome-Gd-DTPA is able to pass through the uncompromised BBB and detect an early stage glioma that cannot be seen with conventional contrast-enhanced MRI. PMID:26519740

Synthetic biology platform technologies for antimicrobial applications.

PubMed

Braff, Dana; Shis, David; Collins, James J

2016-10-01

The growing prevalence of antibiotic resistance calls for new approaches in the development of antimicrobial therapeutics. Likewise, improved diagnostic measures are essential in guiding the application of targeted therapies and preventing the evolution of therapeutic resistance. Discovery platforms are also needed to form new treatment strategies and identify novel antimicrobial agents. By applying engineering principles to molecular biology, synthetic biologists have developed platforms that improve upon, supplement, and will perhaps supplant traditional broad-spectrum antibiotics. Efforts in engineering bacteriophages and synthetic probiotics demonstrate targeted antimicrobial approaches that can be fine-tuned using synthetic biology-derived principles. Further, the development of paper-based, cell-free expression systems holds promise in promoting the clinical translation of molecular biology tools for diagnostic purposes. In this review, we highlight emerging synthetic biology platform technologies that are geared toward the generation of new antimicrobial therapies, diagnostics, and discovery channels. Copyright © 2016 Elsevier B.V. All rights reserved.

Performance of Traditional and Molecular Methods for Detecting Biological Agents in Drinking Water

USGS Publications Warehouse

Francy, Donna S.; Bushon, Rebecca N.; Brady, Amie M.G.; Bertke, Erin E.; Kephart, Christopher M.; Likirdopulos, Christina A.; Mailot, Brian E.; Schaefer, Frank W.; Lindquist, H.D. Alan

2009-01-01

To reduce the impact from a possible bioterrorist attack on drinking-water supplies, analytical methods are needed to rapidly detect the presence of biological agents in water. To this end, 13 drinking-water samples were collected at 9 water-treatment plants in Ohio to assess the performance of a molecular method in comparison to traditional analytical methods that take longer to perform. Two 100-liter samples were collected at each site during each sampling event; one was seeded in the laboratory with six biological agents - Bacillus anthracis (B. anthracis), Burkholderia cepacia (as a surrogate for Bu. pseudomallei), Francisella tularensis (F. tularensis), Salmonella Typhi (S. Typhi), Vibrio cholerae (V. cholerae), and Cryptospordium parvum (C. parvum). The seeded and unseeded samples were processed by ultrafiltration and analyzed by use of quantiative polymerase chain reaction (qPCR), a molecular method, and culture methods for bacterial agents or the immunomagnetic separation/fluorescent antibody (IMS/FA) method for C. parvum as traditional methods. Six replicate seeded samples were also processed and analyzed. For traditional methods, recoveries were highly variable between samples and even between some replicate samples, ranging from below detection to greater than 100 percent. Recoveries were significantly related to water pH, specific conductance, and dissolved organic carbon (DOC) for all bacteria combined by culture methods, but none of the water-quality characteristics tested were related to recoveries of C. parvum by IMS/FA. Recoveries were not determined by qPCR because of problems in quantifying organisms by qPCR in the composite seed. Instead, qPCR results were reported as detected, not detected (no qPCR signal), or +/- detected (Cycle Threshold or 'Ct' values were greater than 40). Several sample results by qPCR were omitted from the dataset because of possible problems with qPCR reagents, primers, and probes. For the remaining 14 qPCR results

A screen to identify drug resistant variants to target-directed anti-cancer agents

PubMed Central

Azam, Mohammad; Raz, Tal; Nardi, Valentina; Opitz, Sarah L.

2003-01-01

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair. PMID:14615817

Inosine 5'-Monophosphate Dehydrogenase (IMPDH) as a Potential Target for the Development of a New Generation of Antiprotozoan Agents.

