Promoting evidence based medicine in preclinical medical students via a federated literature search tool.

Science.gov (United States)

Keim, Samuel Mark; Howse, David; Bracke, Paul; Mendoza, Kathryn

2008-01-01

Medical educators are increasingly faced with directives to teach Evidence Based Medicine (EBM) skills. Because of its nature, integrating fundamental EBM educational content is a challenge in the preclinical years. To analyse preclinical medical student user satisfaction and feedback regarding a clinical EBM search strategy. The authors introduced a custom EBM search option with a self-contained education structure to first-year medical students. The implementation took advantage of a major curricular change towards case-based instruction. Medical student views and experiences were studied regarding the tool's convenience, problems and the degree to which they used it to answer questions raised by case-based instruction. Surveys were completed by 70% of the available first-year students. Student satisfaction and experiences were strongly positive towards the EBM strategy, especially of the tool's convenience and utility for answering issues raised during case-based learning sessions. About 90% of the students responded that the tool was easy to use, productive and accessed for half or more of their search needs. This study provides evidence that the integration of an educational EBM search tool can be positively received by preclinical medical students.

Optimum strategies for nuclear energy system development (method of synthesis)

International Nuclear Information System (INIS)

Belenky, V.Z.

1983-01-01

The problem of optimum long-term development of the nuclear energy system is considered. The optimum strategies (i.e. minimum total uranium consumption) for the transition phase leading to a stationary regime of development are found. For this purpose the author has elaborated a new method of solving linear problems of optimal control which can include jumps in trajectories. The method gives a possibility to fulfil a total synthesis of optimum strategies. A key characteristic of the problem is the productivity function of the nuclear energy system which connects technological system parameters with its growth rate. There are only two types of optimum strategies, according to an increasing or decreasing productivity function. Both cases are illustrated with numerical examples. (orig.) [de

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (-)-Lundurine A.

Science.gov (United States)

Huang, Hong-Xiu; Jin, Shuai-Jiang; Gong, Jin; Zhang, Dan; Song, Hao; Qin, Yong

2015-09-14

The bioactive Kopsia alkaloids lundurines A-D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (-)-lundurine A has previously been achieved through a Simmons-Smith cyclopropanation strategy. Here, the total synthesis of (-)-lundurine A was carried out using a metal-catalyzed diazo cyclopropanation strategy. In order to avoid a carbene CH insertion side reaction during cyclopropanation of α-diazo- carboxylates or cyanides, a one-pot, copper-catalyzed Bamford-Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies.

Science.gov (United States)

Versteegden, Luuk R M; de Jonge, Paul K J D; IntHout, Joanna; van Kuppevelt, Toin H; Oosterwijk, Egbert; Feitz, Wout F J; de Vries, Rob B M; Daamen, Willeke F

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study

Preclinical models for obesity research

Directory of Open Access Journals (Sweden)

Perry Barrett

2016-11-01

Full Text Available A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity.

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

Energy Technology Data Exchange (ETDEWEB)

England, Christopher G. [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); Rui, Lixin [University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); Cai, Weibo [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

2017-03-15

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

International Nuclear Information System (INIS)

England, Christopher G.; Rui, Lixin; Cai, Weibo

2017-01-01

Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

Anti-Inflammatory Strategies in Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models.

Science.gov (United States)

Citro, Antonio; Cantarelli, Elisa; Pellegrini, Silvia; Dugnani, Erica; Piemonti, Lorenzo

2018-02-01

The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step toward a better management and outcome of pancreatic islet transplanted patients. Recently, we selected the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. Here, the most clinically used anti-inflammatory compounds (IL1-receptor antagonist, steroids, and TNF-α inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as a single agent and in combination with immunosuppression. No other anti-inflammatory compounds tested (IL1-receptor antagonist, steroids, and TNF-α inhibitor) alone or in combination with CXCR1/2 inhibitor improve islet engraftment and significantly delay graft rejection in the presence of MMF + FK-506 immunosuppressive treatment. These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation.

Novel synthesis strategy for the preparation of individual phytosterol oxides.

Science.gov (United States)

Gao, Junlan; Yue, Qiulin; Ji, Yishun; Cheng, Beijiu; Zhang, Xin

2013-01-30

Sterols (cholesterol and phytosterols) are important structural components of cell membranes and major constituents of lipid metabolism. Research on their oxides, such as the factors affecting oxidation, oxides' structures, and qualitative and quantitative analysis, aroused more attention in this decade. However, the biological roles of individual phytosterol oxides are still unclear because no commercial individual phytosterol oxide standards are available. Different from the traditional chemical synthesis, in the present study, chemical synthesis from a starting phytosterol mixture followed with a semipreparative HPLC separation produced individual oxides. TLC and analytical HPLC were used here to not only monitor the reaction process but also specifically analyze the synthetic intermediates and oxides. The chromatographic results exhibited strict rules and similar characteristics. Finally, for the first time, four individual phytosterol oxides were successfully separated and collected by a semipreparative HPLC system, thus providing a novel strategy for the preparation of individual phytosterol oxides.

Applications of the Preclinical Molecular Imaging in Biomedicine: Gene Therapy

International Nuclear Information System (INIS)

Collantes, M.; Peñuelas, I.

2014-01-01

Gene therapy constitutes a promising option for efficient and targeted treatment of several inherited disorders. Imaging techniques using ionizing radiation as PET or SPECT are used for non-invasive monitoring of the distribution and kinetics of vector-mediated gene expression. In this review the main reporter gene/reporter probe strategies are summarized, as well as the contribution of preclinical models to the development of this new imaging modality previously to its application in clinical arena. [es

A generalizable pre-clinical research approach for orphan disease therapy

Directory of Open Access Journals (Sweden)

Beaulieu Chandree L

2012-06-01

Full Text Available Abstract With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.

EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms

International Nuclear Information System (INIS)

Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard; Dittmann, Klaus; Doerr, Wolfgang; Kasten-Pisula, Ulla; Rodemann, H. Peter

2007-01-01

Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with EGFR inhibitors. These include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Effects and mechanisms may differ for different classes of EGFR inhibitors, for different tumours and for normal tissues. The mechanisms underlying this heterogeneity are currently poorly understood, and predictive assays are not available yet. Importantly, mechanisms and predictors for the combined effects of radiation with EGFR inhibitors appear to be considerably different to those for application of EGFR inhibitors alone or in combination with chemotherapy. Therefore to further evaluate the efficacy and mechanisms of EGFR-inhibition in combined treatments, radiotherapy-specific preclinical research strategies, which include in vivo experiments using local tumour control as an endpoint, as well as animal studies on normal tissue toxicity are needed

Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research.

Science.gov (United States)

Sandberg, Kathryn; Umans, Jason G

2015-05-01

The U.S. National Institutes of Health (NIH) announced last May that steps will be taken to address the over-reliance on male cells and animals in preclinical research. To further address this announcement, in September 2014, scientists with varying perspectives came together at Georgetown University to discuss the following questions. (1) What metrics should the NIH use to assess tangible progress on policy changes designed to address the over-reliance on male cells and animals in preclinical research? (2) How effective can education be in reducing the over-reliance on male cells and animals in preclinical research and what educational initiatives sponsored by the NIH would most likely effect change? (3) What criteria should the NIH use to determine rigorously defined exceptions to the future proposal requirement of a balance of male and female cells and animals in preclinical studies? (4) What additional strategies in addition to proposal requirements should NIH use to reduce the overreliance of male cells and animals in preclinical research? The resulting consensus presented herein includes input from researchers not only from diverse disciplines of basic and translational science including biology, cell and molecular biology, biochemistry, physiology, pharmacology, neuroscience, cardiology, endocrinology, nephrology, psychiatry, and obstetrics and gynecology, but also from recognized experts in publishing, industry, advocacy, science policy, clinical medicine, and population health. We offer our recommendations to aid the NIH as it selects, implements, monitors, and optimizes strategies to correct the over-reliance on male cells and animals in preclinical research. © FASEB.

Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.

Science.gov (United States)

Esquejo, Ryan M; Salatto, Christopher T; Delmore, Jake; Albuquerque, Bina; Reyes, Allan; Shi, Yuji; Moccia, Rob; Cokorinos, Emily; Peloquin, Matthew; Monetti, Mara; Barricklow, Jason; Bollinger, Eliza; Smith, Brennan K; Day, Emily A; Nguyen, Chuong; Geoghegan, Kieran F; Kreeger, John M; Opsahl, Alan; Ward, Jessica; Kalgutkar, Amit S; Tess, David; Butler, Lynne; Shirai, Norimitsu; Osborne, Timothy F; Steinberg, Gregory R; Birnbaum, Morris J; Cameron, Kimberly O; Miller, Russell A

2018-04-08

Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Combinatorial Strategies for Synthesis and Characterization of Alloy Microstructures over Large Compositional Ranges.

Science.gov (United States)

Li, Yanglin; Jensen, Katharine E; Liu, Yanhui; Liu, Jingbei; Gong, Pan; Scanley, B Ellen; Broadbridge, Christine C; Schroers, Jan

2016-10-10

The exploration of new alloys with desirable properties has been a long-standing challenge in materials science because of the complex relationship between composition and microstructure. In this Research Article, we demonstrate a combinatorial strategy for the exploration of composition dependence of microstructure. This strategy is comprised of alloy library synthesis followed by high-throughput microstructure characterization. As an example, we synthesized a ternary Au-Cu-Si composition library containing over 1000 individual alloys using combinatorial sputtering. We subsequently melted and resolidified the entire library at controlled cooling rates. We used scanning optical microscopy and X-ray diffraction mapping to explore trends in phase formation and microstructural length scale with composition across the library. The integration of combinatorial synthesis with parallelizable analysis methods provides a efficient method for examining vast compositional ranges. The availability of microstructures from this vast composition space not only facilitates design of new alloys by controlling effects of composition on phase selection, phase sequence, length scale, and overall morphology, but also will be instrumental in understanding the complex process of microstructure formation in alloys.

Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

Directory of Open Access Journals (Sweden)

Antonio Gonzalez-Bulnes

2016-03-01

Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

Directory of Open Access Journals (Sweden)

Kieron M. G. O’Connell

2012-06-01

Full Text Available Two-directional synthesis represents an ideal strategy for the rapid elaboration of simple starting materials and their subsequent transformation into complex molecular architectures. As such, it is becoming recognised as an enabling technology for diversity-oriented synthesis. Herein, we provide a thorough account of our work combining two-directional synthesis with diversity-oriented synthesis, with particular reference to the synthesis of polycyclic alkaloid scaffolds.

Preclinical Assessment of a Strategy to Minimize the Abuse Liability of Opiate Medications for Pain

Science.gov (United States)

2016-09-01

plans (3). In fact, Bray and colleagues found that pain medication is the most highly abused of all prescribed drugs in the military (4). Prescription...the drug gamma-vinyl GABA (GVG) prior to morphine treatment effectively eliminates the highly addictive nature of this opiate . In these studies, we...widespread risk of opiate addiction in this population. Preclinical imaging studies aim to build a foundation for effective clinical drug development, and the

Neuraxial Analgesia In Neonates And Infants: Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

Science.gov (United States)

Walker, Suellen M.; Yaksh, Tony L.

2015-01-01

Neuraxial agents provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improve analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by addition of clonidine, ketamine, neostigmine or tramadol to single shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side-effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, the second half of this review presents preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial agents with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation prior to adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

Tissue-engineering-based Strategies for Regenerative Endodontics

Science.gov (United States)

Albuquerque, M.T.P.; Valera, M.C.; Nakashima, M.; Nör, J.E.; Bottino, M.C.

2014-01-01

Stemming from in vitro and in vivo pre-clinical and human models, tissue-engineering-based strategies continue to demonstrate great potential for the regeneration of the pulp-dentin complex, particularly in necrotic, immature permanent teeth. Nanofibrous scaffolds, which closely resemble the native extracellular matrix, have been successfully synthesized by various techniques, including but not limited to electrospinning. A common goal in scaffold synthesis has been the notion of promoting cell guidance through the careful design and use of a collection of biochemical and physical cues capable of governing and stimulating specific events at the cellular and tissue levels. The latest advances in processing technologies allow for the fabrication of scaffolds where selected bioactive molecules can be delivered locally, thus increasing the possibilities for clinical success. Though electrospun scaffolds have not yet been tested in vivo in either human or animal pulpless models in immature permanent teeth, recent studies have highlighted their regenerative potential both from an in vitro and in vivo (i.e., subcutaneous model) standpoint. Possible applications for these bioactive scaffolds continue to evolve, with significant prospects related to the regeneration of both dentin and pulp tissue and, more recently, to root canal disinfection. Nonetheless, no single implantable scaffold can consistently guide the coordinated growth and development of the multiple tissue types involved in the functional regeneration of the pulp-dentin complex. The purpose of this review is to provide a comprehensive perspective on the latest discoveries related to the use of scaffolds and/or stem cells in regenerative endodontics. The authors focused this review on bioactive nanofibrous scaffolds, injectable scaffolds and stem cells, and pre-clinical findings using stem-cell-based strategies. These topics are discussed in detail in an attempt to provide future direction and to shed light on

Preclinical models in radiation oncology

Directory of Open Access Journals (Sweden)

Kahn Jenna

2012-12-01

Full Text Available Abstract As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.

Synthesis of N-[methyl-11C]hydromorphone by using multivariate strategies for optimization of radiochemical yields

International Nuclear Information System (INIS)

Rimland, Annika; Bergson, Goeran; Obenius, Ulf; Sjoeberg, Stefan; Langstroem, Bengt

1987-01-01

The synthesis of N-[methyl- 11 C]hydromorphone has been performed by using [ 11 C]methyl iodide and desmethyl hydromorphone in a mixture of dimethylsulphoxide and dimethylformamide as solvent. Optimization of the radiochemical yield by varying the reaction conditions was performed by using multivariate strategies. The labelled hydromorphone was obtained in 72% radiochemical yield in the alkylation reaction with [ 11 C]-methyl iodide, counted from the end of the [ 11 C]methyl iodide synthesis. N-[Methyl- 11 C]hydromorphone was obtained as a ready injectable pharmaceutical solution with a total synthesis time of 40 min and in a 10% total radiochemical yield, with a radiochemical purity > 99.5%, according to HPLC analysis. (author)

Biological prevention and/or treatment strategies for radiation myelopathy. Discussion of a new perspective

International Nuclear Information System (INIS)

Nieder, C.; Ataman, F.; Price, R.E.; Kian Ang, K.

1999-01-01

Background: Radiosensitivity of the spinal cord makes both curative first-line treatment of numerous malignancies and re-irradiation of recurrent or second tumors more difficult. This review discusses recent advances in basic research that alter the view on the pathogenesis of radiation myelopathy, possibly offering strategies for prevention and/or therapy. Results: Available data of developmental neurobiology and preclinical studies of demyelinating diseases revealed interesting insights into oligodendrocyte development, intercellular signaling pathways, and myelination processes. Current findings suggest that administration of cytokines could increase proliferation of oligodendrocyte progenitor cells, enhance their differentiation, upregulate synthesis of myelin constituents, and promote myelin regeneration in the adult central nervous system. Other compounds might also be able to modulate progression of pathogenic processes that eventually lead to radiation myelopathy. This offers several possible biological prevention and/or treatment strategies, which currently are being investigated in animal studies. Conclusions: Technical options as well as optimization of fractionation parameters should be given priority in the attempt to reduce iatrogenic neurotoxicity. However, rational biological strategies could offer a new perspective for many patients. (orig.) [de

Melatonin and breast cancer: Evidences from preclinical and human studies.

Science.gov (United States)

Kubatka, Peter; Zubor, Pavol; Busselberg, Dietrich; Kwon, Taeg Kyu; Adamek, Mariusz; Petrovic, Daniel; Opatrilova, Radka; Gazdikova, Katarina; Caprnda, Martin; Rodrigo, Luis; Danko, Jan; Kruzliak, Peter

2018-02-01

The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Ab Initio Guided Low Temperature Synthesis Strategy for Smooth Face–Centred Cubic FeMn Thin Films

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Friederike Herrig

2018-05-01

Full Text Available The sputter deposition of FeMn thin films with thicknesses in the range of hundred nanometres and beyond requires relatively high growth temperatures for the formation of the face-centred cubic (fcc phase, which results in high thin film roughness. A low temperature synthesis strategy, based on local epitaxial growth of a 100 nm thick fcc FeMn film as well as a Cu nucleation layer on an α-Al2O3 substrate at 160 °C, enables roughness values (Ra as low as ~0.6 nm, which is in the same order of magnitude as the pristine substrate (~0.1 nm. The synthesis strategy is guided by ab initio calculations, indicating very strong interfacial bonding of the Cu nucleation layer to an α-Al2O3 substrate (work of separation 5.48 J/m²—which can be understood based on the high Cu coordination at the interface—and between fcc FeMn and Cu (3.45 J/m². Accompanied by small lattice misfits between these structures, the strong interfacial bonding is proposed to enable the local epitaxial growth of a smooth fcc FeMn thin film. Based on the here introduced synthesis strategy, the implementation of fcc FeMn based thin film model systems for materials with interface dominated properties such as FeMn steels containing κ-carbide precipitates or secondary phases appears meaningful.

Challenges for Preclinical Investigations of Human Biofield Modalities

Science.gov (United States)

Gronowicz, Gloria; Bengston, William

2015-01-01

Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

"Glowing head" mice: a genetic tool enabling reliable preclinical image-based evaluation of cancers in immunocompetent allografts.

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Chi-Ping Day

Full Text Available Preclinical therapeutic assessment currently relies on the growth response of established human cell lines xenografted into immunocompromised mice, a strategy that is generally not predictive of clinical outcomes. Immunocompetent genetically engineered mouse (GEM-derived tumor allograft models offer highly tractable preclinical alternatives and facilitate analysis of clinically promising immunomodulatory agents. Imageable reporters are essential for accurately tracking tumor growth and response, particularly for metastases. Unfortunately, reporters such as luciferase and GFP are foreign antigens in immunocompetent mice, potentially hindering tumor growth and confounding therapeutic responses. Here we assessed the value of reporter-tolerized GEMs as allograft recipients by targeting minimal expression of a luciferase-GFP fusion reporter to the anterior pituitary gland (dubbed the "Glowing Head" or GH mouse. The luciferase-GFP reporter expressed in tumor cells induced adverse immune responses in wildtype mouse, but not in GH mouse, as transplantation hosts. The antigenicity of optical reporters resulted in a decrease in both the growth and metastatic potential of the labeled tumor in wildtype mice as compared to the GH mice. Moreover, reporter expression can also alter the tumor response to chemotherapy or targeted therapy in a context-dependent manner. Thus the GH mice and experimental approaches vetted herein provide concept validation and a strategy for effective, reproducible preclinical evaluation of growth and response kinetics for traceable tumors.

Learning style preferences: A study of pre-clinical medical students in Barbados

OpenAIRE

OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

2017-01-01

Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compar...

Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

International Nuclear Information System (INIS)

Boschi, Stefano; Lodi, Filippo; Fanti, Stefano; Lee, Jason T.; Beykan, Seval; Eberlein, Uta; Buck, Andreas K.; Lassmann, Michael; Slavik, Roger; Wei, Liu; Spick, Claudio; Czernin, Johannes; Cicoria, Gianfranco; Herrmann, Ken

2016-01-01

The aim of this study was to synthesize and preclinically evaluate an 18 F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined. Several conditions for the labeling of 18 F-PSMA-11 via 18 F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed. Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18 F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv. 18 F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible. (orig.)

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.

Science.gov (United States)

Walker, Suellen M; Yaksh, Tony L

2012-09-01

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high-quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, in the second half of this review, we present preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice.

Microbubbles combined with ultrasound therapy in ischemic stroke: A systematic review of in-vivo preclinical studies.

Directory of Open Access Journals (Sweden)

Laurent Auboire

Full Text Available Microbubbles (MBs combined with ultrasound sonothrombolysis (STL appears to be an alternative therapeutic strategy for acute ischemic stroke (IS, but clinical results remain controversial.The aim of this systematic review is to identify the parameters tested; to assess evidence on the safety and efficacy on preclinical data on STL; and to assess the validity and publication bias.Pubmed® and Web of ScienceTM databases were systematically searched from January 1995 to April 2017 in French and English. We included studies evaluating STL on animal stroke model. This systematic review was conducted in accordance with the PRISMA guidelines. Data were extracted following a pre-defined schedule by two of the authors. The CAMARADES criteria were used for quality assessment. A narrative synthesis was conducted.Sixteen studies met the inclusion criteria. The result showed that ultrasound parameters and types of MBs were heterogeneous among studies. Numerous positive outcomes on efficacy were found, but only four studies demonstrated superiority of STL versus recombinant tissue-type plasminogen activator on clinical criteria. Data available on safety are limited.Quality assessment of the studies reviewed revealed a number of biases.Further in vivo studies are needed to demonstrate a better efficacy and safety of STL compared to currently approved therapeutic options.http://syrf.org.uk/protocols/.

Progress in terpene synthesis strategies through engineering of Saccharomyces cerevisiae.

Science.gov (United States)

Paramasivan, Kalaivani; Mutturi, Sarma

2017-12-01

Terpenes are natural products with a remarkable diversity in their chemical structures and they hold a significant market share commercially owing to their distinct applications. These potential molecules are usually derived from terrestrial plants, marine and microbial sources. In vitro production of terpenes using plant tissue culture and plant metabolic engineering, although receiving some success, the complexity in downstream processing because of the interference of phenolics and product commercialization due to regulations that are significant concerns. Industrial workhorses' viz., Escherichia coli and Saccharomyces cerevisiae have become microorganisms to produce non-native terpenes in order to address critical issues such as demand-supply imbalance, sustainability and commercial viability. S. cerevisiae enjoys several advantages for synthesizing non-native terpenes with the most significant being the compatibility for expressing cytochrome P450 enzymes from plant origin. Moreover, achievement of high titers such as 40 g/l of amorphadiene, a sesquiterpene, boosts commercial interest and encourages the researchers to envisage both molecular and process strategies for developing yeast cell factories to produce these compounds. This review contains a brief consideration of existing strategies to engineer S. cerevisiae toward the synthesis of terpene molecules. Some of the common targets for synthesis of terpenes in S. cerevisiae are as follows: overexpression of tHMG1, ERG20, upc2-1 in case of all classes of terpenes; repression of ERG9 by replacement of the native promoter with a repressive methionine promoter in case of mono-, di- and sesquiterpenes; overexpression of BTS1 in case of di- and tetraterpenes. Site-directed mutagenesis such as Upc2p (G888A) in case of all classes of terpenes, ERG20p (K197G) in case of monoterpenes, HMG2p (K6R) in case of mono-, di- and sesquiterpenes could be some generic targets. Efforts are made to consolidate various studies

The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature-A Systematic Review.

Science.gov (United States)

Roffi, Alice; Krishnakumar, Gopal Shankar; Gostynska, Natalia; Kon, Elizaveta; Candrian, Christian; Filardo, Giuseppe

2017-01-01

Long bone defects represent a clinical challenge. Bone tissue engineering (BTE) has been developed to overcome problems associated with conventional methods. The aim of this study was to assess the BTE strategies available in preclinical and clinical settings and the current evidence supporting this approach. A systematic literature screening was performed on PubMed database, searching for both preclinical (only on large animals) and clinical studies. The following string was used: "(Scaffold OR Implant) AND (Long bone defect OR segmental bone defect OR large bone defect OR bone loss defect)." The search retrieved a total of 1573 articles: 51 preclinical and 4 clinical studies were included. The great amount of preclinical papers published over the past few years showed promising findings in terms of radiological and histological evidence. Unfortunately, this in vivo situation is not reflected by a corresponding clinical impact, with few published papers, highly heterogeneous and with small patient populations. Several aspects should be further investigated to translate positive preclinical findings into clinical protocols: the identification of the best biomaterial, with both biological and biomechanical suitable properties, and the selection of the best choice between cells, GFs, or their combination through standardized models to be validated by randomized trials.

Design and biological properties of iodine-123 labeled β-methyl-branched fatty acids

International Nuclear Information System (INIS)

Knapp, F.F. Jr.; Goodman, M.M.

1984-01-01

The synthetic strategy, synthesis, preclinical evaluation and potential clinical applications of 3-methyl-branched radioiodinated iodophenyl- and iodovinyl-substituted fatty acids are reviewed for use as myocardial imaging agents. 50 references, 6 figures

“Glowing Head” Mice: A Genetic Tool Enabling Reliable Preclinical Image-Based Evaluation of Cancers in Immunocompetent Allografts

Science.gov (United States)

Day, Chi-Ping; Carter, John; Ohler, Zoe Weaver; Bonomi, Carrie; El Meskini, Rajaa; Martin, Philip; Graff-Cherry, Cari; Feigenbaum, Lionel; Tüting, Thomas; Van Dyke, Terry; Hollingshead, Melinda; Merlino, Glenn

2014-01-01

Preclinical therapeutic assessment currently relies on the growth response of established human cell lines xenografted into immunocompromised mice, a strategy that is generally not predictive of clinical outcomes. Immunocompetent genetically engineered mouse (GEM)-derived tumor allograft models offer highly tractable preclinical alternatives and facilitate analysis of clinically promising immunomodulatory agents. Imageable reporters are essential for accurately tracking tumor growth and response, particularly for metastases. Unfortunately, reporters such as luciferase and GFP are foreign antigens in immunocompetent mice, potentially hindering tumor growth and confounding therapeutic responses. Here we assessed the value of reporter-tolerized GEMs as allograft recipients by targeting minimal expression of a luciferase-GFP fusion reporter to the anterior pituitary gland (dubbed the “Glowing Head” or GH mouse). The luciferase-GFP reporter expressed in tumor cells induced adverse immune responses in wildtype mouse, but not in GH mouse, as transplantation hosts. The antigenicity of optical reporters resulted in a decrease in both the growth and metastatic potential of the labeled tumor in wildtype mice as compared to the GH mice. Moreover, reporter expression can also alter the tumor response to chemotherapy or targeted therapy in a context-dependent manner. Thus the GH mice and experimental approaches vetted herein provide concept validation and a strategy for effective, reproducible preclinical evaluation of growth and response kinetics for traceable tumors. PMID:25369133

Pre-clinical and clinical development of the first placental malaria vaccine

DEFF Research Database (Denmark)

Pehrson, Caroline; Salanti, Ali; Theander, Thor G

2017-01-01

the condition.  Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical...... vaccine development. However, all papers from these searches were not systematically included.  Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy...

Design and biological properties of iodine-123 labeled. beta. -methyl-branched fatty acids

Energy Technology Data Exchange (ETDEWEB)

Knapp, F.F. Jr.; Goodman, M.M.