PubMed

Fotie, Jean

2018-01-01

Inosine-5'-monophosphate dehydrogenase (IMPDH) is a metabolic enzyme that catalyzes the critical step in guanine nucleotide biosynthesis, and thus is at the center of cell growth and proliferation. However, although this enzyme has been exploited as potential target for the development of immunosuppressive, anticancer, and antiviral agents, the functional importance of IMPDH as a promising antiprotozoan drug target is still in its infancy mainly because of the availability of alternative nucleotides metabolic pathways in many of these parasites. This situation suggests that the inhibition of IMPDH might have little to no effect on the survival of protozoan parasites. As a result, no IMPDH inhibitor is currently commercially available or has advanced to clinical trials as a potential antiprotozoan drug. Nevertheless, recent advances toward the development of selective inhibitors of the IMPDH enzyme from Crystosporidium parvum as potential drug candidates against cryptosporidiosis should revive further investigations of this drug target in other protozoa parasites. The current review examines the chemical structures and biological activities of reported protozoan's IMPDH inhibitors. SciFinder was used to broadly pinpoint reports published on the topic in the chemical literature, with no specific time frame. Opportunities and challenges towards the development of inhibitors of IMPDH enzymes from protozoa parasites as potential chemotherapies toward the respective diseases they cause are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Host range of the inadvertent biological control agent Caloptilia triadicae: an invasive herbivore of Chinese tallowtree

USDA-ARS?s Scientific Manuscript database

An inadvertent biological control agent of the invasive weed Chinese tallowtree (Triadica sebifera) first appeared in North America in 2004. Identified as a Caloptilia triadicae, this leaf miner was found damaging T. sebifera saplings. In Gainesville, FL we exposed naturalized populations of C. tria...

When "Becoming a 50% School" is Success Enough: A Principal-Agent Analysis of Subject Leaders' Target Setting

ERIC Educational Resources Information Center

Davies, Peter; Coates, Gwen; Hammersley-Fletcher, Linda; Mangan, Jean

2005-01-01

Using the perspective of principal-agent theory, we suggest that the target setting process imposed by the government has shifted teachers' focus away from their personal educational priorities. Our evidence suggests that schools with a higher proportion of students with high academic achievement differ in their practice of target setting from…

Interactome Analysis of Microtubule-targeting Agents Reveals Cytotoxicity Bases in Normal Cells.

PubMed

Gutiérrez-Escobar, Andrés Julián; Méndez-Callejas, Gina

2017-12-01

Cancer causes millions of deaths annually and microtubule-targeting agents (MTAs) are the most commonly-used anti-cancer drugs. However, the high toxicity of MTAs on normal cells raises great concern. Due to the non-selectivity of MTA targets, we analyzed the interaction network in a non-cancerous human cell. Subnetworks of fourteen MTAs were reconstructed and the merged network was compared against a randomized network to evaluate the functional richness. We found that 71.4% of the MTA interactome nodes are shared, which affects cellular processes such as apoptosis, cell differentiation, cell cycle control, stress response, and regulation of energy metabolism. Additionally, possible secondary targets were identified as client proteins of interphase microtubules. MTAs affect apoptosis signaling pathways by interacting with client proteins of interphase microtubules, suggesting that their primary targets are non-tumor cells. The paclitaxel and doxorubicin networks share essential topological axes, suggesting synergistic effects. This may explain the exacerbated toxicity observed when paclitaxel and doxorubicin are used in combination for cancer treatment. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Multiple year effects of a biological control agent (Diorhabda carinulata) on Tamarix (saltcedar) ecosystem exchanges of carbon dioxide and water

USDA-ARS?s Scientific Manuscript database

Biological control of Tamarix spp. (saltcedar) with Diorhabda carinulata (the northern tamarisk beetle) is currently underway in several western states U.S.A. through historical releases and the natural migration of this insect. Given the widespread dispersal of this biological control agent and its...

Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

PubMed

Noujaim, Jonathan; Thway, Khin; Bajwa, Zia; Bajwa, Ayeza; Maki, Robert G; Jones, Robin L; Keller, Charles

2015-01-01

Epithelioid sarcoma (ES) is a soft tissue sarcoma of children and young adults for which the preferred treatment for localized disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review, we will summarize clinically relevant biomarkers (e.g., SMARCB1, CA125, dysadherin, and others) with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR, and polykinase inhibitors (e.g., sunitinib) in the management of local and disseminated disease. Toward building a consortium of pharmaceutical, academic, and non-profit collaborators, we will discuss the state of resources for investigating ES with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed toward effective biology-driven therapies.

Drugs That Target Dynamic Microtubules: A New Molecular Perspective

PubMed Central

Stanton, Richard A.; Gernert, Kim M.; Nettles, James H.; Aneja, Ritu

2011-01-01

Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work. PMID:21381049

Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation.