1984-01-01

The synthetic strategy, synthesis, preclinical evaluation and potential clinical applications of 3-methyl-branched radioiodinated iodophenyl- and iodovinyl-substituted fatty acids are reviewed for use as myocardial imaging agents. 50 references, 6 figures. (ACR)

Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

Energy Technology Data Exchange (ETDEWEB)

Visser, Anniek K.D.; Waarde, Aren van; Willemsen, Antoon T.M. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Bosker, Fokko J. [University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Luiten, Paul G.M. [University of Groningen, Center for Behavior and Neurosciences, Department of Molecular Neurobiology, Haren (Netherlands); Boer, Johan A. den [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, University Center of Psychiatry, Groningen (Netherlands); Kema, Ido P. [University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Dierckx, Rudi A.J.O. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University Hospital Ghent, Department of Nuclear Medicine, Ghent (Belgium)

2011-03-15

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are {alpha}-[{sup 11}C]methyltryptophan ([{sup 11}C]AMT) and 5-hydroxy-L-[{beta}-{sup 11}C]tryptophan ([{sup 11}C]5-HTP). Both tracers have advantages and disadvantages. [{sup 11}C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [{sup 11}C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain. (orig.)

Preclinical electrogastrography in experimental pigs

Science.gov (United States)

Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

2010-01-01

Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy.

Science.gov (United States)

Wender, Paul A; Hilinski, Michael K; Skaanderup, Philip R; Soldermann, Nicolas G; Mooberry, Susan L

2006-08-31

An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

Preclinical and clinical safety studies on DNA vaccines.

NARCIS (Netherlands)

Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

2007-01-01

DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and

Problem-based learning in pre-clinical medical education: 22 years of outcome research.

Science.gov (United States)

Hartling, Lisa; Spooner, Carol; Tjosvold, Lisa; Oswald, Anna

2010-01-01

To conduct a systematic review of problem-based learning (PBL) in undergraduate, pre-clinical medical education. A research librarian developed comprehensive search strategies for MEDLINE, PSYCINFO, and ERIC (1985-2007). Two reviewers independently screened search results and applied inclusion criteria. Studies were included if they had a comparison group and reported primary data for evaluative outcomes. One reviewer extracted data and a second reviewer checked data for accuracy. Two reviewers independently assessed methodological quality. Quantitative synthesis was not performed due to heterogeneity. A qualitative review with detailed evidence tables is provided. Thirty unique studies were included. Knowledge acquisition measured by exam scores was the most frequent outcome reported; 12 of 15 studies found no significant differences. Individual studies demonstrated either improved clerkship (N = 3) or residency (N = 1) performance, or benefits on some clinical competencies during internships for PBL (N = 1). Three of four studies found some benefits for PBL when evaluating diagnostic accuracy. Three studies found few differences of clinical (or practical) importance on the impact of PBL on practicing physicians. Twenty-two years of research shows that PBL does not impact knowledge acquisition; evidence for other outcomes does not provide unequivocal support for enhanced learning. Work is needed to determine the most appropriate outcome measures to capture and quantify the effects of PBL. General conclusions are limited by methodological weaknesses and heterogeneity across studies. The critical appraisal of previous studies, conducted as part of this review, provides direction for future research in this area.

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

Directory of Open Access Journals (Sweden)

Valerie C Henderson

Full Text Available The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external or programmatic research activity they primarily address.We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

Science.gov (United States)

Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

2013-01-01

The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

Cation exchange assisted binding-elution strategy for enzymatic synthesis of human milk oligosaccharides (HMOs).

Science.gov (United States)

Zhu, Hailiang; Wu, Zhigang; Gadi, Madhusudhan Reddy; Wang, Shuaishuai; Guo, Yuxi; Edmunds, Garrett; Guan, Wanyi; Fang, Junqiang

2017-09-15

A cation exchange assisted binding-elution (BE) strategy for enzymatic synthesis of human milk oligosaccharides (HMOs) was developed. An amino linker was used to provide the cation ion under acidic condition which can be readily bound to cation exchange resin and then eluted off by saturated ammonium bicarbonate. Ammonium bicarbonate in the collections was easily removed by vacuum evaporation. This strategy circumvented the incompatible issue between glycosyltransferases and solid support or large polymers, and no purification was needed for intermediate products. With current approach, polyLacNAc backbones of HMOs and fucosylated HMOs were synthesized smoothly. Copyright © 2017 Elsevier Ltd. All rights reserved.

How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction.

Science.gov (United States)

Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

2016-01-01

Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. Published by Elsevier Inc.

Synthesis and preclinical evaluation of an Al{sup 18}F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

Energy Technology Data Exchange (ETDEWEB)

Boschi, Stefano; Lodi, Filippo; Fanti, Stefano [S. Orsola-Malpighi University Hospital, Department of Nuclear Medicine, Bologna (Italy); Lee, Jason T. [David Geffen School of Medicine at UCLA, Crump Institute for Molecular Imaging, Los Angeles (United States); Beykan, Seval; Eberlein, Uta; Buck, Andreas K.; Lassmann, Michael [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Slavik, Roger; Wei, Liu; Spick, Claudio; Czernin, Johannes [David Geffen School of Medicine at UCLA, Ahmanson Translational Imaging Division, Los Angeles, CA (United States); Cicoria, Gianfranco [S. Orsola-Malpighi University Hospital, Department of Medical Physics, Bologna (Italy); Herrmann, Ken [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); David Geffen School of Medicine at UCLA, Ahmanson Translational Imaging Division, Los Angeles, CA (United States)

2016-11-15

The aim of this study was to synthesize and preclinically evaluate an {sup 18}F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined. Several conditions for the labeling of {sup 18}F-PSMA-11 via {sup 18}F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed. Quantitative labeling yields could be achieved with >97 % radiochemical purity. The {sup 18}F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv. {sup 18}F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible. (orig.)

Educational strategies for diabetic people at risk for foot neuropathy: synthesis of good evidence

Directory of Open Access Journals (Sweden)

Luciana Catunda Gomes de Menezes

2016-12-01

Full Text Available The aim of the present study was to identify the best evidence concerning health education strategies used in teaching-learning for people with diabetes mellitus who are at risk for foot neuropathy. An integrative review was conducted in the databases PubMed, LILACS, CINAHL and SCOPUS in January 2015; a total of 14 papers was analyzed in detail. The results are shown in a summary table and categories are discussed, covering various health education strategies for prevention and management with patients at risk of foot neuropathy (group; individual in face-to-face visits or via telephone; and using interactive technologies, and a synthesis of the best evidence for the effectiveness of these interventions in reducing diabetic foot complications. It was concluded that all the educational strategies are effective in promoting diabetic foot self-care. However, the group strategies showed greater effectiveness, enabling significant improvements in the knowledge, attitude, and practices of care for feet and general health of diabetic patients.

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

Science.gov (United States)

Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

2017-05-09

To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

[Preclinical study of immunocorrection action of the sum of active substances of Coluria geoides (Pall.) Ledeb. (Rosaceae)].

Science.gov (United States)

Dutova, S V; Karpova, M R; Myadelets, M A; Myasnaya, N V; Sherstoboev, E Yu

2015-01-01

A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties.

NCI Pediatric Preclinical Testing Consortium

Science.gov (United States)

NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

One-pot synthesis of phthalazines and pyridazino-aromatics: a novel strategy for substituted naphthalenes.

Science.gov (United States)

Kessler, Simon N; Wegner, Hermann A

2012-07-06

A new one-pot strategy for the synthesis of phthalazines and pyridazino-aromatics starting from aromatic aldehydes has been developed. A variety of substituents ranging from electron withdrawing to donating is tolerated furnishing the desired 1,2-diazine in good to excellent yields. The products have been applied to the bidentate Lewis acid catalyzed inverse electron-demand Diels-Alder (IEDDA) reaction opening a novel two-step entry into substituted naphthalenes, such as Naproxen.

Polyhomologation based on in situ generated Boron-thexyl-silaboracyclic initiating sites: a novel strategy towards the synthesis of polyethylene-based complex architectures

KAUST Repository

Zhang, Zhen

2015-04-10

A novel strategy, based on the in situ generated Boron-thexyl-silaboracyclic initiating sites for the polyhomologation of dimethylsulfoxonium methylide, has been developed for the synthesis of complex polyethylene-based architectures. As examples, the synthesis of a 4-arm polyethylene star, three (polystyrene)(polyethylene)2 3-miktoarm stars and a PE-branched double graft copolymers are given.

A general strategy toward the rational synthesis of metal tungstate nanostructures using plasma electrolytic oxidation method

Energy Technology Data Exchange (ETDEWEB)

Jiang, Yanan; Liu, Baodan, E-mail: baodanliu@imr.ac.cn; Zhai, Zhaofeng; Liu, Xiaoyuan; Yang, Bing; Liu, Lusheng; Jiang, Xin, E-mail: xjiang@imr.ac.cn

2015-11-30

Graphical abstract: A general strategy for the rational synthesis of tungstate nanostructure has been developed based on plasma electrolytic oxidation (PEO) technology (up). Using this method, ZnWO{sub 4} and NiWO{sub 4} nanostructures with controllable morphologies and superior crystallinity can be easily obtained (down), showing obvious advantage in comparison with conventional hydrothermal and sol–gel methods. - Highlights: • Plasma electrolyte oxidation (PEO) method has been used for the rational synthesis of tungstate nanostructures. • ZnWO{sub 4} nanoplates have strong mechanical adhesion with porous TiO{sub 2} film substrate. • The morphology and dimensional size of ZnWO{sub 4} nanostructures can be selectively tailored by controlling the annealing temperature and growth time. • The PEO method can be widely applied to the growth of various metal oxides. - Abstract: A new method based on conventional plasma electrolytic oxidation (PEO) technology has been developed for the rational synthesis of metal tungstate nanostructures. Using this method, ZnWO{sub 4} and NiWO{sub 4} nanostructures with controllable morphologies (nanorods, nanosheets and microsheets) and superior crystallinity have been synthesized. It has been found that the morphology diversity of ZnWO{sub 4} nanostructures can be selectively tailored through tuning the electrolyte concentration and annealing temperatures, showing obvious advantages in comparison to traditional hydrothermal and sol–gel methods. Precise microscopy analyses on the cross section of the PEO coating and ZnWO{sub 4} nanostructures confirmed that the precursors initially precipitated in the PEO coating and its surface during plasma discharge process are responsible for the nucleation and subsequent growth of metal tungstate nanostructures by thermal annealing. The method developed in this work represents a general strategy toward the rational synthesis of metal oxide nanostructures and the formation mechanism of

A general strategy toward the rational synthesis of metal tungstate nanostructures using plasma electrolytic oxidation method

International Nuclear Information System (INIS)

Jiang, Yanan; Liu, Baodan; Zhai, Zhaofeng; Liu, Xiaoyuan; Yang, Bing; Liu, Lusheng; Jiang, Xin

2015-01-01

Graphical abstract: A general strategy for the rational synthesis of tungstate nanostructure has been developed based on plasma electrolytic oxidation (PEO) technology (up). Using this method, ZnWO 4 and NiWO 4 nanostructures with controllable morphologies and superior crystallinity can be easily obtained (down), showing obvious advantage in comparison with conventional hydrothermal and sol–gel methods. - Highlights: • Plasma electrolyte oxidation (PEO) method has been used for the rational synthesis of tungstate nanostructures. • ZnWO 4 nanoplates have strong mechanical adhesion with porous TiO 2 film substrate. • The morphology and dimensional size of ZnWO 4 nanostructures can be selectively tailored by controlling the annealing temperature and growth time. • The PEO method can be widely applied to the growth of various metal oxides. - Abstract: A new method based on conventional plasma electrolytic oxidation (PEO) technology has been developed for the rational synthesis of metal tungstate nanostructures. Using this method, ZnWO 4 and NiWO 4 nanostructures with controllable morphologies (nanorods, nanosheets and microsheets) and superior crystallinity have been synthesized. It has been found that the morphology diversity of ZnWO 4 nanostructures can be selectively tailored through tuning the electrolyte concentration and annealing temperatures, showing obvious advantages in comparison to traditional hydrothermal and sol–gel methods. Precise microscopy analyses on the cross section of the PEO coating and ZnWO 4 nanostructures confirmed that the precursors initially precipitated in the PEO coating and its surface during plasma discharge process are responsible for the nucleation and subsequent growth of metal tungstate nanostructures by thermal annealing. The method developed in this work represents a general strategy toward the rational synthesis of metal oxide nanostructures and the formation mechanism of metal tungstate nanostructures fabricated by

Modeling the Western Diet for Preclinical Investigations.

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Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

2018-05-01

Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

The basics of preclinical drug development for neurodegenerative disease indications.

Science.gov (United States)

Steinmetz, Karen L; Spack, Edward G

2009-06-12

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

Optimization of precursor synthesis, formulation and stability of 1′-[18 F]fluoroethyl-β-D-lactose ([18 F]FEL) for preclinical studies in detection of pancreatic cancer

International Nuclear Information System (INIS)

Paolillo, Vincenzo; De Palatis, Louis; Alauddin, Mian M.

2014-01-01

Introduction: 1′-[ 18 F]Fluoroethyl-β-D-lactose ([ 18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [ 18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [ 18 F]FEL; we also describe [ 18 F]FEL’s formulation and stability. Methods: Acetylation of D-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-D-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-D-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[ 18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results: Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. Conclusions: A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [ 18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of

Optimization of precursor synthesis, formulation and stability of 1′-[18 F] fluoroethyl-β-d-lactose ([18 F]FEL) for preclinical studies in detection of pancreatic cancer

Science.gov (United States)

Paolillo, Vincenzo; De Palatis, Louis; Alauddin, Mian M.

2014-01-01

Introduction 1′-[18 F]Fluoroethyl-β-d-lactose ([18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [18 F]FEL; we also describe [18 F]FEL’s formulation and stability. Methods Acetylation of d-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-d-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-d-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. Conclusions A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [18 F]FEL should

Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.

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Iglesias, Ainhoa; García-Nimo, Laura; Cocho de Juan, José A; Moreno, José C

2014-03-01

DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

A simple and accurate two-step long DNA sequences synthesis strategy to improve heterologous gene expression in pichia.

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Jiang-Ke Yang

Full Text Available In vitro gene chemical synthesis is a powerful tool to improve the expression of gene in heterologous system. In this study, a two-step gene synthesis strategy that combines an assembly PCR and an overlap extension PCR (AOE was developed. In this strategy, the chemically synthesized oligonucleotides were assembled into several 200-500 bp fragments with 20-25 bp overlap at each end by assembly PCR, and then an overlap extension PCR was conducted to assemble all these fragments into a full length DNA sequence. Using this method, we de novo designed and optimized the codon of Rhizopus oryzae lipase gene ROL (810 bp and Aspergillus niger phytase gene phyA (1404 bp. Compared with the original ROL gene and phyA gene, the codon-optimized genes expressed at a significantly higher level in yeasts after methanol induction. We believe this AOE method to be of special interest as it is simple, accurate and has no limitation with respect to the size of the gene to be synthesized. Combined with de novo design, this method allows the rapid synthesis of a gene optimized for expression in the system of choice and production of sufficient biological material for molecular characterization and biotechnological application.

Recent progress on magnetic iron oxide nanoparticles: synthesis, surface functional strategies and biomedical applications

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Wu, Wei; Wu, Zhaohui; Yu, Taekyung; Jiang, Changzhong; Kim, Woo-Sik

2015-01-01

This review focuses on the recent development and various strategies in the preparation, microstructure, and magnetic properties of bare and surface functionalized iron oxide nanoparticles (IONPs); their corresponding biological application was also discussed. In order to implement the practical in vivo or in vitro applications, the IONPs must have combined properties of high magnetic saturation, stability, biocompatibility, and interactive functions at the surface. Moreover, the surface of IONPs could be modified by organic materials or inorganic materials, such as polymers, biomolecules, silica, metals, etc. The new functionalized strategies, problems and major challenges, along with the current directions for the synthesis, surface functionalization and bioapplication of IONPs, are considered. Finally, some future trends and the prospects in these research areas are also discussed. PMID:27877761

Biological basis of sex differences in drug abuse: preclinical and clinical studies.

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Lynch, Wendy J; Roth, Megan E; Carroll, Marilyn E

2002-11-01

The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains

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Siciliano, Cody A.; Locke, Jason L.; Mathews, Tiffany A.; Lopez, Marcelo F.; Becker, Howard C.; Jones, Sara R.

2017-01-01

Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J × DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings

Study partners should be required in preclinical Alzheimer's disease trials.

Science.gov (United States)

Grill, Joshua D; Karlawish, Jason

2017-12-06

In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Science.gov (United States)

Fawaz, Maria V; Brooks, Allen F; Rodnick, Melissa E; Carpenter, Garrett M; Shao, Xia; Desmond, Timothy J; Sherman, Phillip; Quesada, Carole A; Hockley, Brian G; Kilbourn, Michael R; Albin, Roger L; Frey, Kirk A; Scott, Peter J H

2014-08-20

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

Development of an automated modular system for the synthesis of [11C]acetate.

Science.gov (United States)

Felicini, Chiara; Någren, Kjell; Berton, Andrea; Pascali, Giancarlo; Salvadori, Piero Alberto

2010-12-01

Carboxylation reactions offer a straightforward method for the synthesis of carbon-11 labelled carboxylic acids. Among these, the preparation of carbon-11 (C)-acetate is receiving increasing attention because of diagnostic applications in oncology in addition to its well-established use as a probe for myocardial oxidative metabolism. Although a number of dedicated modules are commercially available, the development of the synthesis on flexible platforms would be beneficial to widen the number of tracers, in particular for preclinical assessment and testing. In this study, the carboxylation reaction was implemented for the synthesis of sodium 1-[C]acetate after the classic route of carboxylation of methylmagnesium chloride by [C]carbon dioxide, followed by the acidic hydrolysis, purification and sterile filtration. This was performed using a commercially available kit of preassembled hardware units and fully compatible components of radiochemistry automation (VarioSystem). The system proved be to highly versatile and inexpensive and allowed a quick translation of the radiochemistry project into a working system even by less experienced personnel, because of predefined interfaces between electronic parts and operating software (preloaded on a laptop and included in the kit). The automatic module proved to be a simple and reliable system for the production of 1-[C]acetate that was prepared in 24 min (total synthesis time) with stable radiochemical yields (20% nondecay corrected) and high radiochemical purity (>97%). The module is used routinely to produce 1-[C]acetate for preclinical studies and is being implemented for the production of the labelled fatty acids.

The basics of preclinical drug development for neurodegenerative disease indications

Directory of Open Access Journals (Sweden)

Spack Edward G

2009-06-01

Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents

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Daniel A. Ladin

2016-10-01

Full Text Available Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated through the endocannabinoid system, which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer development and reduction. However, many studies investigated these roles using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical models and to examine the current standing of cannabinoids currently being tested in human cancer patients.

Challenges and Strategies in the Synthesis of Mesoporous Alumina Powders and Hierarchical Alumina Monoliths

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Anne Galarneau

2012-02-01

Full Text Available A new rapid, very simple and one-step sol-gel strategy for the large-scale preparation of highly porous γ-Al2O3 is presented. The resulting mesoporous alumina materials feature high surface areas (400 m2 g−1, large pore volumes (0.8 mL g−1 and the ��-Al2O3 phase is obtained at low temperature (500 °C. The main advantages and drawbacks of different preparations of mesoporous alumina materials exhibiting high specific surface areas and large pore volumes such as surfactant-nanostructured alumina, sol-gel methods and hierarchically macro-/mesoporous alumina monoliths have been analyzed and compared. The most reproducible synthesis of mesoporous alumina are given. Evaporation-Induced Self-Assembly (EISA is the sole method to lead to nanostructured mesoporous alumina by direct templating, but it is a difficult method to scale-up. Alumina featuring macro- and mesoporosity in monolithic shape is a very promising material for in flow applications; an optimized synthesis is described.

The Economics of Reproducibility in Preclinical Research.

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Leonard P Freedman

2015-06-01

Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

Synthesis and preclinical evaluation of [11C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase

International Nuclear Information System (INIS)

Hicks, Justin W.; Parkes, Jun; Sadovski, Oleg; Tong, Junchao; Houle, Sylvain; Vasdev, Neil; Wilson, Alan A.

2013-01-01

Introduction: Fatty acid amide hydrolase (FAAH) has a significant role in regulating endocannabinoid signaling in the central nervous system. As such, FAAH inhibitors are being actively sought for pain, addiction, and other indications. This has led to the recent pursuit of positron emission tomography (PET) radiotracers targeting FAAH. We report herein the preparation and preclinical evaluation of [ 11 C-carbonyl]PF-04457845, an isotopologue of the potent irreversible FAAH inhibitor. Methods: PF-04457845 was radiolabeled at the carbonyl position via automated [ 11 C]CO 2 -fixation. Ex vivo brain biodistribution of [ 11 C-carbonyl]PF-04457845 was carried out in conscious rats. Specificity was determined by pre-administration of PF-04457845 or URB597 prior to [ 11 C-carbonyl]PF-04457845. In a separate experiment, rats injected with the title radiotracer had whole brains excised, homogenized and extracted to examine irreversible binding to brain parenchyma. Results: The title compound was prepared in 5 ± 1% (n = 4) isolated radiochemical yield based on starting [ 11 C]CO 2 (decay uncorrected) within 25 min from end-of-bombardment in > 98% radiochemical purity and a specific activity of 73.5 ± 8.2 GBq/μmol at end-of-synthesis. Uptake of [ 11 C-carbonyl]PF-04457845 into the rat brain was high (range of 1.2–4.4 SUV), heterogeneous, and in accordance with reported FAAH distribution. Saturable binding was demonstrated by a dose-dependent reduction in brain radioactivity uptake following pre-treatment with PF-04457845. Pre-treatment with the prototypical FAAH inhibitor, URB597, reduced the brain radiotracer uptake in all regions by 71–81%, demonstrating specificity for FAAH. The binding of [ 11 C-carbonyl]PF-04457845 to FAAH at 40 min post injection was irreversible as 98% of the radioactivity in the brain could not be extracted. Conclusions: [ 11 C-carbonyl]PF-04457845 was rapidly synthesized via an automated radiosynthesis. Ex vivo biodistribution studies in

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Science.gov (United States)

Avey, Marc T; Moher, David; Sullivan, Katrina J; Fergusson, Dean; Griffin, Gilly; Grimshaw, Jeremy M; Hutton, Brian; Lalu, Manoj M; Macleod, Malcolm; Marshall, John; Mei, Shirley H J; Rudnicki, Michael; Stewart, Duncan J; Turgeon, Alexis F; McIntyre, Lauralyn

2016-01-01

Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs) as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments) reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47%) of all sub-items (median 51 items; range 37-64). Across all studies, the Methods Section reported less than half (45%) and the Results Section reported less than a third (29%). There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

Science.gov (United States)

Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

2017-11-01

Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection

Science.gov (United States)

2014-01-01

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [18F]lansoprazole, [11C]N-methyl lansoprazole, and [18F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [18F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials. PMID:24896980

Preclinical animal research on therapy dosimetry with dual isotopes

International Nuclear Information System (INIS)

Konijnenberg, Mark W.; Jong, Marion de

2011-01-01

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Preclinical animal research on therapy dosimetry with dual isotopes

Energy Technology Data Exchange (ETDEWEB)

Konijnenberg, Mark W.; Jong, Marion de [Nuclear Medicine Department, Erasmus MC, Rotterdam (Netherlands)

2011-06-15

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Characterization of novel preclinical dose distributions for micro irradiator

International Nuclear Information System (INIS)

Kodra, J; Miles, D; Yoon, S W; Kirsch, D G; Oldham, M

2017-01-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm 3 ) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters. (paper)

Characterization of novel preclinical dose distributions for micro irradiator

Science.gov (United States)

Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

2017-05-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

Directory of Open Access Journals (Sweden)

Amelia Kellar

2015-01-01

Full Text Available Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

Sustainable Strategies for the Synthesis of Organics and Nanomaterials

Science.gov (United States)

The presentation summarizes recent activity in eco-friendly chemical synthesis, which involves benign alternatives, such as the use of supported reagents, and greener reaction medium in aqueous or solvent-free conditions. The synthesis of heterocyclic compounds, coupling reaction...

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Directory of Open Access Journals (Sweden)

Marc T Avey

Full Text Available Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47% of all sub-items (median 51 items; range 37-64. Across all studies, the Methods Section reported less than half (45% and the Results Section reported less than a third (29%. There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe.

Science.gov (United States)

Field, J; Stone, S; Orsini, C; Hussain, A; Vital, S; Crothers, A; Walmsley, D

2018-05-01

Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan-European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills. A request to complete an online questionnaire, in English, was sent electronically to skills leads at all Association of Dental Education in Europe member schools. The questionnaire collected information in relation to institution and country, regulatory requirements to demonstrate safety, details of specific pre-clinical skills courses, learning materials and teaching staff. Forty-eight institutions, from 25 European countries responded. Seven countries (n=7, 28%) reported no requirement to demonstrate student operative safety prior to patient treatment. Several core and operative clinical skills are common to the majority of institutions. The most commonly taught core skills related directly to the clinical environment such as cross-infection control and hand washing. The least common were skills that indirectly related to patient care, such as communication skills and working as a team. There are clear differences within European pre-clinical dental education, and greater efforts are needed to demonstrate that all European students are fit to practice before they start treating patients. Learning outcomes, teaching activities and assessment activities of pre-clinical skills should be shared collaboratively to further standardise curricula. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Strategies for the Green Synthesis of Organics and Nanomaterials

Science.gov (United States)

The presentation summarizes our recent activity in chemical synthesis involving benign alternatives, such as the use of supported reagents, and greener reaction medium in aqueous or solvent-free conditions.1 The synthesis of heterocyclic compounds, coupling reactions, and a varie...

Polyhomologation based on in situ generated Boron-thexyl-silaboracyclic initiating sites: a novel strategy towards the synthesis of polyethylene-based complex architectures

KAUST Repository

Zhang, Zhen; Zhang, Hefeng; Gnanou, Yves; Hadjichristidis, Nikolaos

2015-01-01

A novel strategy, based on the in situ generated Boron-thexyl-silaboracyclic initiating sites for the polyhomologation of dimethylsulfoxonium methylide, has been developed for the synthesis of complex polyethylene-based architectures. As examples

Commentary: IDSA guidelines for improving the teaching of preclinical medical microbiology and infectious diseases.

Science.gov (United States)

Southwick, Frederick; Katona, Peter; Kauffman, Carol; Monroe, Sara; Pirofski, Liise-anne; del Rio, Carlos; Gallis, Harry; Dismukes, William

2010-01-01

Preclinical microbiology and infectious diseases courses too often primarily depend on PowerPoint lectures and notes, combined with multiple-choice tests, as their primary teaching tools. This strategy sets low expectations for students, encouraging short-term memory and discouraging understanding and long-term memory. These methods also fail to stimulate active participation, collaborative learning, and two-way communication with the professor, and they do not respect the students' diverse talents and ways of learning. The Infectious Diseases Society of America Preclinical Curriculum Committee proposes a new approach that emphasizes active learning and understanding and that addresses all of these failures. It consists of five components: (1) "Just-in-time" teaching that requires students to e-mail the answers to two general questions as well as any areas of misunderstanding to the instructor several hours before each lecture, (2) peer instruction or large-group sessions consisting of student teams of four who electronically answer a conceptual question before each major section of the lecture, (3) teaching from edited textbooks and Internet sources, (4) small-group discussions that emphasize pathogenesis and differential diagnosis, and (5) essay questions that encourage and test understanding in addition to recognition. A national consensus on factual content is proposed, with the goals of reducing information overload and minimizing requirements for excessive memorization. These strategies promise to enhance learning and rekindle interest in the field of infectious diseases. Other subspecialty organizations should create similar teaching guidelines that will encourage future medical students to bring a richer understanding of clinical and basic science to the bedside.