PubMed

Liu, Han-Bo; Gao, Wei-Wei; Tangadanchu, Vijai Kumar Reddy; Zhou, Cheng-He; Geng, Rong-Xia

2018-01-01

A series of novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents were designed, synthesized and characterized by IR, NMR and HRMS spectra. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Noticeably, compound 7d could effectively inhibit the growth of A. flavus, E. coli DH52 and MRSA with MIC values of 1, 1 and 8 μg/mL, respectively. Further studies revealed that pyrimidine derivative 7d could exhibit bactericidal mode of action against both Gram positive (S. aureus and MRSA) and Gram negative (P. aeruginosa) bacteria. The active molecule 7d showed low cell toxicity and did not obviously trigger the development of resistance in bacteria even after 16 passages. Furthermore, compound 7d was able to beneficially regulate reactive oxygen species (ROS) generation for an excellent safety profile. Molecular docking study revealed that compound 7d could bind with DNA gyrase by the formation of hydrogen bonds. The preliminary exploration for antimicrobial mechanism disclosed that compound 7d could effectively intercalate into calf thymus DNA to form a steady supramolecular complex, which might further block DNA replication to exert the powerful bioactivities. The binding investigation of compound 7d with human serum albumins (HSA) revealed that this molecule could be effectively transported by HSA. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Host Specificity of Epiplema albida: A Potential Biological Control Agent for Sri Lankan Privet in the Mascarene Islands

PubMed Central

Shaw, Richard H.

2017-01-01

Epiplema albida (Hampson) (Lepidoptera: Uraniidae, Epipleminae) from Sri Lanka, was studied to assess its safety for use as a biological control agent for Sri Lankan privet, Ligustrum robustum subsp. walkeri (Oleaceae) in La Réunion and other Mascarene Islands. Larval no-choice feeding tests using newly hatched larvae, larval development tests, and multiple choice oviposition tests were used. Adult females of E. albida are shown to have highly selective oviposition behaviour and the species is physiologically restricted to very few hosts for feeding and development. The risk to key test plants in La Réunion is minimal, so this species can be considered for use as a biological control agent there, but would need further evaluation for potential use elsewhere. PMID:28788086

Chemiluminescence assay for the detection of biological warfare agents

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

Langry, K; Horn, J

A chemiluminescent homogeneous immunoassay and a hand-size multiassay reader are described that could be used for detecting biological materials. The special feature of the assay is that it employs two different antibodies that each bind to a unique epitope on the same antigen. Each group of epitope-specific antibodies has linked to it an enzyme of a proximal-enzyme pair. One enzyme of the pair utilizes a substrate in high concentration to produce a second substrate required by the second enzyme. This new substrate enables the second enzyme to function. The reaction of the second enzyme is configured to produce light. Thismore » chemiluminescence is detected with a charge-coupled device (CCD) camera. The proximal pair enzymes must be in close proximity to one another to allow the second enzyme to react with the product of the first enzyme. This only occurs when the enzyme-linked antibodies are attached to the antigen, whether antigen is a single protein with multiple epitopes or the surface of a cell with a variety of different antigens. As a result of their juxtaposition, the enzymes produce light only in the presence of the biological material. A brief description is given as to how this assay could be utilized in a personal bio-agent detector system.« less

Assessing the relationship between toxicity and economic cost of oncological target agents: A systematic review of clinical trials