Protein synthesis levels are increased in a subset of individuals with Fragile X syndrome

DEFF Research Database (Denmark)

Jacquemont, Sébastien; Pacini, Laura; Jønch, Aia E

2018-01-01

architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical...... severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS...... and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those...

Extracurricular activities associated with stress and burnout in preclinical medical students

Directory of Open Access Journals (Sweden)

Jawad Fares

2016-09-01

Full Text Available This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12 while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS. The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62% and burnout (75%. Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study.

Extracurricular activities associated with stress and burnout in preclinical medical students.

Science.gov (United States)

Fares, Jawad; Saadeddin, Zein; Al Tabosh, Hayat; Aridi, Hussam; El Mouhayyar, Christopher; Koleilat, Mohamad Karim; Chaaya, Monique; El Asmar, Khalil

2016-09-01

This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.

Science.gov (United States)

Isidro-Llobet, Albert; Hadje Georgiou, Kathy; Galloway, Warren R J D; Giacomini, Elisa; Hansen, Mette R; Méndez-Abt, Gabriela; Tan, Yaw Sing; Carro, Laura; Sore, Hannah F; Spring, David R

2015-04-21

Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.

Preclinical experimental stress studies: protocols, assessment and comparison.

Science.gov (United States)

Bali, Anjana; Jaggi, Amteshwar Singh

2015-01-05

Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

What Comes Next After a Successful Synthesis of a RP entity? USA Prospective

International Nuclear Information System (INIS)

Dence, Carmen S.

2016-01-01

The successful synthesis of a new RP is the first step - although a critical one- to what comes next: to make it available to a patient. This presentation will present an overview of the regulatory process in USA and how to blend the preclinical to translational research. The latter, then may become amenable to the much discussed 'personalized medicine', one of the goals for patient treatment. (author)

Study of the French wind sector: assessment, prospective, and strategy. Final report + Synthesis

International Nuclear Information System (INIS)

Bellini, Robert; Berrou, Yolene; Blot, Jean-Francois; Bodiguel, Aude; Callonnec, Gael; Cals, Guilain; Eyang Mbeng, Rudy; Fiol, Jack; Galiano, Mila; Gerard, Rolland; Gerson, Raphael; Guenard, Vincent; Guillot, Frederic; Guyet, Samy; Khebchache, Bouzid; Marchal, David; Parrouffe, Jean-Michel; Puygrenier, Samuel; Roger, Christophe; Furois, Timothee; Lejzerzon, Victoire; Mouhamad, Sakina; Orta, Louis; Glita, Marc; Meteyer, Herve; Plante, Ludovic; Duclos, Paul; Lettry, Marion; Mathieu, Mathilde; Langlois, Pierre-Albert; Lioret, Sonia; Monnier, Matthieu; Robin-Chevallier, Lucas; Bourdier, Pierre; Duffes, Thomas; Nocodie, Serge; Neveux, Guillaume; Paulou, Julien; Vermeulen, Valentin; Hajjar, Ali; Bouchet, Alexandre; Clicquot De Mentque, Juliette; Jan, Etienne; Pinel, Julie; Haeusler, Laurence; Moro-Goubely, Anne-Gaelle; Berthoin, Guillaume

2017-09-01

This huge document comprises several reports, and first proposes an executive summary which gives a synthetic overview of the present status of wind energy in France and abroad, of an assessment of 15 years of a policy of support to wind energy, of perspectives of development on the medium term, of economic spin-off on the long term, and of the ADEME's role in a national strategy for wind energy. These issues are then addressed in a more detailed way with notably a presentation of complete wind energy costs in France, a synthesis of an international benchmark, a detailed analysis of the support policy (in terms of efficiency, usefulness, costs-benefits), a characterisation of market evolutions, a discussion of constraint evolutions and of development strategies. A synthetic version of this report is then provided. More detailed reports are proposed on the various issues: first, analysis of the chain value, status of the sector in France and international benchmark; secondly, an assessment of the support policy through an assessment, a prospective and strategy, and then a detailed discussion of macro-economic spin-off and of jobs in the sector on the long term in association with wind energy development. A third part proposes a presentation of ADEME's strategy and action plan in favour of wind energy. Finally, a set of appendices contains presentations of survey questionnaires and of survey result processing, presentations of results regarding actors and countries, and presentation of modelling methodologies

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

Directory of Open Access Journals (Sweden)

Sam Illingworth

2017-06-01

Full Text Available Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

Science.gov (United States)

Provencher, Steeve; Archer, Stephen L; Ramirez, F Daniel; Hibbert, Benjamin; Paulin, Roxane; Boucherat, Olivier; Lacasse, Yves; Bonnet, Sébastien

2018-03-30

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from

Ammonia synthesis from N2 and H2O using a lithium cycling electrification strategy at atmospheric pressure

DEFF Research Database (Denmark)

McEnaney, Joshua M.; Singh, Aayush R.; Schwalbe, Jay A.

2017-01-01

Ammonia production is imperative to providing food for a growing world population. However, the primary method of synthetic ammonia production, the Haber Bosch process, is resource demanding and unsustainable. Here we report a novel ammonia production strategy, exemplified in an electrochemical...... lithium cycling process, which provides a pathway to sustainable ammonia synthesis via the ability to directly couple to renewable sources of electricity and can facilitate localized production. Whereas traditional aqueous electrochemical approaches are typically dominated by the hydrogen evolution...... reaction (HER), we are able to circumvent the HER by using a stepwise approach which separates the reduction of N2 from subsequent protonation to NH3, thus our synthesis method is predominantly selective for ammonia production. Density functional theory calculations for thermodynamic and diffusion energy...

Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics.

Science.gov (United States)

Jain, Shweta; Khaiser, Imran M; Thakur, Sophia; Jain, Shikha

2014-05-01

Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases.

Noncovalent synthesis of protein dendrimers

NARCIS (Netherlands)

Lempens, E.H.M.; Baal, van I.; Dongen, van J.L.J.; Hackeng, T.M.; Merkx, M.; Meijer, E.W.

2009-01-01

The covalent synthesis of complex biomolecular systems such as multivalent protein dendrimers often proceeds with low efficiency, thereby making alternative strategies based on noncovalent chemistry of high interest. Here, the synthesis of protein dendrimers using a strong but noncovalent

Therapeutic Strategies for Hereditary Kidney Cancer.

Science.gov (United States)

Sidana, Abhinav; Srinivasan, Ramaprasad

2016-08-01

The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.

Imaging of Protein Synthesis: In Vitro and In Vivo Evaluation of Sc-44-DOTA-Puromycin

Czech Academy of Sciences Publication Activity Database

Eigner, Sebastian; Beckford, Denis R.; Fellner, M.; Loktionova, N.; Piel, M.; Lebeda, Ondřej; Rosch, F.; Ross, T. L.; Eigner-Henke, Kateřina

2013-01-01

Roč. 15, č. 1 (2013), s. 79-86 ISSN 1536-1632 R&D Projects: GA MŠk 2B06165 Institutional support: RVO:61389005 Keywords : protein synthesis * Scandium-44 * DOTA-Pur * therapy control * mu PET * preclinical imaging Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.869, year: 2013 http://link.springer.com/content/pdf/10.1007%2Fs11307-012-0561-3

Protecting-group-free synthesis of taiwaniaquinone H using a one-pot thermal ring expansion/4π-electrocyclization strategy.

Science.gov (United States)

Yan, Xiuxiang; Hu, Xiangdong

2014-06-06

A strategy to the 6-5-6 tricyclic scaffold of taiwaniaquinoids was established on the basis of a one-pot thermal ring expansion/4π-electrocyclization process. The efficiency of this methodology has been demonstrated through its application in the total synthesis of taiwaniaquinone H, which has been accomplished in three steps and 14% overall yield in a protecting-group-free manner starting from commercially available materials.

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis.

Science.gov (United States)

Wring, Stephen A; Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

2017-04-01

SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC 0-∞ ) and C max SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices C max /MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC 0-24 , was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. Copyright © 2017 Wring et al.

Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

Science.gov (United States)

Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

2017-01-01

ABSTRACT SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and Cmax. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices Cmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. PMID:28137806

Kinetic modeling in pre-clinical positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Kuntner, Claudia [AIT Austrian Institute of Technology GmbH, Seibersdorf (Austria). Biomedical Systems, Health and Environment Dept.

2014-07-01

Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges of deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data.

Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

Science.gov (United States)

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

2016-01-01

The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

Recent progress in the direct synthesis of hierarchical zeolites: synthetic strategies and characterization methods

KAUST Repository

Liu, Zhaohui

2017-06-16

Hierarchically structured zeolites combine the merits of microporous zeolites and mesoporous materials to offer enhanced molecular diffusion and mass transfer without compromising the inherent catalytic activities and selectivity of zeolites. This short review gives an introduction to the synthesis strategies for hierarchically structured zeolites with emphasis on the latest progress in the route of ‘direct synthesis’ using various templates. Several characterization methods that allow us to evaluate the ‘quality’ of complex porous structures are also introduced. At the end of this review, an outlook is given to discuss some critical issues and challenges regarding the development of novel hierarchically structured zeolites as well as their applications.

Rigor or mortis: best practices for preclinical research in neuroscience.

Science.gov (United States)

Steward, Oswald; Balice-Gordon, Rita

2014-11-05

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Au-HKUST-1 Composite Nanocapsules: Synthesis with a Coordination Replication Strategy and Catalysis on CO Oxidation.

Science.gov (United States)

Liu, Yongxin; Zhang, Jiali; Song, Lingxiao; Xu, Wenyuan; Guo, Zanru; Yang, Xiaomin; Wu, Xiaoxin; Chen, Xi

2016-09-07

A novel coordination replication of Cu2O redox-template strategy is reported to efficiently fabricate Au-HKUST-1 composite nanocapsule, with a HKUST-1 sandwich shell and an embedded Au nanoparticles layer. The novel synthesis procedure involves forming Au nanoparticles on the surface of Cu2O, transforming partial Cu2O into HKUST-1 shell via coordination replication, and removing the residual Cu2O by acid. The as-prepared Au-HKUST-1 composite nanocapsules displayed high catalytic activity on CO oxidation.

Synthesis imaging in radio astronomy

International Nuclear Information System (INIS)

Perley, R.A.; Schwab, F.R.; Bridle, A.H.

1989-01-01

Recent advances in techniques and instrumentation for radio synthesis imaging in astronomy are discussed in a collection of review essays. Topics addressed include coherence in radio astronomy, the interferometer in practice, primary antenna elements, cross correlators, calibration and editing, sensitivity, deconvolution, self-calibration, error recognition, and image analysis. Consideration is given to wide-field imaging (bandwidth and time-average smearing, noncoplanar arrays, and mosaicking), high-dynamic-range imaging, spectral-line imaging, VLBI, solar imaging with a synthesis telescope, synthesis imaging of spatially coherent objects, noise in images of very bright sources, synthesis observing strategies, and the design of aperture-synthesis arrays

Marker for the pre-clinical development of bone substitute materials

Directory of Open Access Journals (Sweden)

de Wild Michael

2017-09-01

Full Text Available Thin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting. The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

[Impact of microdose clinical trials in the preclinical stage].

Science.gov (United States)

Kim, Soonih

2014-01-01

A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinoma.

Science.gov (United States)

Galal El-Shemi, A; Mohammed Ashshi, A; Oh, E; Jung, B-K; Basalamah, M; Alsaegh, A; Yun, C-O

2018-01-01

Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.

Effects of spatial and spectral frequencies on wide-field functional imaging (wifi) characterization of preclinical breast cancer models

Science.gov (United States)

Moy, Austin; Kim, Jae G.; Lee, Eva Y. H. P.; Choi, Bernard

2010-02-01

A common strategy to study breast cancer is the use of the preclinical model. These models provide a physiologically relevant and controlled environment in which to study both response to novel treatments and the biology of the cancer. Preclinical models, including the spontaneous tumor model and mammary window chamber model, are very amenable to optical imaging and to this end, we have developed a wide-field functional imaging (WiFI) instrument that is perfectly suited to studying tumor metabolism in preclinical models. WiFI combines two optical imaging modalities, spatial frequency domain imaging (SFDI) and laser speckle imaging (LSI). Our current WiFI imaging protocol consists of multispectral imaging in the near infrared (650-980 nm) spectrum, over a wide (7 cm x 5 cm) field of view. Using SFDI, the spatially-resolved reflectance of sinusoidal patterns projected onto the tissue is assessed, and optical properties of the tissue are determined, which are then used to extract tissue chromophore concentrations in the form of oxy-, deoxy-, and total hemoglobin concentrations, and percentage of lipid and water. In the current study, we employ Monte Carlo simulations of SFDI light propagation in order to characterize the penetration depth of light in both the spontaneous tumor model and mammary window chamber model. Preliminary results suggest that different spatial frequency and wavelength combinations have different penetration depths, suggesting the potential depth sectioning capability of the SFDI component of WiFI.

Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials.

Science.gov (United States)

Gdowski, Andrew; Johnson, Kaitlyn; Shah, Sunil; Gryczynski, Ignacy; Vishwanatha, Jamboor; Ranjan, Amalendu

2018-02-12

The process of optimization and fabrication of nanoparticle synthesis for preclinical studies can be challenging and time consuming. Traditional small scale laboratory synthesis techniques suffer from batch to batch variability. Additionally, the parameters used in the original formulation must be re-optimized due to differences in fabrication techniques for clinical production. Several low flow microfluidic synthesis processes have been reported in recent years for developing nanoparticles that are a hybrid between polymeric nanoparticles and liposomes. However, use of high flow microfluidic synthetic techniques has not been described for this type of nanoparticle system, which we will term as nanolipomer. In this manuscript, we describe the successful optimization and functional assessment of nanolipomers fabricated using a microfluidic synthesis method under high flow parameters. The optimal total flow rate for synthesis of these nanolipomers was found to be 12 ml/min and flow rate ratio 1:1 (organic phase: aqueous phase). The PLGA polymer concentration of 10 mg/ml and a DSPE-PEG lipid concentration of 10% w/v provided optimal size, PDI and stability. Drug loading and encapsulation of a representative hydrophobic small molecule drug, curcumin, was optimized and found that high encapsulation efficiency of 58.8% and drug loading of 4.4% was achieved at 7.5% w/w initial concentration of curcumin/PLGA polymer. The final size and polydispersity index of the optimized nanolipomer was 102.11 nm and 0.126, respectively. Functional assessment of uptake of the nanolipomers in C4-2B prostate cancer cells showed uptake at 1 h and increased uptake at 24 h. The nanolipomer was more effective in the cell viability assay compared to free drug. Finally, assessment of in vivo retention in mice of these nanolipomers revealed retention for up to 2 h and were completely cleared at 24 h. In this study, we have demonstrated that a nanolipomer formulation can be successfully

Learning style preferences: A study of pre-clinical medical students in Barbados

Science.gov (United States)

OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

2017-01-01

Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist

Learning style preferences: A study of pre-clinical medical students in Barbados.

Science.gov (United States)

Ojeh, Nkemcho; Sobers-Grannum, Natasha; Gaur, Uma; Udupa, Alaya; Majumder, Md Anwarul Azim

2017-10-01

Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students' learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching

Learning style preferences: A study of Pre-clinical Medical Students in Barbados

Directory of Open Access Journals (Sweden)

NKEMCHO OJEH

2017-10-01

Full Text Available Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V, aural (A, read/write (R and kinesthetic (K] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to preclinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5% and females (60.0%, with tetramodal being the most common. Read/write (33.8% followed by kinesthetic (32.5% were the most common learning style preferences. The sensory modality preference for females was read/write (34.2% and for males it was kinesthetic (40.5%. Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might

Surgeon Involvement in Pre-Clinical Medical Education: Attitudes of Directors of Education

Directory of Open Access Journals (Sweden)

Simon Turner

2012-04-01

Full Text Available Background: Application rates to surgical residencies have shown a downward trend recently. Introducing students to surgeons early in medical school can increase interest in surgery as a career and enhance the instruction of important surgical topics. Directors of undergraduate medical education have unique insight and influence regarding the participation of surgeons in pre-clinical education. Methods: To understand the attitudes of these educators towards surgeons as teachers in pre-clinical programs, a survey was administered to the directors of undergraduate medical education at each of the English-language medical schools in Canada. Results: Educators estimate the participation of surgeons in all categories of pre-clinical education to be low, despite being valuable, and think that it should be increased. The most significant barrier to participation identified was a lack of surgeons’ time. Conclusions: Despite the value of surgeons participating in pre-clinical education, their rate of participation is low. Steps should be taken to facilitate the involvement of surgeons in this phase of education, which may lead to improved education for students and increased student interest in surgery residencies.

Catalytic synthesis of enantiopure mixed diacylglycerols - synthesis of a major M. tuberculosis phospholipid and platelet activating factor

NARCIS (Netherlands)

Fodran, Peter; Minnaard, Adriaan J.

2013-01-01

An efficient catalytic one-pot synthesis of TBDMS-protected diacylglycerols has been developed, starting from enantiopure glycidol. Subsequent migration-free deprotection leads to stereo- and regiochemically pure diacylglycerols. This novel strategy has been applied to the synthesis of a major

Peptide Macrocycles Featuring a Backbone Secondary Amine: A Convenient Strategy for the Synthesis of Lipidated Cyclic and Bicyclic Peptides on Solid Support

DEFF Research Database (Denmark)

Oddo, Alberto; Münzker, Lena; Hansen, Paul Robert

2015-01-01

A convenient strategy for the on-resin synthesis of macrocyclic peptides (3- to 13-mers) via intramolecular halide substitution by a diamino acid is described. The method is compatible with standard Fmoc/tBu SPPS and affords a tail-to-side-chain macrocyclic peptide featuring an endocyclic secondary...

Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol.

Science.gov (United States)

Suen, Colin M; Zhai, Alex; Lalu, Manoj M; Welsh, Christopher; Levac, Brendan M; Fergusson, Dean; McIntyre, Lauralyn; Stewart, Duncan J

2016-05-25

Pulmonary arterial hypertension (PAH) is a rare disease (15 cases per million) that is characterized by widespread loss of the pulmonary microcirculation and elevated pulmonary vascular resistance leading to pathological right ventricular remodeling and ultimately right heart failure. Regenerative cell therapies (i.e., therapies involving cells with stem or progenitor-like properties) could potentially restore the effective lung microcirculation and provide a curative therapy for PAH. Preclinical evidence suggests that regenerative cell therapy using endothelial progenitor cells or mesenchymal stem cells may be beneficial in the treatment of PAH. These findings have led to the completion of a small number of human clinical trials, albeit with modest effect compared to animal studies. The objective of this systematic review is to compare the efficacy and safety of regenerative cell therapies in preclinical models of PAH as well as assess study quality to inform future clinical studies. We will include preclinical studies of PAH in which a regenerative cell type was administered and outcomes compared to a disease control. The primary outcome will be pulmonary hemodynamics as assessed by measurement of right ventricular systolic pressure and/or mean pulmonary arterial pressure. Secondary outcomes will include mortality, survival, right ventricular remodeling, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary acceleration time, tricuspid annular systolic excursion, and right ventricular wall thickness. Electronic searches of MEDLINE and EMBASE databases will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, and

Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

Directory of Open Access Journals (Sweden)

Aurel Popa-Wagner

2018-01-01

Full Text Available The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases.

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

Science.gov (United States)

Wu, Fan; Bansal, Loveleena; Bradshaw‐Pierce, Erica; Chan, Jason R.; Liederer, Bianca M.; Mettetal, Jerome T.; Schroeder, Patricia; Schuck, Edgar; Tsai, Alice; Xu, Christine; Chimalakonda, Anjaneya; Le, Kha; Penney, Mark; Topp, Brian; Yamada, Akihiro

2018-01-01

A cross‐industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering. PMID:29349875

At the Crossroads of Clinical and Preclinical Research for Muscular Dystrophy-Are We Closer to Effective Treatment for Patients?

Science.gov (United States)

Gawlik, Kinga I

2018-05-16

Among diseases affecting skeletal muscle, muscular dystrophy is one of the most devastating and complex disorders. The term 'muscular dystrophy' refers to a heterogeneous group of genetic diseases associated with a primary muscle defect that leads to progressive muscle wasting and consequent loss of muscle function. Muscular dystrophies are accompanied by numerous clinical complications and abnormalities in other tissues that cause extreme discomfort in everyday life. The fact that muscular dystrophy often takes its toll on babies and small children, and that many patients die at a young age, adds to the cruel character of the disease. Clinicians all over the world are facing the same problem: they have no therapy to offer except for symptom-relieving interventions. Patients, their families, but also clinicians, are in urgent need of an effective cure. Despite advances in genetics, increased understanding of molecular mechanisms underlying muscle disease, despite a sweeping range of successful preclinical strategies and relative progress of their implementation in the clinic, therapy for patients is currently out of reach. Only a greater comprehension of disease mechanisms, new preclinical studies, development of novel technologies, and tight collaboration between scientists and physicians can help improve clinical treatment. Fortunately, inventiveness in research is rapidly extending the limits and setting new standards for treatment design. This review provides a synopsis of muscular dystrophy and considers the steps of preclinical and clinical research that are taking the muscular dystrophy community towards the fundamental goal of combating the traumatic disease.

Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy

International Nuclear Information System (INIS)

Krause, Mechthild; Zips, Daniel; Thames, Howard D.; Kummermehr, Johann; Baumann, Michael

2006-01-01

The combination of molecular-targeted agents with irradiation is a highly promising avenue for cancer research and patient care. Molecular-targeted agents are in themselves not curative in solid tumours, whereas radiotherapy is highly efficient in eradicating tumour stem cells. Recurrences after high-dose radiotherapy are caused by only one or few surviving tumour stem cells. Thus, even if a novel agent has the potential to kill only few tumour stem cells, or if it interferes in mechanisms of radioresistance of tumours, combination with radiotherapy may lead to an important improvement in local tumour control and survival. To evaluate the effects of novel agents combined with radiotherapy, it is therefore necessary to use experimental endpoints which reflect the killing of tumour stem cells, in particular tumour control assays. Such endpoints often do not correlate with volume-based parameters of tumour response such as tumour regression and growth delay. This calls for radiotherapy specific research strategies in the preclinical testing of novel anti-cancer drugs, which in many aspects are different from research approaches for medical oncology

Common data elements for preclinical epilepsy research: Standards for data collection and reporting. A TASK3 report of the AES/ILAE Translational Task Force of the ILAE.

Science.gov (United States)

Harte-Hargrove, Lauren C; French, Jacqueline A; Pitkänen, Asla; Galanopoulou, Aristea S; Whittemore, Vicky; Scharfman, Helen E

2017-11-01

The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Reproducibility of preclinical animal research improves with heterogeneity of study samples

Science.gov (United States)

Vogt, Lucile; Sena, Emily S.; Würbel, Hanno

2018-01-01

Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research. PMID:29470495

TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

Science.gov (United States)

Brabetz, Sebastian; Schmidt, Christin; Groebner, Susanne N.; Mack, Norman; Seker-Cin, Huriye; Jones, David T.W.; Chavez, Lukas; Milde, Till; Witt, Olaf; Leary, Sarah E.; Li, Xiao-Nan; Wechsler-Reya, Robert J.; Olson, James M.; Pfister, Stefan M.; Kool, Marcel

2017-01-01

Abstract Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for

Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

Science.gov (United States)

Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

2016-05-01

Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

Visualization, imaging and new preclinical diagnostics in radiation oncology

International Nuclear Information System (INIS)

Cyran, Clemens C; Reiser, Maximilian F; Belka, Claus; Niyazi, Maximilian; Paprottka, Philipp M; Eisenblätter, Michel; Clevert, Dirk A; Rist, Carsten; Nikolaou, Konstantin; Lauber, Kirsten; Wenz, Frederik; Hausmann, Daniel

2014-01-01

Innovative strategies in cancer radiotherapy are stimulated by the growing knowledge on cellular and molecular tumor biology, tumor pathophysiology, and tumor microenvironment. In terms of tumor diagnostics and therapy monitoring, the reliable delineation of tumor boundaries and the assessment of tumor heterogeneity are increasingly complemented by the non-invasive characterization of functional and molecular processes, moving preclinical and clinical imaging from solely assessing tumor morphology towards the visualization of physiological and pathophysiological processes. Functional and molecular imaging techniques allow for the non-invasive characterization of tissues in vivo, using different modalities, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) and optical imaging (OI). With novel therapeutic concepts combining optimized radiotherapy with molecularly targeted agents focusing on tumor cell proliferation, angiogenesis, and cell death, the non-invasive assessment of tumor microcirculation and tissue water diffusion, together with strategies for imaging the mechanisms of cellular injury and repair is of particular interest. Characterizing the tumor microenvironment prior to and in response to irradiation will help to optimize the outcome of radiotherapy. These novel concepts of personalized multi-modal cancer therapy require careful pre-treatment stratification as well as a timely and efficient therapy monitoring to maximize patient benefit on an individual basis. Functional and molecular imaging techniques are key in this regard to open novel opportunities for exploring and understanding the underlying mechanisms with the perspective to optimize therapeutic concepts and translate them into a personalized form of radiotherapy in the near future

Dengue Virus Selectively Annexes Endoplasmic Reticulum-Associated Translation Machinery as a Strategy for Co-opting Host Cell Protein Synthesis.

Science.gov (United States)

Reid, David W; Campos, Rafael K; Child, Jessica R; Zheng, Tianli; Chan, Kitti Wing Ki; Bradrick, Shelton S; Vasudevan, Subhash G; Garcia-Blanco, Mariano A; Nicchitta, Christopher V

2018-04-01

A primary question in dengue virus (DENV) biology is the molecular strategy for recruitment of host cell protein synthesis machinery. Here, we combined cell fractionation, ribosome profiling, and transcriptome sequencing (RNA-seq) to investigate the subcellular organization of viral genome translation and replication as well as host cell translation and its response to DENV infection. We report that throughout the viral life cycle, DENV plus- and minus-strand RNAs were highly partitioned to the endoplasmic reticulum (ER), identifying the ER as the primary site of DENV translation. DENV infection was accompanied by an ER compartment-specific remodeling of translation, where ER translation capacity was subverted from host transcripts to DENV plus-strand RNA, particularly at late stages of infection. Remarkably, translation levels and patterns in the cytosol compartment were only modestly affected throughout the experimental time course of infection. Comparisons of ribosome footprinting densities of the DENV plus-strand RNA and host mRNAs indicated that DENV plus-strand RNA was only sparsely loaded with ribosomes. Combined, these observations suggest a mechanism where ER-localized translation and translational control mechanisms, likely cis encoded, are used to repurpose the ER for DENV virion production. Consistent with this view, we found ER-linked cellular stress response pathways commonly associated with viral infection, namely, the interferon response and unfolded protein response, to be only modestly activated during DENV infection. These data support a model where DENV reprograms the ER protein synthesis and processing environment to promote viral survival and replication while minimizing the activation of antiviral and proteostatic stress response pathways. IMPORTANCE DENV, a prominent human health threat with no broadly effective or specific treatment, depends on host cell translation machinery for viral replication, immune evasion, and virion biogenesis. The

Targeted therapies for non-small-cell lung cancer: biology, rationale, and preclinical results from a radiation oncology perspective

International Nuclear Information System (INIS)

Raben, David; Helfrich, Barb; Bunn, Paul A.