PubMed Central

Tartari, Francesca; Conti, Alessandro

2017-01-01

Target agents are peculiar oncological drugs which differ from the traditional therapies in their ability of recognizing specific molecules expressed by tumor cells and microenvironment. Thus, their toxicity is generally lower than that associated to chemotherapy, and they represent nowadays a new standard of care in a number of tumors. This paper deals with the relationship between economic costs and toxicity of target agents. At this aim, a cluster analysis-based exploration of the main features of a large collection of them is carried out, with a specific focus on the variables leading to the identification of their toxicity and related costs. The analysis of the toxicity is based on the Severe Adverse Events (SAE) and Discontinuation (D) rates of each target agent considering data published on PubMed from 1965 to 2016 in the phase II and III studies that have led to the approval of these drugs for cancer patients by US Food and Drug Administration. The construction of the dataset represents a key step of the research, and is grounded on the critical analysis of a wide set of clinical studies. In order to capture different evaluation strategies of the toxicity, clustering is performed according to three different criteria (including Voronoi tessellation). Our procedure allows us to identify 5 different groups of target agents pooled by similar SAE and D rates and, at the same time, 3 groups based on target agents’ costs for 1 month and for the median whole duration of therapy. Results highlight several specific regularities for toxicity and costs. This study present several limitations, being realized starting from clinical trials and not from individual patients’ data. However, a macroscopic perspective suggests that costs are rather heterogeneous, and they do not clearly follow the clustering based on SAE and D rates. PMID:28829823

Risk assessment and stakeholder perceptions in novel biological control agent release: YST as a case study

USDA-ARS?s Scientific Manuscript database

The objectives of risk assessment are to learn about whether a candidate agent would be safe to use in the environment where release is planned, and to present such information in a clear, understandable format to regulators, stakeholders, and the public. Plant pathogens evaluated for biological co...

Will novel agents for ALL finally change the natural history?

PubMed

Douer, Dan

2014-01-01

Pediatric acute lymphoblastic leukemia (ALL) cure rates have markedly improved over the past years to approximately 85%, but remain at 40%-50% in adults. Redefining current adult chemotherapy regimens is likely to improve the natural course of the disease, but new agents are needed. Immunotherapy approaches for pre-B ALL are in the forefront of research on novel agents; in particular, advances are being made in manipulating autologous T cells either by infusion of a bifunctional antibody (eg, blinatumomab) or by ex vivo genetic modification of chimeric antigen receptors (CARs). The natural course of Philadelphia positive ALL has already improved by targeting ABL/BCR1. Other mutated genes are being discovered and novel small molecules that target their products are being studied in clinical trials. Finally, ALL is a heterogeneous disease and novel agents are likely to impact the natural course of smaller populations of biologically defined ALL subtypes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multi-agent Negotiation Mechanisms for Statistical Target Classification in Wireless Multimedia Sensor Networks

PubMed Central

Wang, Xue; Bi, Dao-wei; Ding, Liang; Wang, Sheng

2007-01-01

The recent availability of low cost and miniaturized hardware has allowed wireless sensor networks (WSNs) to retrieve audio and video data in real world applications, which has fostered the development of wireless multimedia sensor networks (WMSNs). Resource constraints and challenging multimedia data volume make development of efficient algorithms to perform in-network processing of multimedia contents imperative. This paper proposes solving problems in the domain of WMSNs from the perspective of multi-agent systems. The multi-agent framework enables flexible network configuration and efficient collaborative in-network processing. The focus is placed on target classification in WMSNs where audio information is retrieved by microphones. To deal with the uncertainties related to audio information retrieval, the statistical approaches of power spectral density estimates, principal component analysis and Gaussian process classification are employed. A multi-agent negotiation mechanism is specially developed to efficiently utilize limited resources and simultaneously enhance classification accuracy and reliability. The negotiation is composed of two phases, where an auction based approach is first exploited to allocate the classification task among the agents and then individual agent decisions are combined by the committee decision mechanism. Simulation experiments with real world data are conducted and the results show that the proposed statistical approaches and negotiation mechanism not only reduce memory and computation requirements in WMSNs but also significantly enhance classification accuracy and reliability. PMID:28903223

Biological agents: investigation into leprosy and other infectious diseases before indication*

PubMed Central

Antônio, João Roberto; Soubhia, Rosa Maria Cordeiro; Paschoal, Vania Del Arco; Amarante, Carolina Forte; Travolo, Ana Regina Franchi

2013-01-01

Biological agents are widely used for various immune-mediated diseases, with remarkable effectiveness in the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. However, attention needs to be drawn to the adverse effects of these therapies and the risk of reactivating underlying granulomatous infectious diseases such as tuberculosis, leprosy, syphilis, leishmaniasis, among others. The objective of this paper is to describe a case of leprosy in a patient with RA using anti-TNF alfa, demonstrating the need for systematic investigation of skin lesions suggestive of leprosy in patients who require rheumatoid arthritis therapeutic treatment, especially in endemic regions like Brazil. PMID:24346871

[The Functional Role of Exosomes in Cancer Biology and Their Potential as Biomarkers and Therapeutic Targets of Cancer].

PubMed

Naito, Yutaka; Yoshioka, Yusuke; Ochiya, Takahiro

2015-06-01

Intercellular communication plays an important role in the regulation of various cellular events. In particular, cancer cells and the surrounding cells communicate with each other, and this intercellular communication triggers cancer initiation and progression through the secretion of molecules, including growth factors and cytokines. Recent advances in cancer biology have indicated that small membrane vesicles, termed exosomes, also serve as regulatory agents in intercellular communications. Exosomes contain functional cellular components, including proteins and microRNAs (miRNAs), and they transfer these components to recipient cells. This exosome-mediated intercellular communication leads to increased growth, invasion, and metastasis of cancer. Thus, researchers regard exosomes as important cues to understanding the molecular mechanisms of cancer biology. Indeed, several lines of evidence have demonstrated that exosomes can explain multiple aspects of cancer biology. In addition, increasing evidence suggests that exosomes and their specific molecules are also attractive for use as biomarkers and therapeutic targets in cancer. Recent reports showed the efficacy of a novel diagnosis by detecting component molecules of cancer-derived exosomes, including miRNAs and membrane proteins. Furthermore, clinical trials that test the application of exosomes for cancer therapy have already been reported. From these points of view, we will summarize experimental data that support the role of exosomes in cancer progression and the potential of exosomes for use in novel diagnostic and therapeutic approaches for cancer.

Targeting Tim-1 to Circumvent Immune Tolerance in Prostate Cancer

DTIC Science & Technology

2012-09-01

findings that SIM2 is selectively expressed in PCa, that human HLA- A2.1–restricted SIM2 epitopes induce specific T cells in vivo, and that anti -SIM2...TAA, would include a vaccine in conjunction with biologic agents that are known to simultaneously augment antigen presentation by DCs and inhibit...such agents is the agonist antibody that targets TIM-1, a receptor expressed on lymphocytes and dendritic cells that enhances cytotoxic lymphocyte

Differences in seasonal variation between two biotypes of Megamelus scutellaris (Hemiptera: Delphacidae), a biological control agent for Eichhornia crassipes in Florida.

USDA-ARS?s Scientific Manuscript database

Climate matching between the native and adventive ranges of insects used for biological control is a generally accepted strategy for both increasing the likelihood of establishing an agent, as well as improving its overall performance, thereby maximizing the potential utility of an agent across the...

Fabrication and evaluation of tumor-targeted positive MRI contrast agent based on ultrasmall MnO nanoparticles.

PubMed

Huang, Haitao; Yue, Tao; Xu, Ke; Golzarian, Jafar; Yu, Jiahui; Huang, Jin

2015-07-01

Gd(III) chelate is currently used as positive magnetic resonance imaging (MRI) contrast agent in clinical diagnosis, but generally induces the risk of nephrogenic systemic fibrosis (NSF) due to the dissociated Gd(3+) from Gd(III) chelates. To develop a novel positive MRI contrast agent with low toxicity and high sensitivity, ultrasmall MnO nanoparticles were PEGylated via catechol-Mn chelation and conjugated with cRGD as active targeting function to tumor. Particularly, the MnO nanoparticles with a size of ca. 5nm were modified by α,β-poly(aspartic acid)-based graft polymer containing PEG and DOPA moieties and, meanwhile, conjugated with cRGD to produce the contrast agent with a size of ca. 100nm and a longitudinal relaxivity (r1) of 10.2mM(-1)S(-1). Such nanoscaled contrast agent integrated passive- and active-targeting function to tumor, and its efficient accumulation behavior in tumor was verified by in vivo distribution study. At the same time, the PEG moiety played a role of hydrophilic coating to improve the biocompatibility and stability under storing and physiological conditions, and especially might guarantee enough circulation time in blood. Moreover, in vivo MRI revealed a good and long-term effect of enhancing MRI signal for as-fabricated contrast agent while cell viability assay proved its acceptable cytotoxicity for MRI application. On the whole, the as-fabricated PEGylated and cRGD-functionalized contrast agent based on ultrasmall MnO nanoparticles showed a great potential to the T1-weighted MRI diagnosis of tumor. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Immunogenicity of biologic therapies: causes and consequences.