2004-01-01

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small-cell lung cancers (NSCLCs). This presents an opportune target for new treatment strategies designed to selectively interfere with the cancer cell growth cycle. Recent investigations into the biology of the EGFR and its downstream signaling pathways have reminded us of the complexity of cancer cell communications from the cytoplasm to the nucleus. Multiple pathways are activated with stimulation of the autocrine and paracrine EGFR loop, from the ras-raf-MEK activation of ERK 1/2 to the P13K-Akt pathway, each playing an important role in cancer cell survival, invasion, and angiogenesis. Preclinical studies have demonstrated that molecules targeting the EGFR, either through extracellular blockade or intracellular interference with the EGFR-associated tyrosine kinase, reversibly or irreversibly, inhibit cancer cell growth. Potent antitumor effects have been observed in human tumor xenograft models. Preclinical studies have also demonstrated cooperative effects when anti-EGFR agents are combined with radiation or chemotherapy. Many of these agents have now entered into advanced human clinical trials with modest dose-related toxicity despite chronic administration. Encouraging response rates with single-agent targeted therapy have been reported in heavily pretreated patients with advanced NSCLC. In addition, agents targeting the angiogenic pathway, which plays a key role in the regulation of angiogenesis, may play an important role in enhancing the efficacy of anti-EGFR agents. This article will focus on the biology, rationale, and preclinical studies with targeted anti-EGFR and antiangiogenic therapies for the management of NSCLC

Identification of new epilepsy treatments: issues in preclinical methodology.

Science.gov (United States)

Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J; Moshé, Solomon L; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L; Pitkänen, Asla; Stables, James; White, H Steve; O'Brien, Terence J; Simonato, Michele

2012-03-01

Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

Science.gov (United States)

Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

2015-01-01

High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

A cost-effective simulation curriculum for preclinical endodontics.

Science.gov (United States)

Pileggi, Roberta; Glickman, Gerald N

2004-02-01

A challenge in contemporary dental education is to achieve a smooth transition from preclinical teaching environments to patient-care clinics in a cost-effective manner. The preclinical endodontic courses at The University of Texas, Dental Branch at Houston provide a unique learning environment that enables the student to perform endodontic treatment on extracted teeth in a typodont, and be involved in diagnosis and treatment-planning discussions. The specially designed stone typodont used has built-in radiographic capability, and is mounted at each chair in the clinic. During each preclinical session, students are assigned clinical cubicles and proper aseptic protocol is followed. Students are required to wear gloves, masks and eyewear, and place a rubber dam during treatment. Written self-assessment evaluations based upon prescribed criteria are utilised; feedback is given by faculty composed of both full-time endodontists and graduate students who periodically rotate and are calibrated on a regular basis. In the lecture phase, clinical case scenarios are presented to reinforce concepts of diagnosis and emergency care and to help integrate endodontics with other disciplines; a Socratic-like teaching style is established by the faculty facilitator to create an environment for developing critical-thinking and problem-solving skills. The overall feedback from graduating students has been very positive. Advantages of this format are an easier transition to patient management, a more keen interest in specialsation and a perceived increase in levels of confidence.

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

International Nuclear Information System (INIS)

Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G.; Heinen, U.; Reitmeier, A.

2015-01-01

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

Energy Technology Data Exchange (ETDEWEB)

Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Weber, O. [Philips Medical Systems DMC GmbH, Hamburg (Germany); Heinen, U. [Bruker BioSpin MRI GmbH, Ettlingen (Germany); Reitmeier, A. [Medical Center Hamburg-Eppendorf, Hamburg (Germany). Animal Facility; Knopp, T. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Hamburg University of Technology, Hamburg (Germany)

2015-05-15

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

Science.gov (United States)

Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

2017-07-01

Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spatial reversal learning in preclinical scrapie-inoculated mice.

Science.gov (United States)

Lysons, A M; Woollard, S J

1996-04-10

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

Synthesis of S-linked cello-oligosaccharides

DEFF Research Database (Denmark)

Nami, Faranak

, structurally well-defined oligosaccharides made via chemical synthesis can be used as models for the more complex polysaccharides in the investigation of properties such as polysaccharide biosynthesis, degradation and protein-carbohydrate interactions. For this purpose, non-natural substrate analogues forming...... irreversible binding to the enzyme can be employed. Thio-oligosaccharides represent the largest class of specific non-natural inhibitors for glycanases. In this thesis the chemical synthesis of some thio-glucans is presented. The formation of thio-linkages using a classical and non-classical method...... is investigated. Two strategies, relying on either a linear or a convergent strategy, have been employed in the synthesis towards two target molecules. Furthermore, the activity of a glycosyltransferase responsible for the elongation of a pectic polysaccharide has been investigated and partially characterized....

Concise synthesis of new bridged-nicotine analogues

DEFF Research Database (Denmark)

Crestey, François; Hooyberghs, Geert; Kristensen, Jesper Langgaard

2012-01-01

This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively.......This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively....

Hydrothermal synthetic strategies of inorganic semiconducting nanostructures.

Science.gov (United States)

Shi, Weidong; Song, Shuyan; Zhang, Hongjie

2013-07-07

Because of their unique chemical and physical properties, inorganic semiconducting nanostructures have gradually played a pivotal role in a variety of research fields, including electronics, chemical reactivity, energy conversion, and optics. A major feature of these nanostructures is the quantum confinement effect, which strongly depends on their size, shape, crystal structure and polydispersity. Among all developed synthetic methods, the hydrothermal method based on a water system has attracted more and more attention because of its outstanding advantages, such as high yield, simple manipulation, easy control, uniform products, lower air pollution, low energy consumption and so on. Precise control over the hydrothermal synthetic conditions is a key to the success of the preparation of high-quality inorganic semiconducting nanostructures. In this review, only the representative hydrothermal synthetic strategies of inorganic semiconducting nanostructures are selected and discussed. We will introduce the four types of strategies based on exterior reaction system adjustment, namely organic additive- and template-free hydrothermal synthesis, organic additive-assisted hydrothermal synthesis, template-assisted hydrothermal synthesis and substrate-assisted hydrothermal synthesis. In addition, the two strategies based on exterior reaction environment adjustment, including microwave-assisted and magnetic field-assisted hydrothermal synthesis, will be also described. Finally, we conclude and give the future prospects of this research area.

Beyond "implementation strategies": classifying the full range of strategies used in implementation science and practice.

Science.gov (United States)

Leeman, Jennifer; Birken, Sarah A; Powell, Byron J; Rohweder, Catherine; Shea, Christopher M

2017-11-03

Strategies are central to the National Institutes of Health's definition of implementation research as "the study of strategies to integrate evidence-based interventions into specific settings." Multiple scholars have proposed lists of the strategies used in implementation research and practice, which they increasingly are classifying under the single term "implementation strategies." We contend that classifying all strategies under a single term leads to confusion, impedes synthesis across studies, and limits advancement of the full range of strategies of importance to implementation. To address this concern, we offer a system for classifying implementation strategies that builds on Proctor and colleagues' (2013) reporting guidelines, which recommend that authors not only name and define their implementation strategies but also specify who enacted the strategy (i.e., the actor) and the level and determinants that were targeted (i.e., the action targets). We build on Wandersman and colleagues' Interactive Systems Framework to distinguish strategies based on whether they are enacted by actors functioning as part of a Delivery, Support, or Synthesis and Translation System. We build on Damschroder and colleague's Consolidated Framework for Implementation Research to distinguish the levels that strategies target (intervention, inner setting, outer setting, individual, and process). We then draw on numerous resources to identify determinants, which are conceptualized as modifiable factors that prevent or enable the adoption and implementation of evidence-based interventions. Identifying actors and targets resulted in five conceptually distinct classes of implementation strategies: dissemination, implementation process, integration, capacity-building, and scale-up. In our descriptions of each class, we identify the level of the Interactive System Framework at which the strategy is enacted (actors), level and determinants targeted (action targets), and outcomes used to

Web-Mediated Knowledge Synthesis for Educators

Science.gov (United States)

DeSchryver, Michael

2015-01-01

Ubiquitous and instant access to information on the Web is challenging what constitutes 21st century literacies. This article explores the notion of Web-mediated knowledge synthesis, an approach to integrating Web-based learning that may result in generative synthesis of ideas. This article describes the skills and strategies that may support…

Lessons from a pilot project in cognitive task analysis: the potential role of intermediates in preclinical teaching in dental education.

Science.gov (United States)

Walker, Judith; von Bergmann, HsingChi

2015-03-01

The purpose of this study was to explore the use of cognitive task analysis to inform the teaching of psychomotor skills and cognitive strategies in clinical tasks in dental education. Methods used were observing and videotaping an expert at one dental school thinking aloud while performing a specific preclinical task (in a simulated environment), interviewing the expert to probe deeper into his thinking processes, and applying the same procedures to analyze the performance of three second-year dental students who had recently learned the analyzed task and who represented a spectrum of their cohort's ability to undertake the procedure. The investigators sought to understand how experts (clinical educators) and intermediates (trained students) overlapped and differed at points in the procedure that represented the highest cognitive load, known as "critical incidents." Findings from this study and previous research identified possible limitations of current clinical teaching as a result of expert blind spots. These findings coupled with the growing evidence of the effectiveness of peer teaching suggest the potential role of intermediates in helping novices learn preclinical dentistry tasks.

Preclinical diagnosis of Alzheimer's disease: Prevention or prediction?

Directory of Open Access Journals (Sweden)

Ricardo Nitrini

Full Text Available Abstract The diagnosis of Alzheimer's disease (AD for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer's Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD's dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD.

Development of computational small animal models and their applications in preclinical imaging and therapy research

NARCIS (Netherlands)

Xie, Tianwu; Zaidi, Habib

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal

77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

Science.gov (United States)

2012-11-29

...] Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy... Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products,'' dated November... Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product areas covered by this...

Preclinical evaluation of strontium-containing bioactive bone cement

International Nuclear Information System (INIS)

Li, Zhaoyang; Yuan, Ning; Lam, Raymond Wing Moon; Cui, Zhenduo; Yang, Xianjin; Lu, William Weijia

2013-01-01

Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC

Preclinical evaluation of strontium-containing bioactive bone cement

Energy Technology Data Exchange (ETDEWEB)

Li, Zhaoyang, E-mail: lizy@hku.hk [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Yuan, Ning [Department of Laboratory Medicine, Tianjin Chest Hospital, Tianjin 300051 (China); Lam, Raymond Wing Moon [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Cui, Zhenduo; Yang, Xianjin [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Lu, William Weijia, E-mail: wwlu@hku.hk [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China)

2013-12-01

Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC.

Synthesis-Spectroscopy Roadmap Problems: Discovering Organic Chemistry

Science.gov (United States)

Kurth, Laurie L.; Kurth, Mark J.

2014-01-01

Organic chemistry problems that interrelate and integrate synthesis with spectroscopy are presented. These synthesis-spectroscopy roadmap (SSR) problems uniquely engage second-year undergraduate organic chemistry students in the personal discovery of organic chemistry. SSR problems counter the memorize-or-bust strategy that many students tend to…

Is performance in pre-clinical assessment a good predictor of the final Doctor of Medicine grade?

Science.gov (United States)

Al-Wardy, Nadia M; Rizvi, Syed G; Bayoumi, Riad A

2009-12-01

To investigate if any correlation exists between students' grades on their final doctor of Medicine (MD) assessment and their overall preclinical grade point average (GPA) and its component parts. Student data available from the Deanship of Admissions and Registration were analyzed. Pearson correlation coefficient was obtained to assess the degree of linear relationship between performance in the preclinical and the MD assessment of 529 students who graduated from the College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, Oman from June 1998 to June 2005. Simple and multiple regression analyses were performed to evaluate individual and combined impact of the preclinical courses' grades on MD grades. Preclinical GPA correlated highly with MD GPA (r=0.641). The science component taught early in the preclinical phase correlated more strongly (r=0.457) than student electives (r=0.246). This correlation was better in the good English group. Students' performance, however, was best in electives, but worst in English. Most students who had low MD GPA (2.5, and limiting the credit hour requirement of electives by the College seems to be justified.

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

Directory of Open Access Journals (Sweden)

Helen B. Stone

2016-02-01

Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

LENUS (Irish Health Repository)

Rajendran, Simon

2011-04-01

Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in

Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

LENUS (Irish Health Repository)

Rajendran, Simon

2012-01-31

Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in

Preclinical efficacy and safety of herbal formulation for management ...

African Journals Online (AJOL)

Preclinical efficacy and safety of herbal formulation for management of wounds. ... The effects of the treatments on rate of wound closure, epithelialisation time ... inflammation and better tissue remodeling for rats treated with herbal product.

Content and goals of preclinical prosthodontic programs at german-language dental schools.

Science.gov (United States)

Hey, Jeremias; Stimmelmayr, Michael; Hirsch, Christian; Beuer, Florian

2014-04-01

The Association for Dental Education in Europe (ADEE) makes recommendations regarding the skills graduates of European dental schools need to achieve and advises dental schools regarding necessary changes to be made to the curriculum. In 2010 to 2011, a survey was conducted in German-language dental schools to validate the curricula and goals of preclinical prosthodontic programs with regard to laboratory work. The survey was mailed to the course instructors of the preclinical programs at 37 dental schools. Of these, 35 schools returned the completed survey, resulting in a response rate of 95%. Bent wire, wax-up exercises, metal-ceramic single crowns, fixed dental prostheses, cast metal single crowns, temporary removable dental prostheses, and full dentures were part of the dental laboratory work at most schools; however, most instructors considered laboratory work as less important, and there were few similarities among the programs in this area. According to the instructors responsible for preclinical education, honing of fine motor skills, realistic self-assessment, and the ability to work independently were the main goals of the programs. The results of this survey show that with regard to laboratory work, there were more differences than similarities among preclinical prosthodontic programs at German-language dental schools, contrary to the recommendations of the ADEE. These findings should be taken into account when program reforms are planned. © 2013 by the American College of Prosthodontists.

METHODOLOGICAL APPROACHES TO EXPERT EVALUATION OF PRECLINICAL AND CLINICAL TRIALS OF HUMAN IMMUNOGLOBULIN PRODUCTS

Directory of Open Access Journals (Sweden)

V. B. Ivanov

2017-01-01

Full Text Available The article considers the experience of Russian and leading foreign regulatory agencies in organisation and conduction of preclinical and clinical trials of human immunoglobulin products. The authors suggest a classification of human immunoglobulins and provide updated information on authorization of these products in Russia. The article summarizes methodological approaches, basic scientific principles and criteria relating to expert evaluation of preclinical and clinical trials of blood products. The authors further define the expert body’s requirements for data on preclinical and clinical trials of human normal immuniglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases which are submitted as part of applications for marketing authorization or marketing authorization variation. The article suggests programs of preclinical and clinical trials for human normal immunoglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases that are aligned with the Russian legislation and Eurasian Economic Union’s regulations on medicines circulation, and have been elaborated with respect to the guidelines of the European Medicines Agency.

The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

Science.gov (United States)

Chen, Zhengming; Yang, Ji; Skolnick, Phil

The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

The role of radiolabelled compounds in preclinical drug development

International Nuclear Information System (INIS)

Hawkins, D.R.

1988-01-01

The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

Pre-Clinical Medical Students' Exposure to and Attitudes Toward Pharmaceutical Industry Marketing.

Science.gov (United States)

Fein, Eric H; Vermillion, Michelle L; Uijtdehaage, Sebastian H J

2007-12-01

Background - Recent studies have examined the exposures and attitudes of physicians and third- and fourth-year medical students toward pharmaceutical industry marketing, but fewer studies have addressed these topics among pre-clinical medical students. Thus, the purpose of this study was to assess pre-clinical students' level of exposure to the pharmaceutical industry and their attitudes toward marketing. Method - First and second-year medical students at UCLA completed a 40-item survey based on previous studies. Results - Over three quarters of pre-clinical students (78.5% or 226 of 288) responded to the survey. Exposure to pharmaceutical industry marketing started very early in medical school. Most second-year students (77%) had received gifts including drug samples after three semesters. Most felt that this would not affect their future prescribing behavior. Conclusions - These findings and findings from related studies, coupled with the students' desire to learn more about the issue, suggest that an early educational intervention addressing this topic may be warranted in American medical schools.

Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

Directory of Open Access Journals (Sweden)

Susanne Krasemann

Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

A one-pot strategy for biomimetic synthesis and self-assembly of gold nanoparticles

International Nuclear Information System (INIS)

Wang Yi; Li Yuanfang; Zhao Xijuan; Huang Chengzhi; Chen Liqiang; Peng Li

2010-01-01

A simple, one-pot and controllable strategy is reported in this contribution for biomimetic synthesis and self-assembly of gold nanoparticles (Au-NPs). It involves our synthesized polyaldehyde dextran (PAD), which has been proved to be a biomacromolecule with excellent biocompatibility and biodegradability, acting as both a reducing agent and a stabilizer. The morphology of the as-prepared Au-NP assemblies can be controlled by adjusting the reaction conditions, such as the concentration of aldehyde in PAD, the reaction time and the temperature. Investigations of the mechanism suggest that stabilizers may distribute on different crystal facets of NPs non-uniformly owing to the different binding forces, and dipole-dipole interaction of NPs could be the main driving force for the assembly of Au-NPs. In addition, intermolecular hydrogen bonding interaction of stabilizers could also act as a possible driving force. The excellent biocompatibility of the Au-NP assemblies makes them promising candidates for fabricating future optical nanodevices and application in biological systems.

A one-pot strategy for biomimetic synthesis and self-assembly of gold nanoparticles

Science.gov (United States)

Wang, Yi; Chen, Li Qiang; Li, Yuan Fang; Zhao, Xi Juan; Peng, Li; Zhi Huang, Cheng

2010-07-01

A simple, one-pot and controllable strategy is reported in this contribution for biomimetic synthesis and self-assembly of gold nanoparticles (Au-NPs). It involves our synthesized polyaldehyde dextran (PAD), which has been proved to be a biomacromolecule with excellent biocompatibility and biodegradability, acting as both a reducing agent and a stabilizer. The morphology of the as-prepared Au-NP assemblies can be controlled by adjusting the reaction conditions, such as the concentration of aldehyde in PAD, the reaction time and the temperature. Investigations of the mechanism suggest that stabilizers may distribute on different crystal facets of NPs non-uniformly owing to the different binding forces, and dipole-dipole interaction of NPs could be the main driving force for the assembly of Au-NPs. In addition, intermolecular hydrogen bonding interaction of stabilizers could also act as a possible driving force. The excellent biocompatibility of the Au-NP assemblies makes them promising candidates for fabricating future optical nanodevices and application in biological systems.

Identification of new treatments for epilepsy: issues in preclinical methodology

Science.gov (United States)

Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

2013-01-01

Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

Molecular imaging: current status and emerging strategies

International Nuclear Information System (INIS)

Pysz, M.A.; Gambhir, S.S.; Willmann, J.K.

2010-01-01

In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use positron-emission tomography (PET) or single photon-emission computed tomography (SPECT)-based techniques. In ongoing preclinical research, novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multi-modality molecular imaging. Contrast-enhanced molecular ultrasound (US) with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and US imaging with molecularly-targeted microbubbles are attractive strategies as they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and US techniques involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with US. Current preclinical findings and advances in instrumentation, such as endoscopes and microcatheters, suggest that these molecular imaging methods have numerous potential clinical applications and will be translated into clinical use in the near future.

Collaborative learning in pre-clinical dental hygiene education.

Science.gov (United States)

Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

2013-04-01

Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

Science.gov (United States)

2014-01-01

Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical

Preclinical and Clinical Development of a YFV 17 D-Based Chimeric Vaccine against West Nile Virus

Directory of Open Access Journals (Sweden)

Gustavo H. Dayan

2013-12-01

Full Text Available Substantial success has been achieved in the development and implementation of West Nile (WN vaccines for horses; however, no human WN vaccines are approved. This review focuses on the construction, pre-clinical and clinical characterization of ChimeriVax-WN02 for humans, a live chimeric vaccine composed of a yellow fever (YF 17D virus in which the prM-E envelope protein genes are replaced with the corresponding genes of the WN NY99 virus. Pre-clinical studies demonstrated that ChimeriVax-WN02 was significantly less neurovirulent than YF 17D in mice and rhesus and cynomolgus monkeys. The vaccine elicited neutralizing antibody titers after inoculation in hamsters and monkeys and protected immunized animals from lethal challenge including intracerebral inoculation of high dose of WN NY99 virus. Safety, viremia and immunogenicity of ChimeriVax-WN02 were assessed in one phase I study and in two phase II clinical trials. No safety signals were detected in the three clinical trials with no remarkable differences in incidence of adverse events (AEs between vaccine and placebo recipients. Viremia was transient and the mean viremia levels were low. The vaccine elicited strong and durable neutralizing antibody and cytotoxic T cell responses. WN epidemiology impedes a classical licensure pathway; therefore, innovative licensure strategies should be explored.

Synthesis strategy: building a culturally sensitive mid-range theory of risk perception using literary, quantitative, and qualitative methods.

Science.gov (United States)

Siaki, Leilani A; Loescher, Lois J; Trego, Lori L

2013-03-01

This article presents a discussion of development of a mid-range theory of risk perception. Unhealthy behaviours contribute to the development of health inequalities worldwide. The link between perceived risk and successful health behaviour change is inconclusive, particularly in vulnerable populations. This may be attributed to inattention to culture. The synthesis strategy of theory building guided the process using three methods: (1) a systematic review of literature published between 2000-2011 targeting perceived risk in vulnerable populations; (2) qualitative and (3) quantitative data from a study of Samoan Pacific Islanders at high risk of cardiovascular disease and diabetes. Main concepts of this theory include risk attention, appraisal processes, cognition, and affect. Overarching these concepts is health-world view: cultural ways of knowing, beliefs, values, images, and ideas. This theory proposes the following: (1) risk attention varies based on knowledge of the health risk in the context of health-world views; (2) risk appraisals are influenced by affect, health-world views, cultural customs, and protocols that intersect with the health risk; (3) strength of cultural beliefs, values, and images (cultural identity) mediate risk attention and risk appraisal influencing the likelihood that persons will engage in health-promoting behaviours that may contradict cultural customs/protocols. Interventions guided by a culturally sensitive mid-range theory may improve behaviour-related health inequalities in vulnerable populations. The synthesis strategy is an intensive process for developing a culturally sensitive mid-range theory. Testing of the theory will ascertain its usefulness for reducing health inequalities in vulnerable groups. © 2012 Blackwell Publishing Ltd.

Nanocrystal conversion chemistry: A unified and materials-general strategy for the template-based synthesis of nanocrystalline solids

International Nuclear Information System (INIS)

Vasquez, Yolanda; Henkes, Amanda E.; Chris Bauer, J.; Schaak, Raymond E.

2008-01-01

The concept of nanocrystal conversion chemistry, which involves the use of pre-formed nanoparticles as templates for chemical transformation into derivative solids, has emerged as a powerful approach for designing the synthesis of complex nanocrystalline solids. The general strategy exploits established synthetic capabilities in simple nanocrystal systems and uses these nanocrystals as templates that help to define the composition, crystal structure, and morphology of product nanocrystals. This article highlights key examples of 'conversion chemistry' approaches to the synthesis of nanocrystalline solids using a variety of techniques, including galvanic replacement, diffusion, oxidation, and ion exchange. The discussion is organized according to classes of solids, highlighting the diverse target systems that are accessible using similar chemical concepts: metals, oxides, chalcogenides, phosphides, alloys, intermetallic compounds, sulfides, and nitrides. - Graphical abstract: Nanocrystal conversion chemistry uses pre-formed nanoparticles as templates for chemical transformation into derivative solids, helping to define the composition, crystal structure, and morphology of product nanocrystals that have more complex features than their precursor templates. This article highlights the application of this concept to diverse classes of solids, including metals, oxides, chalcogenides, phosphides, alloys, intermetallics, sulfides, and nitrides

Footprints of Optimal Protein Assembly Strategies in the Operonic Structure of Prokaryotes

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Jan Ewald

2015-04-01

Full Text Available In this work, we investigate optimality principles behind synthesis strategies for protein complexes using a dynamic optimization approach. We show that the cellular capacity of protein synthesis has a strong influence on optimal synthesis strategies reaching from a simultaneous to a sequential synthesis of the subunits of a protein complex. Sequential synthesis is preferred if protein synthesis is strongly limited, whereas a simultaneous synthesis is optimal in situations with a high protein synthesis capacity. We confirm the predictions of our optimization approach through the analysis of the operonic organization of protein complexes in several hundred prokaryotes. Thereby, we are able to show that cellular protein synthesis capacity is a driving force in the dissolution of operons comprising the subunits of a protein complex. Thus, we also provide a tested hypothesis explaining why the subunits of many prokaryotic protein complexes are distributed across several operons despite the presumably less precise co-regulation.

Preclinical Pharmacokinetic/Pharmacodynamic Modeling and Simulation in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

OpenAIRE

Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen JMA; Raybon, Joseph

2015-01-01

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its...

Preclinical test: bacterial reverse mutation test for 18F-fluorocholine produced in CDTN

International Nuclear Information System (INIS)

Mendes, Bruno M.; Bispo, Ana Carolina A.; Campos, Danielle C.; Silva, Juliana B.

2013-01-01

The choline labeled with fluorine-18 (18FCH) is being considered as a great importance radiopharmaceutical due to its effective detection of many type of malignant neoplasm. The research related to 18 F-fluorocholine synthesis in CDTN was initiated in 2010. In order to obtain clinical research approval, as well as to register 18 FCH for marketing, safety and efficacy preclinical testing are required. The present work evaluated the 18 FCH genotoxic potential through the bacterial reverse mutation test (Ames test) using Salmonella typhimurium TA-98, TA-100, TA-1535 and TA-1537 strains and Escherichia coli WP2 uvrA strain. The reverse mutation test in bacteria for fluorcolina was conducted in two stages. Initially the method was applied to 'cold' fluorocholine molecule (19FCH). Subsequently, the decayed product of 18 FCH synthesis was evaluated. The first step was performed in order to examine the FCH molecule mutagenicity. The second was carried out to determine the mutagenic potential of final product. All strains were tested in triplicate for each exposure concentration, in the presence and absence of metabolic activation (S-9 mix - 10%). There were no statistically significant increases in revertant colonies rate for any strains tested after their exposure to decayed 18 FCH or 19 FCH. The number of revertant colonies in positive controls was significantly higher than that observed in significant increases in revertant colonies rate for any strains tested after their exposure to decayed 18 FCH or 19 FCH. The number of revertant colonies in positive controls was significantly higher than that observed in negative controls. Based on results of this assay, 18 FCH and 19 FCH, at tested doses, were found to be non-mutagenic in bacterial reverse mutation test. (author)

A meta-analysis of the abscopal effect in preclinical models: Is the biologically effective dose a relevant physical trigger?

Directory of Open Access Journals (Sweden)

Raffaella Marconi

Full Text Available Preclinical in vivo studies using small animals are considered crucial in translational cancer research and clinical implementation of novel treatments. This is of paramount relevance in radiobiology, especially for any technological developments permitted to deliver high doses in single or oligo-fractionated regimens, such as stereotactic ablative radiotherapy (SABR. In this context, clinical success in cancer treatment needs to be guaranteed, sparing normal tissue and preventing the potential spread of disease or local recurrence. In this work we introduce a new dose-response relationship based on relevant publications concerning preclinical models with regard to delivered dose, fractionation schedule and occurrence of biological effects on non-irradiated tissue, abscopal effects.We reviewed relevant publications on murine models and the abscopal effect in radiation cancer research following PRISMA methodology. In particular, through a log-likelihood method, we evaluated whether the occurrence of abscopal effects may be related to the biologically effective dose (BED. To this aim, studies accomplished with different tumor histotypes were considered in our analysis including breast, colon, lung, fibrosarcoma, pancreas, melanoma and head and neck cancer. For all the tumors, the α / β ratio was assumed to be 10 Gy, as generally adopted for neoplastic cells.Our results support the hypothesis that the occurrence rate of abscopal effects in preclinical models increases with BED. In particular, the probability of revealing abscopal effects is 50% when a BED of 60 Gy is generated.Our study provides evidence that SABR treatments associated with high BEDs could be considered an effective strategy in triggering the abscopal effect, thus shedding light on the promising outcomes revealed in clinical practice.

Image-guided drug delivery: preclinical applications and clinical translation

NARCIS (Netherlands)

Ojha, Tarun; Rizzo, Larissa; Storm, Gerrit; Kiessling, Fabian; Lammers, Twan Gerardus Gertudis Maria

2015-01-01

Image-guided drug delivery refers to the combination of drug targeting and imaging. Preclinically, image-guided drug delivery can be used for several different purposes, including for monitoring biodistribution, target site accumulation, off-target localization, drug release and drug efficacy.

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

International Nuclear Information System (INIS)

Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

2012-01-01

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt max and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. ► Haemodynamic

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

Science.gov (United States)

Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

2014-01-01

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

The development of neural stimulators: a review of preclinical safety and efficacy studies.

Science.gov (United States)

Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

2018-05-14

Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to

Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry ...

African Journals Online (AJOL)

Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry. ... Nigerian Hospital Practice ... Abstract. Medical training provides an environment in which proper and professional attitudes towards psychiatric patients can be acquired.

Elective courses for medical students during the preclinical curriculum: a systematic review and evaluation

Directory of Open Access Journals (Sweden)

Ankit Agarwal

2015-05-01

Full Text Available Objective: Preclinical medical student electives are prevalent at medical schools across the United States, but the range of electives available and their impact on medical student education are not well described in the literature. The objective of this article is to review the literature relating to preclinical medical student electives and their impact on medical student educational outcomes. Methods: We reviewed studies that met the following criteria: English-language articles describing preclinical US-based medical electives. We used PubMed journal databases and limited our search for the time period 1999–2014. We excluded electives based in other countries or electives designed for third or fourth year students. Data abstracted included the topic of the elective, qualitative descriptions of the electives, and any associated surveys or exam data associated with the electives. Data were synthesized using descriptive tables sorting electives by broad topic. Reported outcomes and statistical methods were analyzed to assess study quality. Results: We found a wide range of subjects taught in the form of preclinical medical school electives. We identified electives in clinical skills, the humanities, student lifestyle, specialty-specific electives, and an assortment of other miscellaneous electives. Surveys and exams administered to students showed that the electives were universally well received by students. Of the 37 electives identified, 15 electives used quantitative objective assessments, such as knowledge exams, while the remaining tended to use student self-reported results. Conclusions: Preclinical medical student electives are prevalent at medical schools across the United States and have a significant impact on medical student education.

Biosafety preclinical trials of xenogenic, Allogeniec and autologous progenitor cells from fat tissue

OpenAIRE

Melikhova, Vs; Saburina, I.; Repin, V.; Novikova, N.; Murashev, A.; Orlov, A.

2008-01-01

Due to wide spread of new methods of regenerative medicine on basis of stem cells it has become increasingly necessary to establish standards of techniques using them. Preclinical trial of a new technology after receiving preliminary experiment results is a primary stage of its adoption. We carried out the experiments to assess biosafety of autogenous, allergenic and xenogeneic cultures of human and rat cells in models under standard preclinical experiments conditions used in a presentday pha...

Synthesis of S-linked oligoxylans

DEFF Research Database (Denmark)

Bonora, Beatrice

by several families of enzymes,collected under the name of Glycosyl Hydrolases (GHs). Among other methods,the use of enzyme inhibitors like thio-linked oligosaccharides has for a long timebeen a common tool to analyze and characterize these enzymes.In the present work the chemical synthesis of thio......-analogs of xylo- andarabinoxyloglycans is presented. Furthermore, the selection of a reliable method forthe incorporation of thiolinkages in the synthesis of oligoxylans is alsoinvestigated.Therefore, different strategies for assembling S-linked-disaccharides have beenapproached both involving 1-thioglycoside...... donors and thioacceptors. Advantagesand disadvantages concerning the different methods are described and evaluated inrelation to the synthesis of linear and branched oligoxylans....

Early bedside care during preclinical medical education: can technology-enhanced patient simulation advance the Flexnerian ideal?

Science.gov (United States)

Gordon, James A; Hayden, Emily M; Ahmed, Rami A; Pawlowski, John B; Khoury, Kimberly N; Oriol, Nancy E

2010-02-01

Flexner wanted medical students to study at the patient bedside-a remarkable innovation in his time-so that they could apply science to clinical care under the watchful eye of senior physicians. Ever since his report, medical schools have reserved the latter years of their curricula for such an "advanced" apprenticeship, providing clinical clerkship experiences only after an initial period of instruction in basic medical sciences. Although Flexner codified the segregation of preclinical and clinical instruction, he was committed to ensuring that both domains were integrated into a modern medical education. The aspiration to fully integrate preclinical and clinical instruction continues to drive medical education reform even to this day. In this article, the authors revisit the original justification for sequential preclinical-clinical instruction and argue that modern, technology-enhanced patient simulation platforms are uniquely powerful for fostering simultaneous integration of preclinical-clinical content in a way that Flexner would have applauded. To date, medical educators tend to focus on using technology-enhanced medical simulation in clinical and postgraduate medical education; few have devoted significant attention to using immersive clinical simulation among preclinical students. The authors present an argument for the use of dynamic robot-mannequins in teaching basic medical science, and describe their experience with simulator-based preclinical instruction at Harvard Medical School. They discuss common misconceptions and barriers to the approach, describe their curricular responses to the technique, and articulate a unifying theory of cognitive and emotional learning that broadens the view of what is possible, feasible, and desirable with simulator-based medical education.

Preclinical assessment of adjunctive tPA and DNase for peritoneal dialysis associated peritonitis.

Directory of Open Access Journals (Sweden)

Amanda L McGuire

Full Text Available A major complication of peritoneal dialysis is the development of peritonitis, which is associated with reduced technique and patient survival. The inflammatory response elicited by infection results in a fibrin and debris-rich environment within the peritoneal cavity, which may reduce the effectiveness of antimicrobial agents and predispose to recurrence or relapse of infection. Strategies to enhance responses to antimicrobial agents therefore have the potential to improve patient outcomes. This study presents pre-clinical data describing the compatibility of tPA and DNase in combination with antimicrobial agents used for the treatment of PD peritonitis. tPA and DNase were stable in standard dialysate solution and in the presence of antimicrobial agents, and were safe when given intraperitoneally in a mouse model with no evidence of local or systemic toxicity. Adjunctive tPA and DNase may have a role in the management of patients presenting with PD peritonitis.

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

Directory of Open Access Journals (Sweden)

Preeti Chhabra

2011-01-01

Full Text Available Clinical islet transplantation is a -cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the -cells regenerative capacity of stem cells.

Preclinical animal research on therapy dosimetry with dual isotopes

NARCIS (Netherlands)

M.W. Konijnenberg (Mark); M. de Jong (Marion)

2011-01-01

textabstractPreclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of

Subjective and Objective Evaluation of PBL Outcomes in Preclinical ...

African Journals Online (AJOL)

Subjective and Objective Evaluation of PBL Outcomes in Preclinical Medical Students. ... ABSTRACT: Problem based learning curriculum is widely recognized as a progressive, learner-centered, active learning approach and is currently used in the entire medical curriculum in over 10% of medical schools worldwide.

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

Science.gov (United States)

2016-01-01

Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure–activity relationship, and finally lead to the synthesis of a more potent compound. PMID:27660690

Total synthesis of putative 11-epi-lyngbouilloside aglycon

Directory of Open Access Journals (Sweden)

Amandine Kolleth

2016-08-01

Full Text Available We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.

Is medical students' moral orientation changeable after preclinical medical education?

Science.gov (United States)

Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

2012-03-01

Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

Science.gov (United States)

Ng, Samuel Y; Yoshida, Noriaki; Christie, Amanda L; Ghandi, Mahmoud; Dharia, Neekesh V; Dempster, Joshua; Murakami, Mark; Shigemori, Kay; Morrow, Sara N; Van Scoyk, Alexandria; Cordero, Nicolas A; Stevenson, Kristen E; Puligandla, Maneka; Haas, Brian; Lo, Christopher; Meyers, Robin; Gao, Galen; Cherniack, Andrew; Louissaint, Abner; Nardi, Valentina; Thorner, Aaron R; Long, Henry; Qiu, Xintao; Morgan, Elizabeth A; Dorfman, David M; Fiore, Danilo; Jang, Julie; Epstein, Alan L; Dogan, Ahmet; Zhang, Yanming; Horwitz, Steven M; Jacobsen, Eric D; Santiago, Solimar; Ren, Jian-Guo; Guerlavais, Vincent; Annis, D Allen; Aivado, Manuel; Saleh, Mansoor N; Mehta, Amitkumar; Tsherniak, Aviad; Root, David; Vazquez, Francisca; Hahn, William C; Inghirami, Giorgio; Aster, Jon C; Weinstock, David M; Koch, Raphael

2018-05-22

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

Utilization of blended learning to teach preclinical endodontics.

Science.gov (United States)

Maresca, Cristina; Barrero, Carlos; Duggan, Dereck; Platin, Enrique; Rivera, Eric; Hannum, Wallace; Petrola, Frank

2014-08-01

Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level.

Synthesis of Optimal Strategies Using HyTech

DEFF Research Database (Denmark)

Bouyer, Patricia; Cassez, Franck; Larsen, Kim Guldstrand

2005-01-01

Priced timed (game) automata extend timed (game) automata with costs on both locations and transitions. The problem of synthesizing an optimal winning strategy for a priced timed game under some hypotheses has been shown decidable in [P. Bouyer, F. Cassez, E. Fleury, and K.G. Larsen. Optimal...... strategies in priced timed game automata. Research Report BRICS RS-04-4, Denmark, Feb. 2004. Available at http://www.brics.dk/RS/04/4/]. In this paper, we present an algorithm for computing the optimal cost and for synthesizing an optimal strategy in case there exists one. We also describe the implementation...

Automated solid-phase peptide synthesis to obtain therapeutic peptides

Directory of Open Access Journals (Sweden)

Veronika Mäde

2014-05-01

Full Text Available The great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

Meta-Synthesis of Research on Information Seeking Behaviour

Science.gov (United States)

Urquhart, Christine

2011-01-01

Introduction: Meta-synthesis methods may help to make more sense of information behaviour research evidence. Aims and objectives: The objectives are to: 1) identify and examine the theoretical research strategies commonly used in information behaviour research; 2) discuss meta-synthesis methods that might be appropriate to the type of research…

In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

OpenAIRE

Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

2017-01-01

Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

The interplay between academic performance and quality of life among preclinical students.

Science.gov (United States)

Shareef, Mohammad Abrar; AlAmodi, Abdulhadi A; Al-Khateeb, Abdulrahman A; Abudan, Zainab; Alkhani, Mohammed A; Zebian, Sanderlla I; Qannita, Ahmed S; Tabrizi, Mariam J

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

Automated synthesis of an {sup 18}F-labelled pyridine-based alkylating agent for high yield oligonucleotide conjugation

Energy Technology Data Exchange (ETDEWEB)

Guggenberg, Elisabeth von; Sader, Jayden A.; Wilson, John S.; Shahhosseini, Soraya; Koslowsky, Ingrid; Wuest, Frank [Edmonton PET Centre, Division of Oncologic Imaging, Department of Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, AB, T6G 1Z2 (Canada); Mercer, John R. [Edmonton PET Centre, Division of Oncologic Imaging, Department of Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, AB, T6G 1Z2 (Canada)], E-mail: johnmerc@cancerboard.ab.ca

2009-09-15

Alkylating agents have been shown to be very promising for the radiolabelling of oligonucleotides with fluorine-18. In this report we describe the fully automated synthesis of 2-bromo-N-[3-(2-[{sup 18}F]fluoropyridin-3-yloxy)propyl]acetamide ([{sup 18}F]FPyBrA) utilizing a modular synthesis unit. Reaction conditions for the coupling of this pyridine-based alkylating agent at the 5' end of a fully phosphorothioated random 20-mer DNA sequence were optimized to achieve very high radiochemical yields (>90%) and a maximum specific activity of 5-6 GBq/{mu}moL. The potential for rapid purification by solid phase extraction without need of chromatographic isolation of the radiolabelled oligonucleotide presents an overall benefit for the application of oligonucleotides in preclinical studies and potential clinical applications.

Development of computational small animal models and their applications in preclinical imaging and therapy research.

Science.gov (United States)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

Energy Technology Data Exchange (ETDEWEB)

Xie, Tianwu [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Geneva Neuroscience Center, Geneva University, Geneva CH-1205 (Switzerland); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen 9700 RB (Netherlands)

2016-01-15

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

International Nuclear Information System (INIS)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

Science.gov (United States)

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Prediction of antibiotic resistance: time for a new preclinical paradigm?

DEFF Research Database (Denmark)

Sommer, Morten Otto Alexander; Munck, Christian; Toft-Kehler, Rasmus Vendler

2017-01-01

Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development. In this ......Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development....... In this Opinion article, we argue that the traditional procedures that are used for the prediction of antibiotic resistance today could be markedly improved by including a broader analysis of bacterial fitness, infection dynamics, horizontal gene transfer and other factors. This will lead to more informed...

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

Science.gov (United States)

Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

2017-01-01

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

Regenerative strategies for the treatment of knee joint disabilities

CERN Document Server

Reis, Rui

2017-01-01

This book presents regenerative strategies for the treatment of knee joint disabilities. The book is composed of four main sections totaling 19 chapters which review the current knowledge on the clinical management and preclinical regenerative strategies. It examines the role of different natural-based biomaterials as scaffolds and implants for addressing different tissue lesions in the knee joint. Section one provides an updated and comprehensive discussion on articular cartilage tissue regeneration. Section two focuses on the important contributions for bone and osteochondral tissue engineering. Section three overview the recent advances on meniscus repair/regeneration strategies. Finally, section four further discusses the current strategies for treatment of ligament lesions. Each chapter is prepared by world know expert on their fields, so we do firmly believe that the proposed book will be a reference in the area of biomaterials for regenerative medicine.

Evaluation of Cholinergic Deficiency in Preclinical Alzheimer’s Disease Using Pupillometry

Directory of Open Access Journals (Sweden)

Shaun Frost

2017-01-01

Full Text Available Cortical cholinergic deficiency is prominent in Alzheimer’s disease (AD, and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR in AD (N=14 and cognitively normal healthy control (HC, N=115 participants, with the HC group stratified according to high (N=38 and low (N=77 neocortical amyloid burden (NAB. Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p<0.05, maximum velocity p<0.0005, average velocity p<0.005, and constriction amplitude p<0.00005. The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.

Enhancing translation: guidelines for standard pre-clinical experiments in mdx mice.

Science.gov (United States)

Willmann, Raffaella; De Luca, Annamaria; Benatar, Michael; Grounds, Miranda; Dubach, Judith; Raymackers, Jean-Marc; Nagaraju, Kanneboyina

2012-01-01

Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy. Copyright © 2011 Elsevier B.V. All rights reserved.

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

Directory of Open Access Journals (Sweden)

Carlo Abbate

2014-01-01

Full Text Available Objective. We describe a case of dementia with Lewy bodies (DLB that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI- DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS. The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

Monochromatic minibeam radiotherapy: theoretical and experimental dosimetry for preclinical treatment plans

Energy Technology Data Exchange (ETDEWEB)

Deman, P; Vautrin, M; Stupar, V; Barbier, E L; Elleaume, H; Esteve, F; Adam, J F, E-mail: adam@esrf.fr [INSERM, U836, BP 170, Grenoble Cedex 9, F-38042 (France)

2011-07-21

Monochromatic x-ray minibeam radiotherapy is a new radiosurgery approach based on arrays of submillimetric interlaced planar x-ray beams. The aim of this study was to characterize the dose distributions obtained with this new modality when being used for preclinical trials. Monte Carlo simulations were performed in water phantoms. Percentage depth-dose curves and dose profiles were computed for single incidences and interleaved incidences of 80 keV planar x-ray minibeam (0.6 x 5 mm) arrays. Peak to valley dose ratios were also computed at various depths for an increasing number of minibeams. 3D experimental polymer gel (nPAG) dosimetry measurements were performed using MRI devices designed for small animal imaging. These very high spatial resolution (50 {mu}m) dose maps were compared to the simulations. Preclinical minibeams dose distributions were fully characterized. Experimental dosimetry correlated well with Monte Carlo calculations (Student t-tests: p > 0.1). F98 tumor-bearing rats were also irradiated with interleaved minibeams (80 keV, prescribed dose: 25 Gy). This associated preclinical trial serves as a proof of principle of the technique. The mean survival time of irradiated glioma-bearing rats increased significantly, when compared to the untreated animals (59.6 {+-} 2.8 days versus 28.25 {+-} 0.75 days, p < 0.001).

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Science.gov (United States)

Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

2016-03-01

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

Science.gov (United States)

Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

2017-10-03

To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

Strategies in Gene Therapy for Glioblastoma

International Nuclear Information System (INIS)

Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

2013-01-01

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy

Strategies in Gene Therapy for Glioblastoma

Energy Technology Data Exchange (ETDEWEB)

Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S., E-mail: mviapiano@partners.org [Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

2013-10-22

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy.

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

Directory of Open Access Journals (Sweden)

Chinmay A. Shukla

2017-05-01

Full Text Available The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

A STRATEGY FOR DEVELOPING NEW TREATMENT PARADIGMS FOR NEUROPSYCHIATRIC AND NEUROCOGNITIVE SYMPTOMS IN ALZHEIMER’S DISEASE

Directory of Open Access Journals (Sweden)

Hugo eGeerts

2013-04-01

Full Text Available Successful disease-modifying drug development for Alzheimer’s disease has hit a roadblock with the recent failures of amyloid-based therapies, highlighting the translational disconnect between preclinical animal models and clinical outcome. Although disease-modifying therapies are the Holy Grail to pursue, symptomatic therapies addressing cognitive and neuropsychiatric aspects of the disease are also extremely important for the quality of life of patients and caregivers. Despite the fact that neuropsychiatric problems in Alzheimer patients are the major driver for costs associated with institutionalization, no good preclinical animal models with predictive validity have been documented. We propose a combination of quantitative systems pharmacology (QSP, phenotypic screening and preclinical animal models as a novel strategy for addressing the bottleneck in both cognitive and neuropsychiatric drug discovery and development for Alzheimer’s disease. Preclinical animal models such as transgene rats documenting changes in neurotransmitters with tau and amyloid pathology will provide key information that together with human imaging, pathology and clinical data will inform the virtual patient model. In this way QSP modeling can partially overcome the translational disconnect and reduce the attrition of drug programs in the clinical setting. This approach is different from target driven drug discovery as it aims to restore emergent properties of the networks and therefore likely will identify multitarget drugs. We review examples on how this hybrid humanized QSP approach has been helpful in predicting clinical outcomes in schizophrenia treatment and cognitive impairment in Alzheimer’s disease and expand on how this strategy could be applied to neuropsychiatric symptoms in dementia. We believe such an innovative approach when used carefully could change the R&D paradigm for symptomatic treatment in Alzheimer’s disease.

Preclinical test: bacterial reverse mutation test for {sup 18}F-fluorocholine produced in CDTN

Energy Technology Data Exchange (ETDEWEB)

Mendes, Bruno M.; Bispo, Ana Carolina A.; Campos, Danielle C.; Silva, Juliana B., E-mail: bmm@cdtn.br, E-mail: acab@cdtn.br, E-mail: dcc@cdtn.br, E-mail: silvajb@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

2013-07-01

The choline labeled with fluorine-18 (18FCH) is being considered as a great importance radiopharmaceutical due to its effective detection of many type of malignant neoplasm. The research related to {sup 18}F-fluorocholine synthesis in CDTN was initiated in 2010. In order to obtain clinical research approval, as well as to register {sup 18}FCH for marketing, safety and efficacy preclinical testing are required. The present work evaluated the {sup 18}FCH genotoxic potential through the bacterial reverse mutation test (Ames test) using Salmonella typhimurium TA-98, TA-100, TA-1535 and TA-1537 strains and Escherichia coli WP2 uvrA strain. The reverse mutation test in bacteria for fluorcolina was conducted in two stages. Initially the method was applied to 'cold' fluorocholine molecule (19FCH). Subsequently, the decayed product of {sup 18}FCH synthesis was evaluated. The first step was performed in order to examine the FCH molecule mutagenicity. The second was carried out to determine the mutagenic potential of final product. All strains were tested in triplicate for each exposure concentration, in the presence and absence of metabolic activation (S-9 mix - 10%). There were no statistically significant increases in revertant colonies rate for any strains tested after their exposure to decayed {sup 18}FCH or {sup 19}FCH. The number of revertant colonies in positive controls was significantly higher than that observed in significant increases in revertant colonies rate for any strains tested after their exposure to decayed {sup 18}FCH or {sup 19}FCH. The number of revertant colonies in positive controls was significantly higher than that observed in negative controls. Based on results of this assay, {sup 18}FCH and {sup 19}FCH, at tested doses, were found to be non-mutagenic in bacterial reverse mutation test. (author)

Nanotechnology and nuclear medicine; research and preclinical applications.

Science.gov (United States)

Assadi, Majid; Afrasiabi, Kolsoom; Nabipour, Iraj; Seyedabadi, Mohammad

2011-01-01

The birth of nanotechnology in human society was around 2000 years ago and soon found applications in various fields. In this article, we highlight the current status of research and preclinical applications and also future prospects of nanotechnology in medicine and in nuclear medicine. The most important field is cancer. A regular nanotechnology training program for nuclear medicine physicians may be welcome.

Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation

Science.gov (United States)

Chhabra, Preeti; Brayman, Kenneth L.

2011-01-01

Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells. PMID:22046502

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

Science.gov (United States)

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding

Synthesis and stability of monolayer-protected Au38 clusters

NARCIS (Netherlands)

Toikkanen, O.; Ruiz, V.; Rönnholm, G.; Kalkkinen, N.; Liljeroth, P.W.; Quinn, B.M.

2008-01-01

A synthesis strategy to obtain monodisperse hexanethiolate-protected Au38 clusters based on their resistance to etching upon exposure to a hyperexcess of thiol is reported. The reduction time in the standard Brust−Schiffrin two-phase synthesis was optimized such that Au38 were the only clusters that

Preclinical stress research: where are we headed? An early career investigator's perspective.

Science.gov (United States)

Gururajan, Anand; Kos, Aron; Lopez, Juan Pablo

2018-03-07

Stress is a major risk factor in the development of various psychiatric disorders such as depression, anxiety and post-traumatic stress disorder. The use of stress paradigms in preclinical contexts is essential to advance our understanding of the pathophysiology of these disorders. However, they are not without their limitations and in this commentary, we have examined some of the practical issues associated with their use. We also highlight some of the latest techniques to identify their neuromolecular correlates as well as the potentially important and integrative role of computational neuroscience. Finally, we share our perspective on future directions in the field of preclinical stress research.

Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa.

Directory of Open Access Journals (Sweden)

Robert A Harrison

2017-10-01

Full Text Available Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa.We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a 'gold standard' comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom.None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro

Game-based verification and synthesis

DEFF Research Database (Denmark)

Vester, Steen

and the environment behaves. Synthesis of strategies in games can thus be used for automatic generation of correct-by-construction programs from specifications. We consider verification and synthesis problems for several well-known game-based models. This includes both model-checking problems and satisfiability...... can be extended to solve finitely-branching turn-based games more efficiently. Further, the novel concept of winning cores in parity games is introduced. We use this to develop a new polynomial-time under-approximation algorithm for solving parity games. Experimental results show that this algorithm...... corresponds directly to a program for the corresponding entity of the system. A strategy for a player which ensures that the player wins no matter how the other players behave then corresponds to a program ensuring that the specification of the entity is satisfied no matter how the other entities...

Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.

Science.gov (United States)

Fancher, R Marcus; Zhang, Hongjian; Sleczka, Bogdan; Derbin, George; Rockar, Richard; Marathe, Punit

2011-07-01

A preclinical canine model capable of predicting a compound's potential for pH-dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra-animal variability. Pretreatment of pentagastrin (6 µg/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

Enzymatic Synthesis of Ampicillin: Nonlinear Modeling, Kinetics Estimation, and Adaptive Control

Directory of Open Access Journals (Sweden)

Monica Roman

2012-01-01

Full Text Available Nowadays, the use of advanced control strategies in biotechnology is quite low. A main reason is the lack of quality of the data, and the fact that more sophisticated control strategies must be based on a model of the dynamics of bioprocesses. The nonlinearity of the bioprocesses and the absence of cheap and reliable instrumentation require an enhanced modeling effort and identification strategies for the kinetics. The present work approaches modeling and control strategies for the enzymatic synthesis of ampicillin that is carried out inside a fed-batch bioreactor. First, a nonlinear dynamical model of this bioprocess is obtained by using a novel modeling procedure for biotechnology: the bond graph methodology. Second, a high gain observer is designed for the estimation of the imprecisely known kinetics of the synthesis process. Third, by combining an exact linearizing control law with the on-line estimation kinetics algorithm, a nonlinear adaptive control law is designed. The case study discussed shows that a nonlinear feedback control strategy applied to the ampicillin synthesis bioprocess can cope with disturbances, noisy measurements, and parametric uncertainties. Numerical simulations performed with MATLAB environment are included in order to test the behavior and the performances of the proposed estimation and control strategies.

Impact of diet restriction in the management of diabetes: evidences from preclinical studies.