PubMed

Boehncke, Wolf-Henning; Brembilla, Nicolo Costantino

2018-04-25

Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events. Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment. Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.

Gd-functionalised Au nanoparticles as targeted contrast agents in MRI: relaxivity enhancement by polyelectrolyte coating.

PubMed

Warsi, Muhammad Farooq; Adams, Ralph W; Duckett, Simon B; Chechik, Victor

2010-01-21

Monolayer-protected, Gd(3+)-functionalised gold nanoparticles with enhanced spin-lattice relaxivity (r(1)) were prepared; adsorption of polyelectrolytes on these materials further increased r(1) and ligand exchange with a biotin-derivatised disulfide led to a prototype avidin-targeted contrast agent.

“Design characteristics of the CORRONA CERTAIN study: a comparative effectiveness study of biologic agents for rheumatoid arthritis patients”

PubMed Central

2014-01-01

Background Comparative effectiveness research has recently attracted considerable attention. The Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) is an ongoing prospective cohort study of adult patients with Rheumatoid Arthritis (RA). Methods/Design CERTAIN uses the existing Consortium of Rheumatology Researchers of North America (CORRONA) network of participating private and academic sites in order to recruit patients fulfilling the 1987 ACR criteria that have at least moderate disease activity. Patients starting or switching biologic agents either anti-TNF therapy or a non anti-TNF biologic are eligible for enrollment, depending on the treatment selected by their physician. Enrollment is expected to be completed by March of 2014, and 2711 patients will participate in the study. As of October 7th 2013, 2234 patients have been enrolled. Patient visits and laboratory blood work are mandated every three months for one year. Safety data is collected through one year and beyond. The primary comparative effectiveness endpoint is attainment of low RA disease activity at one year among patients who have been exposed to at least one prior TNF-α inhibitor agent prior to enrollment. Multiple secondary effectiveness and safety endpoints will be addressed by investigating the entire population enrolled (naïve and biologic experienced). Discussion The unique design features of CERTAIN will inform comparative effectiveness and safety questions for choosing biologic agents for the management of RA. PMID:24690143

Host plant oviposition preference of Ceratapion basicorne (Coleoptera:Apionidae), a potential biological control agent of yellow starthistle

USDA-ARS?s Scientific Manuscript database

Ceratapion basicorne (Coleoptera: Apionidae) is a weevil native to Europe and western Asia that is being evaluated as a prospective classical biological control agent of Centaurea solstitialis (yellow starthistle) in the United States. Choice oviposition experiments were conducted under laboratory ...

Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.

PubMed

Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

2015-07-09

Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents

PubMed Central

Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

2015-01-01

Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents. PMID:26158513

Phenology and temperature-dependent development of Ceutorhynchus assimilis, a potential biological control agent for Lepidium draba

USDA-ARS?s Scientific Manuscript database

Heart-podded hoary cress (Lepidium draba) is an alien weed that has invaded rangeland in the northwestern USA. A host race (i;e; host-specific biotype) of the weevil, Ceutorhynchus assimilis, is being evaluated as a prospective biological control agent. This biotype is only known from southern Eur...

Decontamination issues for chemical and biological warfare agents: how clean is clean enough?

PubMed

Raber, E; Jin, A; Noonan, K; McGuire, R; Kirvel, R D

2001-06-01

The objective of this assessment is to determine what level of cleanup will be required to meet regulatory and stakeholder needs in the case of a chemical and/or biological incident at a civilian facility. A literature review for selected, potential chemical and biological warfare agents shows that dose information is often lacking or controversial. Environmental regulatory limits or other industrial health guidelines that could be used to help establish cleanup concentration levels for such agents are generally unavailable or not applicable for a public setting. Although dose information, cleanup criteria, and decontamination protocols all present challenges to effective planning, several decontamination approaches are available. Such approaches should be combined with risk-informed decision making to establish reasonable cleanup goals for protecting health, property, and resources. Key issues during a risk assessment are to determine exactly what constitutes a safety hazard and whether decontamination is necessary or not for a particular scenario. An important conclusion is that cleanup criteria are site dependent and stakeholder specific. The results of a modeling exercise for two outdoor scenarios are presented to reinforce this conclusion. Public perception of risk to health, public acceptance of recommendations based on scientific criteria, political support, time constraints, and economic concerns must all be addressed in the context of a specific scenario to yield effective and acceptable decontamination.

Intelligent Design of Nano-Scale Molecular Imaging Agents

PubMed Central

Kim, Sung Bae; Hattori, Mitsuru; Ozawa, Takeaki

2012-01-01

Visual representation and quantification of biological processes at the cellular and subcellular levels within living subjects are gaining great interest in life science to address frontier issues in pathology and physiology. As intact living subjects do not emit any optical signature, visual representation usually exploits nano-scale imaging agents as the source of image contrast. Many imaging agents have been developed for this purpose, some of which exert nonspecific, passive, and physical interaction with a target. Current research interest in molecular imaging has mainly shifted to fabrication of smartly integrated, specific, and versatile agents that emit fluorescence or luminescence as an optical readout. These agents include luminescent quantum dots (QDs), biofunctional antibodies, and multifunctional nanoparticles. Furthermore, genetically encoded nano-imaging agents embedding fluorescent proteins or luciferases are now gaining popularity. These agents are generated by integrative design of the components, such as luciferase, flexible linker, and receptor to exert a specific on–off switching in the complex context of living subjects. In the present review, we provide an overview of the basic concepts, smart design, and practical contribution of recent nano-scale imaging agents, especially with respect to genetically encoded imaging agents. PMID:23235326

Intelligent design of nano-scale molecular imaging agents.

PubMed

Kim, Sung Bae; Hattori, Mitsuru; Ozawa, Takeaki

2012-12-12

Visual representation and quantification of biological processes at the cellular and subcellular levels within living subjects are gaining great interest in life science to address frontier issues in pathology and physiology. As intact living subjects do not emit any optical signature, visual representation usually exploits nano-scale imaging agents as the source of image contrast. Many imaging agents have been developed for this purpose, some of which exert nonspecific, passive, and physical interaction with a target. Current research interest in molecular imaging has mainly shifted to fabrication of smartly integrated, specific, and versatile agents that emit fluorescence or luminescence as an optical readout. These agents include luminescent quantum dots (QDs), biofunctional antibodies, and multifunctional nanoparticles. Furthermore, genetically encoded nano-imaging agents embedding fluorescent proteins or luciferases are now gaining popularity. These agents are generated by integrative design of the components, such as luciferase, flexible linker, and receptor to exert a specific on-off switching in the complex context of living subjects. In the present review, we provide an overview of the basic concepts, smart design, and practical contribution of recent nano-scale imaging agents, especially with respect to genetically encoded imaging agents.

The biology of cancer: what do oncology nurses really need to know.

PubMed

Eggert, Julie

2011-02-01

To describe the impact of genetics and genomics on the biology of cancer and the implications for patient care. Pubmed; CINAHL. Cancer research in genetics/genomics has identified new mechanisms influencing personalized risk assessment/management, early detection, cancer treatment, and long-term screening/surveillance. Understanding the basics of genetics/genomics on the biology of cancer will facilitate patient education and care delivery, including the administration and monitoring of genetically targeted therapies whose toxicities may in part be mediated by the molecular pathways targeted by the specific agent. Copyright © 2011 Elsevier Inc. All rights reserved.

Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites☆

PubMed Central

Pham, James S.; Dawson, Karen L.; Jackson, Katherine E.; Lim, Erin E.; Pasaje, Charisse Flerida A.; Turner, Kelsey E.C.; Ralph, Stuart A.

2013-01-01

Aminoacyl-tRNA synthetases are central enzymes in protein translation, providing the charged tRNAs needed for appropriate construction of peptide chains. These enzymes have long been pursued as drug targets in bacteria and fungi, but the past decade has seen considerable research on aminoacyl-tRNA synthetases in eukaryotic parasites. Existing inhibitors of bacterial tRNA synthetases have been adapted for parasite use, novel inhibitors have been developed against parasite enzymes, and tRNA synthetases have been identified as the targets for compounds in use or development as antiparasitic drugs. Crystal structures have now been solved for many parasite tRNA synthetases, and opportunities for selective inhibition are becoming apparent. For different biological reasons, tRNA synthetases appear to be promising drug targets against parasites as diverse as Plasmodium (causative agent of malaria), Brugia (causative agent of lymphatic filariasis), and Trypanosoma (causative agents of Chagas disease and human African trypanosomiasis). Here we review recent developments in drug discovery and target characterisation for parasite aminoacyl-tRNA synthetases. PMID:24596663

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.