Science.gov (United States)

Krishan, Pawan; Bedi, Onkar; Rani, Monika

2018-03-01

The inappropriate dietary habits lead to the onset of age-related pathologies which include diabetes and cardiovascular ailments. Dietary restriction and nutritional therapy play an important role in the prevention of these chronic ailments. Preclinical research provides a basis for the therapeutic exploration of new dietary interventions for the clinical trials to potentiate the scientific management of diabetes and its related complications which further help in translating these nutritional improvements from bench to bedside. Within the same context, numerous therapeutically proved preclinical dietary interventions like high-fiber diet, caloric restriction, soy isoflavone-containing diets, etc., have shown the promising results for the management of diabetes and the associated complications. The focus of the present review is to highlight the various preclinical evidences of diet restriction for the management of diabetes and which will be helpful for enlightening the new ideas of nutritional therapy for future research exploration. In addition, some potential approaches are also discussed which are associated with various nutritional interventions to combat progressive diabetes and the associated disorders. Graphical abstract ᅟ.

Recent Progress in Chemical and Chemoenzymatic Synthesis of Carbohydrates

Science.gov (United States)

Muthana, Saddam; Cao, Hongzhi; Chen, Xi

2011-01-01

Summary The important roles that carbohydrates play in biological processes and their potential application in diagnosis, therapeutics, and vaccine development have made them attractive synthetic targets. Despite ongoing challenges, tremendous progresses have been made in recent years for the synthesis of carbohydrates. The chemical glycosylation methods have become more sophisticated and the synthesis of oligosaccharides has become more predictable. Simplified one-pot glycosylation strategy and automated synthesis are increasingly used to obtain biologically important glycans. On the other hand, chemoenzymatic synthesis continues to be a powerful alternative for obtaining complex carbohydrates. This review highlights recent progress in chemical and chemoenzymatic synthesis of carbohydrates with a particular focus on the methods developed for the synthesis of oligosaccharides, polysaccharides, glycolipids, and glycosylated natural products. PMID:19833544

A Flexible, Preclinical, Medical School Curriculum Increases Student Academic Productivity and the Desire to Conduct Future Research

Science.gov (United States)

Peacock, Justin G.; Grande, Joseph P.

2015-01-01

In 2006, small blocks of flexible curriculum time, termed selectives, were implemented in the Mayo Medical School preclinical curriculum. Selectives permitted students to pursue professional endeavors, such as research, service, and career exploration, in the preclinical years. The purpose of this study was to survey current and former Mayo…

Preliminary study for small animal preclinical hadrontherapy facility

Energy Technology Data Exchange (ETDEWEB)

Russo, G. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Pisciotta, P., E-mail: pietro.pisciotta@ibfm.cnr.it [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cirrone, G.A.P.; Romano, F. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Acquaviva, R. [University of Catania, Catania (Italy); Gilardi, M.C. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Cuttone, G. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy)

2017-02-21

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Preliminary study for small animal preclinical hadrontherapy facility

Science.gov (United States)

Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

2017-02-01

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Preliminary study for small animal preclinical hadrontherapy facility

International Nuclear Information System (INIS)

Russo, G.; Pisciotta, P.; Cirrone, G.A.P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M.C.; Cuttone, G.

2017-01-01

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.

Science.gov (United States)

Andrews, Nick A; Latrémolière, Alban; Basbaum, Allan I; Mogil, Jeffrey S; Porreca, Frank; Rice, Andrew S C; Woolf, Clifford J; Currie, Gillian L; Dworkin, Robert H; Eisenach, James C; Evans, Scott; Gewandter, Jennifer S; Gover, Tony D; Handwerker, Hermann; Huang, Wenlong; Iyengar, Smriti; Jensen, Mark P; Kennedy, Jeffrey D; Lee, Nancy; Levine, Jon; Lidster, Katie; Machin, Ian; McDermott, Michael P; McMahon, Stephen B; Price, Theodore J; Ross, Sarah E; Scherrer, Grégory; Seal, Rebecca P; Sena, Emily S; Silva, Elizabeth; Stone, Laura; Svensson, Camilla I; Turk, Dennis C; Whiteside, Garth

2016-04-01

There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration sponsored a consensus meeting of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) Working Group. International participants from universities, funding agencies, government agencies, industry, and a patient advocacy organization attended. Reduction of publication bias, increasing the ability of others to faithfully repeat experimental methods, and increased transparency of data reporting were specifically discussed. Parameters deemed essential to increase confidence in the published literature were clear, specific reporting of an a priori hypothesis and definition of primary outcome measure. Power calculations and whether measurement of minimal meaningful effect size to determine these should be a core component of the preclinical research effort provoked considerable discussion, with many but not all agreeing. Greater transparency of reporting should be driven by scientists, journal editors, reviewers, and grant funders. The conduct of high-quality science that is fully reported should not preclude novelty and innovation in preclinical pain research, and indeed, any efforts that curtail such innovation would be misguided. We believe that to achieve the goal of finding effective new treatments for patients with pain, the pain field needs to deal with these challenging issues.

The effect of learning styles and study behavior on success of preclinical students in pharmacology.

Science.gov (United States)

Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

2016-01-01

To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

A Novel Strategy for Synthesis of Gold Nanoparticle Self Assemblies

NARCIS (Netherlands)

Verma, Jyoti; Lal, Sumit; van Veen, Henk A.; van Noorden, Cornelis J. F.

2014-01-01

Gold nanoparticle self assemblies are one-dimensional structures of gold nanoparticles. Gold nanoparticle self assemblies exhibit unique physical properties and find applications in the development of biosensors. Methodologies currently available for lab-scale and commercial synthesis of gold

Manufacture of Third-Generation Lentivirus for Preclinical Use, with Process Development Considerations for Translation to Good Manufacturing Practice.

Science.gov (United States)

Gándara, Carolina; Affleck, Valerie; Stoll, Elizabeth Ann

2018-02-01

Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet, the manufacture of these vectors is challenging, especially at high titers required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation. The goals of this paper are to report the protocol for manufacturing high-titer third-generation lentivirus for preclinical testing and to provide detailed information on considerations for translating preclinical viral vector manufacture toward scaled-up platforms and processes in order to make gene therapies under Good Manufacturing Practice that are suitable for clinical trials.

Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies

International Nuclear Information System (INIS)

Amacher, David E.

2011-01-01

Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the 'two hit' theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R and D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.

A preclinical mouse model of invasive lobular breast cancer metastasis

NARCIS (Netherlands)

Doornebal, Chris W.; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Klijn, Christiaan N.; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W.; Jonkers, Jos; de Visser, Karin E.

2013-01-01

Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous

Altered whole-brain white matter networks in preclinical Alzheimer's disease

Directory of Open Access Journals (Sweden)

Florian Udo Fischer

2015-01-01

Our results suggest an impairment of WM networks in preclinical AD that is detectable while other structural imaging markers do not yet indicate incipient neurodegeneration. Moreover, these findings are specific to WM networks and cannot be explained by other surrogates of global WM integrity.

DNA nanomaterials for preclinical imaging and drug delivery.

Science.gov (United States)

Jiang, Dawei; England, Christopher G; Cai, Weibo

2016-10-10

Besides being the carrier of genetic information, DNA is also an excellent biological organizer to establish well-designed nanostructures in the fields of material engineering, nanotechnology, and biomedicine. DNA-based materials represent a diverse nanoscale system primarily due to their predictable base pairing and highly regulated conformations, which greatly facilitate the construction of DNA nanostructures with distinct shapes and sizes. Integrating the emerging advancements in bioconjugation techniques, DNA nanostructures can be readily functionalized with high precision for many purposes ranging from biosensors to imaging to drug delivery. Recent progress in the field of DNA nanotechnology has exhibited collective efforts to employ DNA nanostructures as smart imaging agents or delivery platforms within living organisms. Despite significant improvements in the development of DNA nanostructures, there is limited knowledge regarding the in vivo biological fate of these intriguing nanomaterials. In this review, we summarize the current strategies for designing and purifying highly-versatile DNA nanostructures for biological applications, including molecular imaging and drug delivery. Since DNA nanostructures may elicit an immune response in vivo, we also present a short discussion of their potential toxicities in biomedical applications. Lastly, we discuss future perspectives and potential challenges that may limit the effective preclinical and clinical employment of DNA nanostructures. Due to their unique properties, we predict that DNA nanomaterials will make excellent agents for effective diagnostic imaging and drug delivery, improving patient outcome in cancer and other related diseases in the near future. Copyright © 2016 Elsevier B.V. All rights reserved.

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis.

Science.gov (United States)

He, Hongliang; Lancina, Michael G; Wang, Jing; Korzun, William J; Yang, Hu; Ghosh, Shobha

2017-06-01

Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein-associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

Directory of Open Access Journals (Sweden)

Melissa Lo Monaco

2018-01-01

Full Text Available Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs or induced pluripotent stem cells (iPSCs have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures.

Science.gov (United States)

Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

2018-01-01

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

Pyro-synthesis of functional nanocrystals.

Science.gov (United States)

Gim, Jihyeon; Mathew, Vinod; Lim, Jinsub; Song, Jinju; Baek, Sora; Kang, Jungwon; Ahn, Docheon; Song, Sun-Ju; Yoon, Hyeonseok; Kim, Jaekook

2012-01-01

Despite nanomaterials with unique properties playing a vital role in scientific and technological advancements of various fields including chemical and electrochemical applications, the scope for exploration of nano-scale applications is still wide open. The intimate correlation between material properties and synthesis in combination with the urgency to enhance the empirical understanding of nanomaterials demand the evolution of new strategies to promising materials. Herein we introduce a rapid pyro-synthesis that produces highly crystalline functional nanomaterials under reaction times of a few seconds in open-air conditions. The versatile technique may facilitate the development of a variety of nanomaterials and, in particular, carbon-coated metal phosphates with appreciable physico-chemical properties benefiting energy storage applications. The present strategy may present opportunities to develop "design rules" not only to produce nanomaterials for various applications but also to realize cost-effective and simple nanomaterial production beyond lab-scale limitations.

The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

Energy Technology Data Exchange (ETDEWEB)

Marks, Louise, E-mail: louise.marks@astrazeneca.com [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Kirk, Sarah [Innovative Medicines, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Valentin, Jean-Pierre [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom)

2012-09-01

Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. �

Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder.

Science.gov (United States)

Gamache, Karine; Pitman, Roger K; Nader, Karim

2012-12-01

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α₂-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.

Sexuality and gender identity teaching within preclinical medical training in New Zealand: content, attitudes and barriers.

Science.gov (United States)

Taylor, Oscar; Rapsey, Charlene M; Treharne, Gareth J

2018-06-22

To investigate inclusion of sexuality and gender identity content, attitudes and barriers to inclusion of content in preclinical curricula of New Zealand medical schools from the perspective of key teaching staff. Staff responsible for curriculum oversight at New Zealand's two medical schools were invited to complete a mixed-methods survey about sexuality and gender identity content in their modules. Of 24 respondents, the majority included very little content relating to sexuality or gender identity (33%) or none at all (54%). This content was deemed important by most participants (69%), and none believed there should be less such content in their curriculum. Time was reported to be the main barrier limiting inclusion of such content. Our finding of limited content is consistent with international literature. Our findings extend the literature by revealing that barriers to greater inclusion of content are not due to overt negative attitudes. Staff responsible for preclinical medical curriculum oversight have positive attitudes about content relating to sexuality and gender identity but perceive curriculum space to be a limiting barrier. This is important as it informs approaches to change. Future interventions with medical schools should focus on methods to increase diverse content as part of existing teaching, education to increase knowledge of LGBTQI relevant material and potentially incorporate strategies used to address unconscious bias. Addressing the perceived barriers of time constraints and lack of relevance is required to ensure medical students receive training to develop the competencies to provide positive healthcare experiences for all patients regardless of sexuality and gender identity.

SU-E-T-606: Performance of MR-Based 3D FXG Dosimetry for Preclinical Irradiation

Energy Technology Data Exchange (ETDEWEB)

Welch, M [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Jaffray, D [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON (Canada); Department of Radiation Oncology, University of Toronto, Toronto, ON (Canada); TECHNA Institute for the Advancement of Technology for Health, Toronto, ON (Canada)

2015-06-15

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MR and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation

Colloidal Flower-Shaped Iron Oxide Nanoparticles: Synthesis Strategies and Coatings

DEFF Research Database (Denmark)

Gavilán, Helena; Kowalski, Anja; Heinke, David

2017-01-01

The assembly of magnetic cores into regular structures may notably influence the properties displayed by a magnetic colloid. In this work, key synthesis parameters driving the self-assembly process capable of organizing colloidal magnetic cores into highly regular and reproducible multi-core nano...

Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate

NARCIS (Netherlands)

Gerlag, Daniëlle M.; Hollis, Sally; Layton, Mark; Vencovský, Jiří; Szekanecz, Zoltán; Braddock, Martin; Tak, Paul P.; Oparanov, Boycho; Stoilov, Rumen; Yaneva, Tanya; Batalov, Anastas; Arteaga, Edgardo Tobias; Escalante, William Otero; Velez, Patricia; Restrepo, Jose Molina; Augustinova, Sevda; Blahova, Anna; Dvorak, Zdenek; Novosad, Libor; Rosa, Jan; Stehlikova, Helena; Vitek, Petr; Balazs, Tibor; Seregely, Katalin; Szombati, Istvan; Tarjan, Katalin; Csengei, Gabor; Galeazzi, Mauro; Saleniece, Sarmite; Saulite-Kandevica, Daina; Coleiro, Bernard; Badurski, Janusz; Brzosko, Marek; Chudzik, Dariusz; Gruszecka-Marczynska, Katarzyna; Hensel, Joanna; Pokrzywnicka-Gajek, Ines; Korpanty-Danda, Joanna; Sochocka-Bykowska, Malgorzata; Tlustochowicz, Witold; Stopinska-Polaszewska, Maria; Gluszko, Piotr; Nedelcovici, Corina; Radulescu, Florin; Gavrila, Mirea; Tanasescu, Coman; Korshunov, Nikolay; Matsievskaia, Galina; Damjanov, Nemanja; Dimic, Aleksandar

2010-01-01

To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were

Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy.

Science.gov (United States)

Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison; Kass, David A; McNally, Elizabeth M; Metzger, Joseph M; Spurney, Christopher F; Kinnett, Kathi

2016-02-01

A recent working group meeting focused on contemporary cardiac issues in Duchenne muscular dystrophy (DMD) was hosted by the National Heart, Lung, and Blood Institute in collaboration with the Parent Project Muscular Dystrophy. An outcome of this meeting was to provide freely available detailed protocols for preclinical animal studies. The goal of these protocols is to improve the quality and reproducibility of cardiac preclinical studies aimed at developing new therapeutics for the prevention and treatment of DMD cardiomyopathy.

Theory of mind and empathy in preclinical and clinical Huntington's disease.

Science.gov (United States)

Adjeroud, Najia; Besnard, Jérémy; El Massioui, Nicole; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique; Allain, Philippe

2016-01-01

We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Synthesis of monoterpene piperidines from the iridoid glucoside antirrhinoside

DEFF Research Database (Denmark)

Franzyk, Henrik; Frederiksen, Signe Maria; Jensen, Søren Rosendal

1997-01-01

Synthesis of five novel piperidine monoterpene alkaloids using the iridoid glucoside antirrhinoside as a synthon is described. Two strategies for their preparation were investigated: the first possible pathway involved an intermediate diol from which the piperidine ring was expected to be constru......Synthesis of five novel piperidine monoterpene alkaloids using the iridoid glucoside antirrhinoside as a synthon is described. Two strategies for their preparation were investigated: the first possible pathway involved an intermediate diol from which the piperidine ring was expected...... to be constructed via reaction of its ditosylate with an amine; the second strategy involved a double reductive amination as the key step to the piperidine ring, which proved successful. The stereochemistry of C-5 and C-9 in the obtained piperidine monoterpenes was the same as that reported for alfa...

Minimum energy consumption process synthesis for energy saving

Energy Technology Data Exchange (ETDEWEB)

Xiao-Ping, Jia [Institute for Petroleum and Chemical Industry, Qingdao University of Science and Technology, Qingdao 266042, Shandong (China); Department of Environmental Science and Engineering, Tsinghua University, Beijing 100084 (China); Fang, Wang; Shu-Guang, Xiang; Xin-Sun, Tan; Fang-Yu, Han [Institute for Petroleum and Chemical Industry, Qingdao University of Science and Technology, Qingdao 266042, Shandong (China)

2008-05-15

The paper presents a synthesis strategy for the chemical processes with energy saving. The concept of minimum energy consumption process (MECP) is proposed. Three characteristics of MECP are introduced, including thermodynamic minimum energy demand, energy consumption efficiency and integration degree. These characteristics are evaluated according to quantitative thermodynamic analysis and qualitative knowledge rules. The procedure of synthesis strategy is proposed to support the generation of MECP alternatives, which combine flowsheet integration and heat integration. The cases studies will focus on how integration degrees of a process affect the energy-saving results. The separation sequences of the hydrodealkylation of toluene (HDA) process and ethanol distillation process as case studies are used to illustrate. (author)

Total Synthesis of Adunctin B.

Science.gov (United States)

Dethe, Dattatraya H; Dherange, Balu D

2018-03-16

Total synthesis of (±)-adunctin B, a natural product isolated from Piper aduncum (Piperaceae), has been achieved using two different strategies, in seven and three steps. The efficient approach features highly atom economical and diastereoselective Friedel-Crafts acylation, alkylation reaction and palladium catalyzed Wacker type oxidative cyclization.

A review of targeted therapies evaluated by the Pediatric Preclinical Testing Program for osteosarcoma

Directory of Open Access Journals (Sweden)

Valerie eSampson

2013-05-01

Full Text Available Osteosarcoma, the most common malignant bone tumor of childhood, is a high grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical end points for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

Preclinical models for an innovative glioblastoma therapeutical strategy by 188Re-SSS encapsulated in nano-tools: translational view

International Nuclear Information System (INIS)

Cikankowitz, A.; Belloche, C.; Verger, E.; Garcion, E.; Hindre, F.; Chassain, G.; Fellah, B.; Abadie, J.; Chouin, N.; Ibisch, C.; Davodeau, F.; Couez, D.; Lepareur, N.; Lacoeuille, F.; Menei, P.

2015-01-01

Full text of publication follows. Aim: Glioblastoma (GBM) is the most frequent cancer of the nervous system and therapies currently used cannot treat definitively this disease. By the way of NucSan (Nuclear for health) program which supports research development about the use of radio pharmaceutics in oncology, the aim of the proposed work is to provide evidences that internal radiotherapy through lipid nanocapsules loaded with Rhenium-188 (LNC 188 Re-SSS) is an alternative therapeutic strategy for GBM that can be translated to human medicine. Previous works have shown a remarkable efficiency of this tool among syngeneic rats linked with local and peripheral recruitments of the immune system's effectors. In this context, two animal models have been chosen to validate the feasibility of this new innovative therapy design (LNC 188 Re-SSS stereotactic injection). Materials and methods: the syngeneic six weeks old C57BL/6J female mice were treated 6 or 12 days after stereotactic GL261 cells implantation, by a single injection of increasing activities of LNC 188 Re-SSS (0,925; 1,85 and 2,7 MBq/5μl). MRI was used to follow tumor progression to determine the mass volume through the selection of regions of interest. The increased median survival time (IMST) was also assessed for treated mice versus control mice (stereotactic injection of saline solution). For long time survival animals (3 times the median survival time), they were rechallenged through the same procedure in the other hemisphere. The brachy-cephalic dog bearing spontaneous tumor will lead to additional evidences to specifically highlight the potential of this innovative technology for GBM treatment. In order to validate procedures of intracerebral injections, a stereotactic head frame specially designed for dog has been conceived which allow both images acquisition (MRI-SPECT and PET) and the achievement of biopsies. Results/Perspectives: as previously observed on rat models, the preliminary data show

Neuroprotection in Parkinson's disease: A systematic review of the preclinical data

NARCIS (Netherlands)

Douna, H.; Bavelaar, B.M.; Pellikaan, H.; Olivier, B.; Pieters, T.

2012-01-01

Aim: This study aimed to systematically review the preclinical data of neuroprotective agents for Parkinson's disease (PD) to support the translation of these compounds. Methods: The study consisted of two phases. In phase I, Pubmed and Scopus were systematically searched for neuroprotective agents

Metal-Organic Frameworks: Building Block Design Strategies for the Synthesis of MOFs.

KAUST Repository

Luebke, Ryan

2014-09-01

A significant and ongoing challenge in materials chemistry and furthermore solid state chemistry is to design materials with the desired properties and characteristics. The field of Metal-Organic Frameworks (MOFs) offers several strategies to address this challenge and has proven fruitful at allowing some degree of control over the resultant materials synthesized. Several methodologies for synthesis of MOFs have been developed which rely on use of predetermined building blocks. The work presented herein is focused on the utilization of two of these design principles, namely the use of molecular building blocks (MBBs) and supermolecular building blocks (SBBs) to target MOF materials having desired connectivities (topologies). These design strategies also permit the introduction of specific chemical moieties, allowing for modification of the MOFs properties. This research is predominantly focused on two platforms (rht-MOFs and ftw-MOFs) which topologically speaking are edge transitive binodal nets; ftw being a (4,12)-connected net and rht being a (3,24)-connected net. These highly connected nets (at least one node having connectivity greater than eight) have been purposefully targeted to increase the predictability of structural outcome. A general trend in topology is that there is an inverse relationship between the connectivity of the node(s) and the number of topological outcomes. Therefore the key to this research (and to effective use of the SBB and MBB approaches) is identification of conditions which allow for reliable formation of the targeted MBBs and SBBs. In the case of the research presented herein: a 12-connected Group IV or Rare Earth based hexanuclear MBB and a 24-connected transition metal based SBB were successfully targeted and synthesized. These two synthetic platforms will be presented and used as examples of how these design methods have been (and can be further) utilized to modify existing materials or develop new materials for gas storage and

Role of SimMan in teaching clinical skills to preclinical medical students

Directory of Open Access Journals (Sweden)

Swamy Meenakshi

2013-02-01

Full Text Available Abstract Background Simulation training has potential in developing clinical skills in pre-clinical medical students, but there is little evidence on its effectiveness. Methods Twenty four first year graduate entry preclinical medical students participated in this crossover study. They were divided into two groups, one performed chest examination on each other and the other used SimMan. The groups then crossed over. A pretest, midtest and post-test was conducted in which the students answered the same questionnaire with ten questions on knowledge, and confidence levels rated using a 5 point Likert scale. They were assessed formatively using the OSCE marking scheme. At the end of the session, 23 students completed a feedback questionnaire. Data was analyzed using one-way ANOVA and independent t-test. Results When the two groups were compared, there was no significant difference in the pretest and the post-test scores on knowledge questions whereas the midtest scores increased significantly (P Mean confidence ratings increased from the pretest to midtest and then further in the post-test for both groups. Their confidence ratings increased significantly in differentiating between normal and abnormal signs [Group starting with SimMan, between pretest and midtest (P= 0.01 and group starting with peer examination, between midtest and post-test (P=0.02]. When the students’ ability to perform examination on each other for both groups was compared, there was a significant increase in the scores of the group starting with SimMan (P=0.007. Conclusions This pilot study demonstrated a significant improvement in the students’ knowledge and competence to perform chest examination after simulation with an increase in the student’s perceived levels of confidence. Feedback from the students was extremely positive. SimMan acts as a useful adjunct to teach clinical skills to preclinical medical students by providing a simulated safe environment and thus aids

Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using Diffuse and Mechanical TBI Animal Models

Science.gov (United States)

2016-05-01

Award Number: PT075653 (grant) W81XWH-08-2-0153 (contract) TITLE: Treatment of TBI with Hormonal and Pharmacological Support, Preclinical...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-08-2-0153 Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using...rats. Our in vivo tests also included MRI imaging, focusing on edema resolution and reduction of diffuse axonal damage (fractional anisotropy

Machine-learned and codified synthesis parameters of oxide materials

Science.gov (United States)

Kim, Edward; Huang, Kevin; Tomala, Alex; Matthews, Sara; Strubell, Emma; Saunders, Adam; McCallum, Andrew; Olivetti, Elsa

2017-09-01

Predictive materials design has rapidly accelerated in recent years with the advent of large-scale resources, such as materials structure and property databases generated by ab initio computations. In the absence of analogous ab initio frameworks for materials synthesis, high-throughput and machine learning techniques have recently been harnessed to generate synthesis strategies for select materials of interest. Still, a community-accessible, autonomously-compiled synthesis planning resource which spans across materials systems has not yet been developed. In this work, we present a collection of aggregated synthesis parameters computed using the text contained within over 640,000 journal articles using state-of-the-art natural language processing and machine learning techniques. We provide a dataset of synthesis parameters, compiled autonomously across 30 different oxide systems, in a format optimized for planning novel syntheses of materials.

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

DEFF Research Database (Denmark)

Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

2016-01-01

Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

Deep Machine Learning Application to the Detection of Preclinical Neurodegenerative Diseases of Aging

Directory of Open Access Journals (Sweden)

Mathew J. Summers

2017-12-01

Full Text Available Artificial intelligence (AI deep learning protocols offer solutions to complex data processing and analysis. Increasingly these solutions are being applied in the healthcare field, most commonly in processing complex medical imaging data used for diagnosis. Current models apply AI to screening populations of patients for markers of disease and report detection accuracy rates exceeding those of human data screening. In this paper, we explore an alternate model for AI deployment, that of monitoring and analysing an individual’s level of function over time. In adopting this approach, we propose that AI may provide highly accurate and reliable detection of preclinical disease states associated with aging-related neurodegenerative diseases. One of the key challenges facing clinical detection of preclinical phases of diseases such as dementia is the high degree of inter-individual variability in aging-related changes to cognitive function. AI based monitoring of an individual over time offers the potential for the early detection of change in function for the individual, rather than relying on comparing the individual’s performance to population norms. We explore an approach to developing AI platforms for individual monitoring and preclinical disease detection and examine the potential benefits to the stakeholders in this technological development.

Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

Science.gov (United States)

Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

2016-12-01

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cardiac safety implications of hNav1.5 blockade and a framework for preclinical evaluation

Directory of Open Access Journals (Sweden)

Gul eErdemli

2012-01-01

Full Text Available The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a preclinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

Preclinical models of shock and sepsis: what can they tell us?

NARCIS (Netherlands)

Marshall, John C.; Deitch, Edwin; Moldawer, Lyle L.; Opal, Steven; Redl, Heinz; van der Poll, Tom

2005-01-01

The goal of translational research is to transform biologic knowledge into new treatments for human disease. Although preclinical models replicate some of the features of the disease process modeled, they invariably fail to reproduce the complexity of human illness, and by their very experimental

The preclinical discovery and development of dolutegravir for the treatment of HIV.

Science.gov (United States)

Bailly, Fabrice; Cotelle, Philippe

2015-01-01

Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients. This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014. The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.

Regenerative medicine provides alternative strategies for the treatment of anal incontinence.