New cardioprotective agent flokalin and its supramolecular complexes with target amino acids: An integrated mass-spectrometry and quantum-chemical study

NASA Astrophysics Data System (ADS)

Pashynska, Vlada; Stepanian, Stepan; Gömöry, Ágnes; Vékey, Károly; Adamowicz, Ludwik

2017-10-01

This study is devoted to examining the molecular structure and molecular mechanisms of action of the recently developed cardioprotective agent flokalin (Fl), a fluorine containing analogue of pinacidil, which is known as an activator of ATP sensitive potassium membrane channels. A combined experimental and computational investigation of flokalin and its biologically relevant supramolecular complexes with selected amino acids involved in KATP-channels proteins is performed by electrospray ionization mass spectrometry (ESI MS) and by B3LYP/aug-cc-pVDZ quantum-mechanical calculations. First Fl solution is probed by ESI MS and a characteristic mass spectrum of the agent is obtained. Next the intermolecular interactions of Fl with the potentially targeted aminoacids (AA), Lys and Thr, are experimentally investigated. The spectra of the model Fl:AA systems (in 1:1 M ratio) contain information on the ions characteristic to the individual components of the mixtures; though the most interesting spectral results from the biophysical view point are related to the ions of stable molecular clusters formed by flokalin with AA. The peaks of such ions are quite prominent in the spectrum for the Fl:Lys system and less prominent for Fl:Thr. The equilibrium geometries and the corresponding interaction energies of the noncovalent supramolecular complexes registered in the mass spectra are determined in the quantum chemical calculations. The formation of the stable noncovalent complexes of Fl with Lyz and Thr revealed by the ESI MS probing and by the theoretical modelling testify to a possibility of interaction of flokalin with the KATP-channel domains enriched with the two amino acids in biological systems.

Multi-agent-based bio-network for systems biology: protein-protein interaction network as an example.

PubMed

Ren, Li-Hong; Ding, Yong-Sheng; Shen, Yi-Zhen; Zhang, Xiang-Feng

2008-10-01

Recently, a collective effort from multiple research areas has been made to understand biological systems at the system level. This research requires the ability to simulate particular biological systems as cells, organs, organisms, and communities. In this paper, a novel bio-network simulation platform is proposed for system biology studies by combining agent approaches. We consider a biological system as a set of active computational components interacting with each other and with an external environment. Then, we propose a bio-network platform for simulating the behaviors of biological systems and modelling them in terms of bio-entities and society-entities. As a demonstration, we discuss how a protein-protein interaction (PPI) network can be seen as a society of autonomous interactive components. From interactions among small PPI networks, a large PPI network can emerge that has a remarkable ability to accomplish a complex function or task. We also simulate the evolution of the PPI networks by using the bio-operators of the bio-entities. Based on the proposed approach, various simulators with different functions can be embedded in the simulation platform, and further research can be done from design to development, including complexity validation of the biological system.

Targeted therapy using nanotechnology: focus on cancer

PubMed Central

Sanna, Vanna; Pala, Nicolino; Sechi, Mario

2014-01-01

Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

Life history and host range of Oxydia vesulia transpeneus, an unsuitable biological control agent of Brazilian peppertree

USDA-ARS?s Scientific Manuscript database

The suitability of Oxydia vesulia (Cramer) (Lepidoptera: Geometridae) was assessed as a potential biological control agent of the invasive weed Brazilian Peppertree Schinus terebinthifolia. Larvae were collected in Brazil feeding on the plant in its native range and colonized in quarantine where lif...

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

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.

Systemic approaches identify a garlic-derived chemical, Z-ajoene, as a glioblastoma multiforme cancer stem cell-specific targeting agent.

PubMed

Jung, Yuchae; Park, Heejoo; Zhao, Hui-Yuan; Jeon, Raok; Ryu, Jae-Ha; Kim, Woo-Young

2014-07-01

Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFβ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.

PubMed

Narayanan, Bhagavathi A

2006-12-01

Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B

The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.