Science.gov (United States)

Gräs, Søren; Tolstrup, Cæcilie Krogsgaard; Lose, Gunnar

2017-03-01

Anal incontinence is a common disorder but current treatment modalities are not ideal and the development of new treatments is needed. The aim of this review was to identify the existing knowledge of regenerative medicine strategies in the form of cellular therapies or bioengineering as a treatment for anal incontinence caused by anal sphincter defects. PubMed was searched for preclinical and clinical studies in English published from January 2005 to January 2016. Animal studies have demonstrated that cellular therapy in the form of local injections of culture-expanded skeletal myogenic cells stimulates repair of both acute and 2 - 4-week-old anal sphincter injuries. The results from a small clinical trial with ten patients and a case report support the preclinical findings. Animal studies have also demonstrated that local injections of mesenchymal stem cells stimulate repair of sphincter injuries, and a complex bioengineering strategy for creation and implantation of an intrinsically innervated internal anal sphincter construct has been successfully developed in a series of animal studies. Cellular therapies with myogenic cells and mesenchymal stem cells and the use of bioengineering technology to create an anal sphincter are new potential strategies to treat anal incontinence caused by anal sphincter defects, but the clinical evidence is extremely limited. The use of culture-expanded autologous skeletal myogenic cells has been most intensively investigated and several clinical trials were ongoing at the time of this report. The cost-effectiveness of such a therapy is an issue and muscle fragmentation is suggested as a simple alternative.

Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

Energy Technology Data Exchange (ETDEWEB)

Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R. [Heidelberg Univ., Mannheim (Germany). Computer Assisted Clinical Medicine

2014-07-01

The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

International Nuclear Information System (INIS)

Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R.

2014-01-01

The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

Appreciation of symmetry in natural product synthesis.

Science.gov (United States)

Bai, Wen-Ju; Wang, Xiqing

2017-12-13

Covering: 2012 to June 2017This review aims to show that complex natural product synthesis can be streamlined by taking advantage of molecular symmetry. Various strategies to construct molecules with either evident or hidden symmetry are illustrated. Insights regarding the origins and adjustments of these strategies as well as inspiring new methodological developments are deliberated. When a symmetric strategy fails, the corresponding reason is analysed and an alternative approach is briefly provided. Finally, the importance of exploiting molecular symmetry and future research directions are discussed.

Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy.

Science.gov (United States)

Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J; Williams, Kayode; Guan, Yun

2018-01-01

Traditional spinal cord stimulation (SCS) requires that paresthesia overlaps chronic painful areas. However, the new paradigm high-frequency SCS (HF-SCS) does not rely on paresthesia. A review of preclinical and clinical studies regarding the use of paresthesia-free HF-SCS for various chronic pain states. We reviewed available literatures on HF-SCS, including Nevro's paresthesia-free ultra high-frequency 10 kHz therapy (HF10-SCS). Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, and manual searches of the bibliographies of known primary and review articles. The primary goal is to describe the present developing conceptions of preclinical mechanisms of HF-SCS and to review clinical efficacy on paresthesia-free HF10-SCS for various chronic pain states. HF10-SCS offers a novel pain reduction tool without paresthesia for failed back surgery syndrome and chronic axial back pain. Preclinical findings indicate that potential mechanisms of action for paresthesia-free HF-SCS differ from those of traditional SCS. To fully understand and utilize paresthesia-free HF-SCS, mechanistic study and translational research will be very important, with increasing collaboration between basic science and clinical communities to design better trials and optimize the therapy based on mechanistic findings from effective preclinical models and approaches. Future research in these vital areas may include preclinical and clinical components conducted in parallel to optimize the potential of this technology. © 2017 International Neuromodulation Society.

ZnO template strategy for the synthesis of 3D interconnected graphene nanocapsules from coal tar pitch as supercapacitor electrode materials

Science.gov (United States)

He, Xiaojun; Li, Xiaojing; Ma, Hao; Han, Jiufeng; Zhang, Hao; Yu, Chang; Xiao, Nan; Qiu, Jieshan

2017-02-01

3D interconnected graphene nanocapsules (GNCs) were prepared from diverse aromatic hydrocarbons by a nano-ZnO-template strategy coupled with in-situ KOH activation technique. The as-made graphene networks feature thin carbonaceous shells with well-balanced micropores and mesopores. Such 3D porous networks provide freeways for good electron conduction, short pores for ion fast transport, and abundant micropores for ion adsorption. As the electrodes in supercapacitors, the unique 3D GNCs show a high capacitance of 277 F g-1 at 0.05 A g-1, a good rate performance of 194 F g-1 at 20 A g-1, and an excellent cycle stability with over 97.4% capacitance retention after 15000 cycles in 6 M KOH electrolyte. This synthesis strategy paves a universal way for mass production of 3D graphene materials from diverse aromatic hydrocarbon sources including coal tar pitch and petroleum pitch for high performance supercapacitors as well as support and sorbent.

Synthesis of natural products of therapeutic significance

Indian Academy of Sciences (India)

system

2015-11-07

Nov 7, 2015 ... potential activity, while more natural products await the ... Treaty that prohibits commercial exploitation of Antarctic resources, the development of a synthetic strategy that allows the synthesis of palmerolide A and an array of its.

Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

Science.gov (United States)

2014-05-16

FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

Amphoteric Borylketenimines: Versatile Intermediates in the Synthesis of Borylated Heterocycles.

Science.gov (United States)

Kaldas, Sherif J; O'Keefe, Kowan T V; Mendoza-Sanchez, Rodrigo; Yudin, Andrei K

2017-07-21

We report the first synthesis of amphoteric borylketenimines from ethynyl N-methyliminodiacetic acid (MIDA) boronate and sulfonyl azides via copper catalysis. In situ trapping of these intermediates with various nucleophiles provided access to novel borylated azetidimines, iminocoumarins, amides, iminooxetanes, and amidines. The described strategy based on borylketenimines offers high levels of chemo- and regioselectivity, enabling the synthesis of unprecedented borylated molecules. This work highlights the unexplored utility of borylketenimines in the synthesis of potentially bioactive molecules. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Appropriate experimental approaches for predicting abuse potential and addictive qualities in preclinical drug discovery.

Science.gov (United States)

Mead, Andy N

2014-11-01

Drug abuse is an increasing social and public health issue, putting the onus on drug developers and regulatory agencies to ensure that the abuse potential of novel drugs is adequately assessed prior to product launch. This review summarizes the core preclinical data that frequently contribute to building an understanding of abuse potential for a new molecular entity, in addition to highlighting models that can provide increased resolution regarding the level of risk. Second, an important distinction between abuse potential and addiction potential is drawn, with comments on how preclinical models can inform on each. While the currently adopted preclinical models possess strong predictive validity, there are areas for future refinement and research. These areas include a more refined use of self-administration models to assess relative reinforcement; and the need for open innovation in pursuing improvements. There is also the need for careful scientifically driven application of models rather than a standardization of methodologies, and the need to explore the opportunities that may exist for enhancing the value of physical dependence and withdrawal studies by focusing on withdrawal-induced drug seeking, rather than broad symptomology.

Hollow Micro-/Nanostructures: Synthesis and Applications

KAUST Repository

Lou, Xiong Wen (David)

2008-11-03

Hollow micro-nanostructures are of great interest in many current and emerging areas of technology. Perhaps the best-known example of the former is the use of fly-ash hollow particles generated from coal power plants as partial replacement for Portland cement, to produce concrete with enhanced strength and durability. This review is devoted to the progress made in the last decade in synthesis and applications of hollow micro-nanostructures. We present a comprehensive overview of synthetic strategies for hollow structures. These strategies are broadly categorized into four themes, which include well-established approaches, such as conventional hard-templating and soft-templating methods, as well as newly emerging methods based on sacrificial templating and template-free synthesis. Success in each has inspired multiple variations that continue to drive the rapid evolution of the field. The Review therefore focuses on the fundamentals of each process, pointing out advantages and disadvantages where appropriate. Strategies for generating more complex hollow structures, such as rattle-type and nonspherical hollow structures, are also discussed. Applications of hollow structures in lithium batteries, catalysis and sensing, and biomedical applications are reviewed. © 2008 WILEY-VCH Verlag GmbH & Co. KGaA,.

Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

Science.gov (United States)

Edwardson, Matthew A.; Wang, Ximing; Liu, Brent; Ding, Li; Lane, Christianne J.; Park, Caron; Nelsen, Monica A.; Jones, Theresa A; Wolf, Steven L; Winstein, Carolee J; Dromerick, Alexander W.

2017-01-01

Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

Designing Preclinical Instruction of Psychomotor Skills (IV)--Instructional Engineering: Evaluation Phase.

Science.gov (United States)

Guenzel, Pamela J.; And Others

1995-01-01

The fourth article in a four-part series on instructional design discusses evaluation of a psychomotor skills unit taught in preclinical dental education. Issues examined include piloting of instructional materials, analysis and revision of materials based on student performance, syllabus design and content, influence of faculty characteristics,…

One-pot synthesis of linear- and three-arm star-tetrablock quarterpolymers via sequential metal-free ring-opening polymerization using a "catalyst switch" strategy

KAUST Repository

Zhao, Junpeng; Pahovnik, David; Gnanou, Yves; Hadjichristidis, Nikolaos

2014-01-01

A "catalyst switch" strategy has been used to sequentially polymerize four different heterocyclic monomers. In the first step, epoxides (1,2-butylene oxide and ethylene oxide) were successively polymerized from a monohydroxy or trihydroxy initiator in the presence of a strong phosphazene base promoter (t-BuP4). Then, an excess of diphenyl phosphate (DPP) was introduced, followed by addition and polymerization of a cyclic carbonate (trimethylene carbonate) and a cyclic ester (δ-valerolactone or ε-caprolactone). DPP acted as both neutralizer of the phosphazenium alkoxide (polyether chain end) and activator of the cyclic carbonate/ester. Using this method, linear- and star-tetrablock quarterpolymers were prepared in one pot. This work is emphasizing the strength of the previously developed catalyst switch strategy for the facile metal-free synthesis of complex macromolecular architectures. © 2014 Wiley Periodicals, Inc.

One-pot synthesis of linear- and three-arm star-tetrablock quarterpolymers via sequential metal-free ring-opening polymerization using a "catalyst switch" strategy

KAUST Repository

Zhao, Junpeng

2014-08-06

A "catalyst switch" strategy has been used to sequentially polymerize four different heterocyclic monomers. In the first step, epoxides (1,2-butylene oxide and ethylene oxide) were successively polymerized from a monohydroxy or trihydroxy initiator in the presence of a strong phosphazene base promoter (t-BuP4). Then, an excess of diphenyl phosphate (DPP) was introduced, followed by addition and polymerization of a cyclic carbonate (trimethylene carbonate) and a cyclic ester (δ-valerolactone or ε-caprolactone). DPP acted as both neutralizer of the phosphazenium alkoxide (polyether chain end) and activator of the cyclic carbonate/ester. Using this method, linear- and star-tetrablock quarterpolymers were prepared in one pot. This work is emphasizing the strength of the previously developed catalyst switch strategy for the facile metal-free synthesis of complex macromolecular architectures. © 2014 Wiley Periodicals, Inc.

Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs.

Science.gov (United States)

Köster, Ursula; Nolte, Ingo; Michel, Martin C

2016-02-01

Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

New anti-angiogenic strategies in pediatric solid malignancies: agents and biomarkers of a near future.

Science.gov (United States)

Taylor, Melissa; Rössler, Jochen; Geoerger, Birgit; Vassal, Gilles; Farace, Françoise

2010-07-01

Antiangiogenic strategies are affording considerable interest and have become a major milestone in therapeutics of various adult cancers. However, progress has been slow to expand such therapies to patients with pediatric solid malignancies. This review discusses the principal pathways for angiogenesis in pediatric solid malignancies and summarizes recent preclinical and clinical data on antiangiogenesis strategies in these tumors. The reader will gain state-of-the-art knowledge in the current advancements of antiangiogenic therapies in pediatric clinical trials in regard to supporting preclinical data, and in the status of potential biomarkers investigated for monitoring angiogenesis inhibitors. Mechanisms of resistance to antiangiogenic therapy will also be discussed. Finally, we describe our experience in the monitoring of circulating endothelial cells and progenitors and their potential role as biomarkers of metastatic disease and resistance to antiangiogenic therapies. Evaluation and development of antiangiogenesis protocols are starting and represent a crucial step in the management of pediatric solid malignancies today. Emphasis should be placed on the development of proper surrogate markers to monitor antiangiogenic activity and on the possible long-term effects of these therapies in a pediatric population.

Synthesis, development and preclinical study of EDDA based 99mTc-5-fluorouracil for brain imaging

International Nuclear Information System (INIS)

Ahmed, N.; Nuclear Medicine, Oncology and Radiotherapy Institute; Saeed, A.M.; Fatima, S.; Irfan, J.; Zia, M.; Zia, N.; Raza, A.

2016-01-01

5-Fluorouracil is used as an antineoplastic agent in solid tumors. The study was conducted to analyze the effect of EDDA on synthesis of 5-fluorouracil with 99m Tc. The 99m Tc-5-flurouracil was formulated using stannous agent, and EDDA. This complex was stable for 4 h, with post labeling efficiency of 92 %. The distribution study in animal model showed that after 30 min 35 ± 8 % of injected dose cross the blood brain barrier and excreted through kidney with no sign of toxicity. It was concluded that the addition of EDDA modified the labeling side in 5-fluorouracil for 99m Tc, which localized in brain and hence can be used further for brain imaging study. (author)

Build/Couple/Pair and Multifunctional Catalysis Strategies for the Synthesis of Heterocycles from Simple Starting Materials

DEFF Research Database (Denmark)

Ascic, Erhad

. Multifunctional Catalysis: Synthesis of Heterocycles from Simple Starting Materials A multifunctional catalysis approach, involving a ruthenium-catalyzed tandem ringclosing metathesis/isomerization/N-acyliminium cyclization sequence, is described. Double bonds created during ring-closing metathesis isomerize......, a series of interesting indolizidinones are formed in good yields with excellent diastereoselectivities, including a formal total synthesis of the antiparasitic natural product harmicine and the first total synthesis of mescalotam. Furthermore, preliminary asymmetric variants of the tandem process have...

Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Energy Technology Data Exchange (ETDEWEB)

Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B. [Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Medicine, Division of Hematology/Oncology, Boston, MA (United States)

2014-09-05

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

International Nuclear Information System (INIS)

Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B.

2014-01-01

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC

[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

Science.gov (United States)

Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

1998-01-01

The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

Effect of 5-aminolevulinic acid on erythropoiesis: A preclinical in vitro characterization for the treatment of congenital sideroblastic anemia

International Nuclear Information System (INIS)

Fujiwara, Tohru; Okamoto, Koji; Niikuni, Ryoyu; Takahashi, Kiwamu; Okitsu, Yoko; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Ichinohasama, Ryo; Nakamura, Yukio; Nakajima, Motowo; Tanaka, Tohru; Harigae, Hideo

2014-01-01

Highlights: • Treatment with ALA induces erythroid differentiation of K562 cells. • Transportation of ALA into erythroid cells occurs predominantly via SLC36A1. • ALA restores defects in ALAS2 in human iPS cell-derived erythroblasts. • ALA may represent a novel therapeutic option for CSA caused by ALAS2 mutations. - Abstract: Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly

Effect of 5-aminolevulinic acid on erythropoiesis: A preclinical in vitro characterization for the treatment of congenital sideroblastic anemia

Energy Technology Data Exchange (ETDEWEB)

Fujiwara, Tohru [Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai (Japan); Department of Molecular Hematology/Oncology, Tohoku University Graduate School, Sendai (Japan); Okamoto, Koji; Niikuni, Ryoyu [Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai (Japan); Takahashi, Kiwamu [SBI Pharmaceuticals Co., Ltd., Tokyo (Japan); Okitsu, Yoko; Fukuhara, Noriko; Onishi, Yasushi [Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai (Japan); Ishizawa, Kenichi [Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai (Japan); Clinical Research, Innovation and Education Center, Tohoku University Hospital, Sendai (Japan); Ichinohasama, Ryo [Department of Hematopathology, Tohoku University Graduate School, Sendai (Japan); Nakamura, Yukio [Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki (Japan); Nakajima, Motowo; Tanaka, Tohru [SBI Pharmaceuticals Co., Ltd., Tokyo (Japan); Harigae, Hideo, E-mail: harigae@med.tohoku.ac.jp [Department of Hematology and Rheumatology, Tohoku University Graduate School, Sendai (Japan); Department of Molecular Hematology/Oncology, Tohoku University Graduate School, Sendai (Japan)

2014-11-07

Highlights: • Treatment with ALA induces erythroid differentiation of K562 cells. • Transportation of ALA into erythroid cells occurs predominantly via SLC36A1. • ALA restores defects in ALAS2 in human iPS cell-derived erythroblasts. • ALA may represent a novel therapeutic option for CSA caused by ALAS2 mutations. - Abstract: Congenital sideroblastic anemia (CSA) is a hereditary disorder characterized by microcytic anemia and bone marrow sideroblasts. The most common form of CSA is attributed to mutations in the X-linked gene 5-aminolevulinic acid synthase 2 (ALAS2). ALAS2 is a mitochondrial enzyme, which utilizes glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA), a crucial precursor in heme synthesis. Therefore, ALA supplementation could be an effective therapeutic strategy to restore heme synthesis in CSA caused by ALAS2 defects. In a preclinical study, we examined the effects of ALA in human erythroid cells, including K562 cells and human induced pluripotent stem cell-derived erythroid progenitor (HiDEP) cells. ALA treatment resulted in significant dose-dependent accumulation of heme in the K562 cell line. Concomitantly, the treatment substantially induced erythroid differentiation as assessed using benzidine staining. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis confirmed significant upregulation of heme-regulated genes, such as the globin genes [hemoglobin alpha (HBA) and hemoglobin gamma (HBG)] and the heme oxygenase 1 (HMOX1) gene, in K562 cells. Next, to investigate the mechanism by which ALA is transported into erythroid cells, quantitative RT-PCR analysis was performed on previously identified ALA transporters, including solute carrier family 15 (oligopeptide transporter), member (SLC15A) 1, SLC15A2, solute carrier family 36 (proton/amino acid symporter), member (SLC36A1), and solute carrier family 6 (neurotransmitter transporter), member 13 (SLC6A13). Our analysis revealed that SLC36A1 was abundantly

Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

Science.gov (United States)

Siegler, Elizabeth Louise; Wang, Pin

2018-05-01

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

Fluorous Parallel Synthesis of A Hydantoin/Thiohydantoin Library

Science.gov (United States)

Lu, Yimin; Zhang, Wei

2007-01-01

Fluorous tagging strategy is applied to solution-phase parallel synthesis of a library containing hydantoin and thiohydantoin analogs. Two perfluoroalkyl (Rf)-tagged α-amino esters each react with 6 aromatic aldehydes under reductive amination conditions. Twelve amino esters then each react with 10 isocyanates and isothiocyanates in parallel. The resulting 120 ureas and thioureas undergo spontaneous cyclization to form the corresponding hydantoins and thiohydantoins. The intermediate and final product purifications are performed with solid-phase extraction (SPE) over FluoroFlash™ cartridges, no chromatography is required. Using standard instruments and straightforward SPE technique, one chemist accomplished the 120-member library synthesis in less than 5 working days, including starting material synthesis and product analysis. PMID:15789556

Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

Directory of Open Access Journals (Sweden)

Samarasekera Dharmabandu N

2011-05-01

Full Text Available Abstract Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA, strategic approach (SA and surface apathetic or superficial approach (SAA. The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST questionnaire. Results A total of 187 pre clinical (M: F = 96:91, 124 clinical (M: F = 61:63 and 53 post graduate trainees (M: F = 50:3 participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01, but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04 but females preferred a passive transmission of information (p Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed.

The preclinical discovery and development of quetiapine for the treatment of mania and depression.

Science.gov (United States)

Miranda, Aline Silva de; Moreira, Fabrício A; Teixeira, Antônio Lúcio

2017-05-01

Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

Fully automated synthesis of ¹¹C-acetate as tumor PET tracer by simple modified solid-phase extraction purification.

Science.gov (United States)

Tang, Xiaolan; Tang, Ganghua; Nie, Dahong

2013-12-01

Automated synthesis of (11)C-acetate ((11)C-AC) as the most commonly used radioactive fatty acid tracer is performed by a simple, rapid, and modified solid-phase extraction (SPE) purification. Automated synthesis of (11)C-AC was implemented by carboxylation reaction of MeMgBr on a polyethylene Teflon loop ring with (11)C-CO2, followed by acidic hydrolysis with acid and SCX cartridge, and purification on SCX, AG11A8 and C18 SPE cartridges using a commercially available (11)C-tracer synthesizer. Quality control test and animals positron emission tomography (PET) imaging were also carried out. A high and reproducible decay-uncorrected radiochemical yield of (41.0 ± 4.6)% (n=10) was obtained from (11)C-CO2 within the whole synthesis time about 8 min. The radiochemical purity of (11)C-AC was over 95% by high-performance liquid chromatography (HPLC) analysis. Quality control test and PET imaging showed that (11)C-AC injection produced by the simple SPE procedure was safe and efficient, and was in agreement with the current Chinese radiopharmaceutical quality control guidelines. The novel, simple, and rapid method is readily adapted to the fully automated synthesis of (11)C-AC on several existing commercial synthesis module. The method can be used routinely to produce (11)C-AC for preclinical and clinical studies with PET imaging. Copyright © 2013 Elsevier Ltd. All rights reserved.

Challenges and strategies in the repair of ruptured annulus fibrosus

Directory of Open Access Journals (Sweden)

CC Guterl

2013-01-01

Full Text Available Lumbar discectomy is the surgical procedure most frequently performed for patients suffering from low back pain and sciatica. Disc herniation as a consequence of degenerative or traumatic processes is commonly encountered as the underlying cause for the painful condition. While discectomy provides favourable outcome in a majority of cases, there are conditions where unmet requirements exist in terms of treatment, such as large disc protrusions with minimal disc degeneration; in these cases, the high rate of recurrent disc herniation after discectomy is a prevalent problem. An effective biological annular repair could improve the surgical outcome in patients with contained disc herniations but otherwise minor degenerative changes. An attractive approach is a tissue-engineered implant that will enable/stimulate the repair of the ruptured annulus. The strategy is to develop three-dimensional scaffolds and activate them by seeding cells or by incorporating molecular signals that enable new matrix synthesis at the defect site, while the biomaterial provides immediate closure of the defect and maintains the mechanical properties of the disc. This review is structured into (1 introduction, (2 clinical problems, current treatment options and needs, (3 biomechanical demands, (4 cellular and extracellular components, (5 biomaterials for delivery, scaffolding and support, (6 pre-clinical models for evaluation of newly developed cell- and material-based therapies, and (7 conclusions. This article highlights that an interdisciplinary approach is necessary for successful development of new clinical methods for annulus fibrosus repair. This will benefit from a close collaboration between research groups with expertise in all areas addressed in this review.

Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.

Science.gov (United States)

Ishida, Kazuyoshi; Berger, Miles; Nadler, Jacob; Warner, David S

2014-01-01

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

Science.gov (United States)

Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

2015-06-01

Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

NARCIS (Netherlands)

van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

2005-01-01

Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

A Synthesis of Language Learning Strategies: Current Issues, Problems and Claims Made in Learner Strategy Research

Science.gov (United States)

Barjesteh, Hamed; Mukundan, Jayakaran; Vaseghi, Reza

2014-01-01

The current paper presented theoretical assumptions behind language learning strategies (LLS) and an overview of methods used to identify learners' strategies, first, and then summarized what have been reported from large number of descriptive studies of strategies by language learners. Moreover, the paper tried to present the variety of…

Developing Potential Candidates of Preclinical Preeclampsia

Directory of Open Access Journals (Sweden)

Sandra Founds

2015-11-01

Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

Ethical Considerations of Preclinical Testing

Directory of Open Access Journals (Sweden)

Allen Goldenthal

2015-12-01

Full Text Available The numbers of animal tests being conducted are on a sharp incline.  Much of this increase is directly due to our ability to generate transgenic models and knock-outs, thereby increasing the validity of the animal model but not necessarily correlating directly with any translational medical benefits to the human counterpart.  In spite of our best efforts, there still exist species differences that prevent the application directly from animal to human, and in some examples having a completely different and adverse effect from that seen in the animal model. There are several ways in which we can improve the opportunity for a positive test outcome and at the same time reduce the animal usage which is associated with our current animal testing practices. The benefit of the 3R’s is that they encourage us not only to avoid wastage of life but that they require us to provide considerable foresight and extrapolated thought before directly engaging in the preclinical testing phase.

Strategies for the etiological therapy of cystic fibrosis.

Science.gov (United States)

Maiuri, Luigi; Raia, Valeria; Kroemer, Guido

2017-11-01

Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies.

Synthesis of Biochemical Applications on Digital Microfluidic Biochips with Operation Execution Time Variability

DEFF Research Database (Denmark)

Alistar, Mirela; Pop, Paul

2015-01-01

that each biochemical operation in an application is characterized by a worst-case execution time (wcet). However, during the execution of the application, due to variability and randomness in biochemical reactions, operations may finish earlier than their wcetswcets, resulting in unexploited slack...... in the schedule. In this paper, we first propose an online synthesis strategy that re-synthesizes the application at runtime when operations experience variability in their execution time, exploiting thus the slack to obtain shorter application completion times. We also propose a quasi-static synthesis strategy...... approaches have been proposed for the synthesis of digital microfluidic biochips, which, starting from a biochemical application and a given biochip architecture, determine the allocation, resource binding, scheduling, placement and routing of the operations in the application. Researchers have assumed...

Schedulability-Driven Communication Synthesis for Time Triggered Embedded Systems

DEFF Research Database (Denmark)

Pop, Paul; Eles, Petru; Peng, Zebo

2006-01-01

We present an approach to static priority preemptive process scheduling for the synthesis of hard real-time distributed embedded systems where communication plays an important role. The communication model is based on a time-triggered protocol. We have developed an analysis for the communication...... delays proposing four different message scheduling policies over a time-triggered communication channel. Optimization strategies for the synthesis of communication are developed, and the four approaches to message scheduling are compared using extensive experiments...

Schedulability-Driven Communication Synthesis for Time Triggered Embedded Systems

DEFF Research Database (Denmark)

Pop, Paul; Eles, Petru; Peng, Zebo

1999-01-01

We present an approach to static priority preemptive process scheduling for the synthesis of hard real-time distributed embedded systems where communication plays an important role. The communication model is based on a time-triggered protocol. We have developed an analysis for the communication...... delays proposing four different message scheduling policies over a time-triggered communication channel. Optimization strategies for the synthesis of communication are developed, and the four approaches to message scheduling are compared using extensive experiments....

Schedulability-Driven Communication Synthesis for Time Triggered Embedded Systems

DEFF Research Database (Denmark)

Pop, Paul; Eles, Petru; Peng, Zebo

2004-01-01

We present an approach to static priority preemptive process scheduling for the synthesis of hard real-time distributed embedded systems where communication plays an important role. The communication model is based on a time-triggered protocol. We have developed an analysis for the communication...... delays with four different message scheduling policies over a time-triggered communication channel. Optimization strategies for the synthesis of communication are developed, and the four approaches to message scheduling are compared using extensive experiments....

The prevalence and consequences of burnout on a group of preclinical dental students.

Science.gov (United States)

Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

2015-01-01

The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment.

The Australian Medical Schools Assessment Collaboration: benchmarking the preclinical performance of medical students.

Science.gov (United States)

O'Mara, Deborah A; Canny, Ben J; Rothnie, Imogene P; Wilson, Ian G; Barnard, John; Davies, Llewelyn

2015-02-02

To report the level of participation of medical schools in the Australian Medical Schools Assessment Collaboration (AMSAC); and to measure differences in student performance related to medical school characteristics and implementation methods. Retrospective analysis of data using the Rasch statistical model to correct for missing data and variability in item difficulty. Linear model analysis of variance was used to assess differences in student performance. 6401 preclinical students from 13 medical schools that participated in AMSAC from 2011 to 2013. Rasch estimates of preclinical basic and clinical science knowledge. Representation of Australian medical schools and students in AMSAC more than doubled between 2009 and 2013. In 2013 it included 12 of 19 medical schools and 68% of medical students. Graduate-entry students scored higher than students entering straight from school. Students at large schools scored higher than students at small schools. Although the significance level was high (P performance. The effect on performance of multiple assessments compared with the test items as part of a single end-of-year examination was negligible. The variables investigated explain only 12% of the total variation in student performance. An increasing number of medical schools are participating in AMSAC to monitor student performance in preclinical sciences against an external benchmark. Medical school characteristics account for only a small part of overall variation in student performance. Student performance was not affected by the different methods of administering test items.

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

International Nuclear Information System (INIS)

Medin, Paul M.; Boike, Thomas P.

2011-01-01

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Perceptions of Teaching Methods for Preclinical Oral Surgery: A Comparison with Learning Styles.

Science.gov (United States)

Omar, Esam

2017-01-01

Dental extraction is a routine part of clinical dental practice. For this reason, understanding the way how students' extraction knowledge and skills development are important. To date, there is no accredited statement about the most effective method for the teaching of exodontia to dental students. Students have different abilities and preferences regarding how they learn and process information. This is defined as learning style. In this study, the effectiveness of active learning in the teaching of preclinical oral surgery was examined. The personality type of the groups involved in this study was determined, and the possible effect of personality type on learning style was investigated. This study was undertaken over five years from 2011 to 2015. The sample consisted of 115 students and eight staff members. Questionnaires were submitted by 68 students and all eight staff members involved. Three measures were used in the study: The Index of Learning Styles (Felder and Soloman, 1991), the Myers-Briggs Type Indicator (MBTI), and the styles of learning typology (Grasha and Hruska-Riechmann). Findings indicated that demonstration and minimal clinical exposure give students personal validation. Frequent feedback on their work is strongly indicated to build the cognitive, psychomotor, and interpersonal skills needed from preclinical oral surgery courses. Small group cooperative active learning in the form of demonstration and minimal clinical exposure that gives frequent feedback and students' personal validation on their work is strongly indicated to build the skills needed for preclinical oral surgery courses.

Natural product synthesis at the interface of chemistry and biology

Science.gov (United States)

2014-01-01

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID:25043880

A facile and scalable strategy for synthesis of size-tunable NiCo2O4 with nanocoral-like architecture for high-performance supercapacitors

International Nuclear Information System (INIS)

Tao, Yan; Ruiyi, Li; Zaijun, Li; Yinjun, Fang

2014-01-01

Graphical abstract: We reported a facile and scalable strategy for synthesis of size-tunable NiCo 2 O 4 with nanocoral-like architecture. The unique structure will improve faradaic redox reaction and mass transfer, NiCo 2 O 4 offers excellent electrochemical performance for supercapacitors. - Highlights: • We reported a facile and scalable strategy for synthesis of size-tunable NiCo 2 O 4 withnanocoral-lide architecture. • Combination of microwave and tertbutanol as medium creates ultrathin nickel/cobalt double hydroxide with flowerclusters. • The method is very simple, rapid and efficient, it can be used for large scale productionof nanomaterials. • The size of NiCo 2 O 4 nanocorals is easy to be can be controlled by adjusting calcination temperature. • Unique structure enhances rates of electron transfer and mass transport, NiCo 2 O 4 shows high electrochemical performance. - Abstract: There is a great need to develop high-performance electroactive materials for supercapacitors. The study reported a facile and scalable strategy for synthesis of size-tunable NiCo 2 O 4 with nanocoral-like architecture. Cobalt nitrate and nickel nitrate were dissolved in a tertbutanol solution and heated to reflux state under microwave radiation. The amounts of ammonia was dropped into the mixed solution to form nickel/cobalt double hydroxides. The reaction can complete within 15 min with the productivity of 99.9%. The obtained double hydroxides display flowercluster-like ultrathin nanostructure. The double hydroxide was calcined into different NiCo 2 O 4 products using different calcination temperature, including 400 °C, 500 °C, 600 °C and 700 °C. The resulting NiCo 2 O 4 is of nanocoral-like architecture. Interestingly, the size of coral can be easily controlled by adjusting the temperature. The NiCo 2 O 4 prepared at 400°C gives a minimum building block size (10.2 nm) and maximum specific surface area (108.8 m 2 ·g −1 ). The unique structure will greatly

Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies.

Science.gov (United States)

Homberg, Judith R; Kyzar, Evan J; Stewart, Adam Michael; Nguyen, Michael; Poudel, Manoj K; Echevarria, David J; Collier, Adam D; Gaikwad, Siddharth; Klimenko, Viktor M; Norton, William; Pittman, Julian; Nakamura, Shun; Koshiba, Mamiko; Yamanouchi, Hideo; Apryatin, Sergey A; Scattoni, Maria Luisa; Diamond, David M; Ullmann, Jeremy F P; Parker, Matthew O; Brown, Richard E; Song, Cai; Kalueff, Allan V

2016-01-01

Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

Gold-catalyzed Alkyne Hydroxylation: Synthesis of 2-Substituted Benzo[b]furan Compounds

Institute of Scientific and Technical Information of China (English)

ZHANG Yuan; XIN Zhi-Jun; XUE Ji-Jun; LI Ying

2008-01-01

A strategy concerning the synthesis of 2-substituted benzo[b]furan compounds from o-alkynyl phenols via a gold-catalyzed alkyne hydroxylation is described, which allows the rapid synthesis of various 2-substituted benzo[b]furan derivatives in excellent yields under mild conditions. The o-alkynyl phenol precursors were readily prepared with a Sonogashira coupling reaction.

Sex differences in the vulnerability to drug abuse: a review of preclinical studies.

Science.gov (United States)

Roth, Megan E; Cosgrove, Kelly P; Carroll, Marilyn E

2004-10-01

Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms of action underlying these sex differences. This review examines the preclinical literature on sex differences and ovarian hormonal influences on drug self-administration in animals. It summarizes the findings on the effects of these variables during different phases of drug addiction. Possible differences in the mechanisms of action of drugs of abuse due to interactions with sex differences or ovarian hormonal factors are considered. The animal literature on sex differences in drug abuse treatment effectiveness is also discussed.

Secondhand Smoke Exposure and Preclinical Markers of Cardiovascular Risk in Toddlers.

Science.gov (United States)

Groner, Judith A; Huang, Hong; Joshi, Mandar S; Eastman, Nicholas; Nicholson, Lisa; Bauer, John Anthony

2017-10-01

To investigate relationships between secondhand smoke exposure in young children and several preclinical markers of cardiovascular risk that have been established as relevant to adult populations. There were 139 children, 2-5 years of age, enrolled in a cross-sectional study. Secondhand smoke exposure was objectively determined by hair nicotine level; a comprehensive panel of clinical markers (morning blood pressure, fasting glucose and insulin, lipid profiles, inflammation) and research markers (markers of oxidation, endothelial stress, and endothelial repair) of cardiovascular risk status were assessed. Univariate and multivariate linear regression were used to evaluate relationships between secondhand smoke exposure and cardiovascular risk markers. Hair nicotine levels were correlated directly with blood pressure and serum C-reactive protein, and inversely correlated with serum high-density lipoprotein cholesterol and endothelial cell progenitor cell prevalence. In multivariate analyses, these relationships remained when controlled for age, sex, body mass index z-score, maternal education, and method of payment. Additionally, in multivariate analyses, hair nicotine level was significantly negatively correlated with total antioxidant capacity. These results support the view that secondhand smoke exposure in the very young has a detectable relationship with several markers of cardiovascular risk, long before the emergence of clinical disease. Further studies to define mechanisms and strategies to prevent and mitigate these risks early in life are warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthetic Strategies for Converting Carbohydrates into Carbocycles by the Use of Olefin Metathesis

DEFF Research Database (Denmark)

Madsen, Robert

2007-01-01

This microreview covers recent advances in the use of ring-closing metathesis for the synthesis of carbocycles from carbohydrates. Various strategies for the synthesis of a,w-dienes from carbohydrates are presented, which give rise to a large variety of dienes with different stereochemistry, prot...

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

Science.gov (United States)

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery

Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors

International Nuclear Information System (INIS)

Christiaans, Johannes A.M.; Klein, Pieter J.; Metaxas, Athanasios; Kooijman, Esther J.M.; Schuit, Robert C.; Leysen, Josée E.; Lammertsma, Adriaan A.; Berckel, Bart N.M. van; Windhorst, Albert D.

2014-01-01

Introduction: The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods: N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results: N-((5-(4-fluoro-2-[ 11 C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49 ± 3% (decay-corrected) yield, affording 4.1 ± 0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of > 99% and with a specific activity of 78 ± 10 GBq/μmol. Conclusion: A new NR2B PET ligand was developed in high yield. [ 11 C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [ 11 C]4 as an NR2B PET ligand

Total Radiosynthesis: Thinking outside “the box”

Science.gov (United States)

Liang, Steven H.; Vasdev, Neil

2016-01-01

. As with the vast majority of drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models prior to optimization or derivatization of the lead molecules/drugs is necessary. Furthermore the exact position of the 11C and 18F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce the radiolabel are needed. Using the principles of total synthesis our laboratory and others have shown that multi-step radiochemical reactions are indeed suitable for preclinical and even clinical use. As the goal of total synthesis is to be concise, we have also simplified the syntheses of radiopharmaceuticals. We are presently developing new strategies via [11C]CO2 fixation which has enabled library radiosynthesis as well as labeling non-activated arenes using [18F]fluoride via iodonium ylides. Both of which have proven to be suitable for human PET imaging. We concurrently utilize state-of-the-art automation technologies including microfluidic flow chemistry and rapid purification strategies for radiopharmaceutical production. In this account we highlight how total radiosynthesis has impacted our radiochemistry program, with prominent examples from others, focusing on its impact towards preclinical and clinical research studies. PMID:27512156

Total Radiosynthesis: Thinking outside "the box".

Science.gov (United States)

Liang, Steven H; Vasdev, Neil

2015-09-01

. As with the vast majority of drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models prior to optimization or derivatization of the lead molecules/drugs is necessary. Furthermore the exact position of the 11 C and 18 F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce the radiolabel are needed. Using the principles of total synthesis our laboratory and others have shown that multi-step radiochemical reactions are indeed suitable for preclinical and even clinical use. As the goal of total synthesis is to be concise, we have also simplified the syntheses of radiopharmaceuticals. We are presently developing new strategies via [ 11 C]CO 2 fixation which has enabled library radiosynthesis as well as labeling non-activated arenes using [ 18 F]fluoride via iodonium ylides. Both of which have proven to be suitable for human PET imaging. We concurrently utilize state-of-the-art automation technologies including microfluidic flow chemistry and rapid purification strategies for radiopharmaceutical production. In this account we highlight how total radiosynthesis has impacted our radiochemistry program, with prominent examples from others, focusing on its impact towards preclinical and clinical research studies.

Synthesis of Methyl Diantilis, a Commercially Important Fragrance

Science.gov (United States)

Miles, William H.; Connell, Katelyn B.

2006-01-01

Synthetic sequences in the undergraduate organic chemistry laboratory illustrate important synthetic strategies, reagents, or experimental techniques, oftentimes resulting in the synthesis of commercially important compounds. A fragrance with a 'spicy, carnation, sweet, vanilla', named after carnations (Dianthus caryophllus), Methyl Diantillis is…

Pharmacological Strategies to Retard Cardiovascular Aging

Science.gov (United States)

Alfaras, Irene; Di Germanio, Clara; Bernier, Michel; Csiszar, Anna; Ungvari, Zoltan; Lakatta, Edward G.; de Cabo, Rafael

2016-01-01

Aging is the major risk factor for cardiovascular diseases (CVD), which are the leading cause of death in the United States. Traditionally, the effort to prevent CVD has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat CVD. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the pro-longevity benefits of various therapeutic strategies that support cardiovascular health. PMID:27174954

Adapting realist synthesis methodology: The case of workplace harassment interventions.

Science.gov (United States)

Carr, Tracey; Quinlan, Elizabeth; Robertson, Susan; Gerrard, Angie

2017-12-01

Realist synthesis techniques can be used to assess complex interventions by extracting and synthesizing configurations of contexts, mechanisms, and outcomes found in the literature. Our novel and multi-pronged approach to the realist synthesis of workplace harassment interventions describes our pursuit of theory to link macro and program level theories. After discovering the limitations of a dogmatic approach to realist synthesis, we adapted our search strategy and focused our analysis on a subset of data. We tailored our realist synthesis to understand how, why, and under what circumstances workplace harassment interventions are effective. The result was a conceptual framework to test our theory-based interventions and provide the basis for subsequent realist evaluation. Our experience documented in this article contributes to an understanding of how, under what circumstances, and with what consequences realist synthesis principles can be customized. Copyright © 2017 John Wiley & Sons, Ltd.

Solventless synthesis of ruthenium nanoparticles

Energy Technology Data Exchange (ETDEWEB)

García-Peña, Nidia G. [Departmento de Tecnociencias, Universidad Nacional Autónoma de México, Centro de Ciencias Aplicadas y Desarrollo Tecnológico, Universidad Nacional Autónoma de México, Cd. Universitaria A.P. 70-186, C.P. 04510 Coyoacán, México D.F. (Mexico); Redón, Rocío, E-mail: rredon@unam.mx [Departmento de Tecnociencias, Universidad Nacional Autónoma de México, Centro de Ciencias Aplicadas y Desarrollo Tecnológico, Universidad Nacional Autónoma de México, Cd. Universitaria A.P. 70-186, C.P. 04510 Coyoacán, México D.F. (Mexico); Herrera-Gomez, Alberto [Estudios Avanzados del Instituto Politécnico Nacional, Campus Juriquilla, Querétaro (Mexico); Fernández-Osorio, Ana Leticia [FES-Cuautitlán, Universidad Nacional Autónoma de México, Edo. de Mexico (Mexico); Bravo-Sanchez, Mariela; Gomez-Sosa, Gustavo [Estudios Avanzados del Instituto Politécnico Nacional, Campus Juriquilla, Querétaro (Mexico)

2015-06-15

Graphical abstract: - Highlights: • Successful synthesis of Ru nanoparticles by a cheap, fast and solventless approach was achieved. • The zero-valent state as well as the by-product/impurity free of the mechanochemical obtained Ru nanoparticles was proven by XPS, TEM and XRD. • Compared to two other synthesis strategies, the above-mentioned synthesis was more suitable to obtain smaller particles with fewer impurities in shorter time. - Abstract: This paper presents a novel solventless method for the synthesis of zero-valent ruthenium nanoparticles Ru(0). The proposed method, although not entirely new in the nanomaterials world, was used for the first time to synthesize zero-valent ruthenium nanoparticles. This new approach has proved to be an environmentally friendly, clean, cheap, fast, and reproducible technique which employs low amounts of solvent. It was optimized through varying amounts of reducing salt on a determined quantity of precursor and measuring the effect of this variation on the average particle size obtained. The resulting products were fully characterized by powder XRD, TEM, HR-TEM, and XPS studies, all of which corroborated the purity of the nanoparticles achieved. In order to verify the advantages of our method over other techniques, we compared our nanoparticles with two common colloidal-synthesized ruthenium nanoparticles.

Pre-clinical evaluation of extracts and essential oils from betel-like ...

African Journals Online (AJOL)

The extracts and oils were preclinically studied based on cyto - and genotoxicity using microculture tetrazolium (MTT) and comet assays. Results: The crude extracts showed an IC50 in leukocytes and HeLa cells of 58.59 -97.31 mg/ml and 34.91-101.79 mg/ml, the LD50 is higher than 5000 mg/kg. With lower values than the ...

Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

Energy Technology Data Exchange (ETDEWEB)

Zhang, Bin [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Wang, Ken Kang-Hsin, E-mail: kwang27@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Yu, Jingjing [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); School of Physics and Information Technology, Shaanxi Normal University, Shaanxi (China); Eslami, Sohrab; Iordachita, Iulian [Laboratory for Computational Sensing and Robotics, Johns Hopkins University, Baltimore, Maryland (United States); Reyes, Juvenal; Malek, Reem [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Department of Oncology and Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland (United States); Patterson, Michael S. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario (Canada); Wong, John W. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States)

2016-04-01

Purpose: In preclinical radiation research, it is challenging to localize soft tissue targets based on cone beam computed tomography (CBCT) guidance. As a more effective method to localize soft tissue targets, we developed an online bioluminescence tomography (BLT) system for small-animal radiation research platform (SARRP). We demonstrated BLT-guided radiation therapy and validated targeting accuracy based on a newly developed reconstruction algorithm. Methods and Materials: The BLT system was designed to dock with the SARRP for image acquisition and to be detached before radiation delivery. A 3-mirror system was devised to reflect the bioluminescence emitted from the subject to a stationary charge-coupled device (CCD) camera. Multispectral BLT and the incomplete variables truncated conjugate gradient method with a permissible region shrinking strategy were used as the optimization scheme to reconstruct bioluminescent source distributions. To validate BLT targeting accuracy, a small cylindrical light source with high CBCT contrast was placed in a phantom and also in the abdomen of a mouse carcass. The center of mass (CoM) of the source was recovered from BLT and used to guide radiation delivery. The accuracy of the BLT-guided targeting was validated with films and compared with the CBCT-guided delivery. In vivo experiments were conducted to demonstrate BLT localization capability for various source geometries. Results: Online BLT was able to recover the CoM of the embedded light source with an average accuracy of 1 mm compared to that with CBCT localization. Differences between BLT- and CBCT-guided irradiation shown on the films were consistent with the source localization revealed in the BLT and CBCT images. In vivo results demonstrated that our BLT system could potentially be applied for multiple targets and tumors. Conclusions: The online BLT/CBCT/SARRP system provides an effective solution for soft tissue targeting, particularly for small, nonpalpable, or

Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

International Nuclear Information System (INIS)

Zhang, Bin; Wang, Ken Kang-Hsin; Yu, Jingjing; Eslami, Sohrab; Iordachita, Iulian; Reyes, Juvenal; Malek, Reem; Tran, Phuoc T.; Patterson, Michael S.; Wong, John W.

2016-01-01

Purpose: In preclinical radiation research, it is challenging to localize soft tissue targets based on cone beam computed tomography (CBCT) guidance. As a more effective method to localize soft tissue targets, we developed an online bioluminescence tomography (BLT) system for small-animal radiation research platform (SARRP). We demonstrated BLT-guided radiation therapy and validated targeting accuracy based on a newly developed reconstruction algorithm. Methods and Materials: The BLT system was designed to dock with the SARRP for image acquisition and to be detached before radiation delivery. A 3-mirror system was devised to reflect the bioluminescence emitted from the subject to a stationary charge-coupled device (CCD) camera. Multispectral BLT and the incomplete variables truncated conjugate gradient method with a permissible region shrinking strategy were used as the optimization scheme to reconstruct bioluminescent source distributions. To validate BLT targeting accuracy, a small cylindrical light source with high CBCT contrast was placed in a phantom and also in the abdomen of a mouse carcass. The center of mass (CoM) of the source was recovered from BLT and used to guide radiation delivery. The accuracy of the BLT-guided targeting was validated with films and compared with the CBCT-guided delivery. In vivo experiments were conducted to demonstrate BLT localization capability for various source geometries. Results: Online BLT was able to recover the CoM of the embedded light source with an average accuracy of 1 mm compared to that with CBCT localization. Differences between BLT- and CBCT-guided irradiation shown on the films were consistent with the source localization revealed in the BLT and CBCT images. In vivo results demonstrated that our BLT system could potentially be applied for multiple targets and tumors. Conclusions: The online BLT/CBCT/SARRP system provides an effective solution for soft tissue targeting, particularly for small, nonpalpable, or

RAFT polymerization mediated bioconjugation strategies

OpenAIRE

Bulmuş, Volga

2011-01-01

This review aims to highlight the use of RAFT polymerization in the synthesis of polymer bioconjugates. It covers two main bioconjugation strategies using the RAFT process: (i) post-polymerization bioconjugations using pre-synthesized reactive polymers, and (ii) bioconjugations via in situ polymerization using biomolecule-modified monomers or chain transfer agents. © 2011 The Royal Society of Chemistry.

Pre-clinical research in small animals using radiotherapy technology. A bidirectional translational approach

International Nuclear Information System (INIS)

Tillner, Falk; Buetof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang; Helmholtz-Zentrum Dresden-Rossendorf, Dresden; Technische Univ. Dresden; Helmholtz-Zentrum Dresden-Rossendorf, Dresden

2014-01-01

For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies

Directory of Open Access Journals (Sweden)

A.G.M. Mostofa

2017-06-01

Full Text Available Thymoquinone (TQ, the main bioactive component of Nigella sativa, has been found to exhibit anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Moreover, TQ can specifically sensitize tumor cells toward conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy and simultaneously minimize therapy-associated toxic effects in normal cells. In this review, we summarized the adjuvant potential of TQ as observed in various in vitro and in vivo animal models and discussed the pharmacological properties of TQ to rationalize its supplementary role in potentiating the efficacy of standard therapeutic modalities namely surgery, radiotherapy, chemotherapy, and immunotherapy. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical levels to delineate its implied utility as a novel complementary adjuvant therapy for cancer treatment.

Tendinopathies and platelet-rich plasma (PRP: from pre-clinical experiments to therapeutic use

Directory of Open Access Journals (Sweden)

Kaux JF

2015-05-01

Full Text Available Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed.

A student-initiated and student-facilitated international health elective for preclinical medical students.

Science.gov (United States)

Vora, Nirali; Chang, Mina; Pandya, Hemang; Hasham, Aliya; Lazarus, Cathy

2010-02-15

Global health education is becoming more important for developing well-rounded physicians and may encourage students toward a career in primary care. Many medical schools, however, lack adequate and structured opportunities for students beginning the curriculum. Second-year medical students initiated, designed, and facilitated a pass-fail international health elective, providing a curricular framework for preclinical medical students wishing to gain exposure to the clinical and cultural practices of a developing country. All course participants (N=30) completed a post-travel questionnaire within one week of sharing their experiences. Screening reflection essays for common themes that fulfill university core competencies yielded specific global health learning outcomes, including analysis of health care determinants. Medical students successfully implemented a sustainable global health curriculum for preclinical student peers. Financial constraints, language, and organizational burdens limit student participation. In future, long-term studies should analyze career impact and benefits to the host country.

Pre-clinical research in small animals using radiotherapy technology. A bidirectional translational approach

Energy Technology Data Exchange (ETDEWEB)

Tillner, Falk; Buetof, Rebecca [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Thute, Prasad [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Krause, Mechthild [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; German Cancer Consortium (DKTK), Dresden (Germany); German Cancer Research Center (DKFZ), Heidelberg (Germany); Enghardt, Wolfgang [Technische Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Univ. Dresden (Germany). Dept. of Radiation Oncology; Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany). Inst. of Radiooncology

2014-07-01

For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained.

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

Science.gov (United States)

Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

Perceptions of Teaching Methods for Preclinical Oral Surgery: A Comparison with Learning Styles

Science.gov (United States)

Omar, Esam

2017-01-01

Purpose: Dental extraction is a routine part of clinical dental practice. For this reason, understanding the way how students’ extraction knowledge and skills development are important. Problem Statement and Objectives: To date, there is no accredited statement about the most effective method for the teaching of exodontia to dental students. Students have different abilities and preferences regarding how they learn and process information. This is defined as learning style. In this study, the effectiveness of active learning in the teaching of preclinical oral surgery was examined. The personality type of the groups involved in this study was determined, and the possible effect of personality type on learning style was investigated. Method: This study was undertaken over five years from 2011 to 2015. The sample consisted of 115 students and eight staff members. Questionnaires were submitted by 68 students and all eight staff members involved. Three measures were used in the study: The Index of Learning Styles (Felder and Soloman, 1991), the Myers-Briggs Type Indicator (MBTI), and the styles of learning typology (Grasha and Hruska-Riechmann). Results and Discussion: Findings indicated that demonstration and minimal clinical exposure give students personal validation. Frequent feedback on their work is strongly indicated to build the cognitive, psychomotor, and interpersonal skills needed from preclinical oral surgery courses. Conclusion: Small group cooperative active learning in the form of demonstration and minimal clinical exposure that gives frequent feedback and students’ personal validation on their work is strongly indicated to build the skills needed for preclinical oral surgery courses. PMID:28357004

Preclinical evaluation of human T lymphocytes in RAG2-/-γc-/- mice

NARCIS (Netherlands)

Rijn, R.S. van

2006-01-01

This thesis describes the development and application of a new model for the preclinical study of human T cells by transfer of huPBMCs into RAG2-/-γc-/- immunodeficient mice. The ultimate goal of treating patients with a malignancy is to eradicate the malignant cells, while keeping hold of damage to

Industrial scale gene synthesis.

Science.gov (United States)

Notka, Frank; Liss, Michael; Wagner, Ralf

2011-01-01

The most recent developments in the area of deep DNA sequencing and downstream quantitative and functional analysis are rapidly adding a new dimension to understanding biochemical pathways and metabolic interdependencies. These increasing insights pave the way to designing new strategies that address public needs, including environmental applications and therapeutic inventions, or novel cell factories for sustainable and reconcilable energy or chemicals sources. Adding yet another level is building upon nonnaturally occurring networks and pathways. Recent developments in synthetic biology have created economic and reliable options for designing and synthesizing genes, operons, and eventually complete genomes. Meanwhile, high-throughput design and synthesis of extremely comprehensive DNA sequences have evolved into an enabling technology already indispensable in various life science sectors today. Here, we describe the industrial perspective of modern gene synthesis and its relationship with synthetic biology. Gene synthesis contributed significantly to the emergence of synthetic biology by not only providing the genetic material in high quality and quantity but also enabling its assembly, according to engineering design principles, in a standardized format. Synthetic biology on the other hand, added the need for assembling complex circuits and large complexes, thus fostering the development of appropriate methods and expanding the scope of applications. Synthetic biology has also stimulated interdisciplinary collaboration as well as integration of the broader public by addressing socioeconomic, philosophical, ethical, political, and legal opportunities and concerns. The demand-driven technological achievements of gene synthesis and the implemented processes are exemplified by an industrial setting of large-scale gene synthesis, describing production from order to delivery. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of the National Teenage Pregnancy Strategy: final synthesis report

OpenAIRE

Wellings, Kaye; Wilkinson, Paul; Kane, Ros

2005-01-01

The Teenage Pregnancy Strategy in England, published in June 1999, is a multifaceted strategy that includes action to both halve the under 18 conception rate by 2010 and provide support to teenage parents to reduce the long term risk of social exclusion by increasing the proportion in education, training and employment. The Strategy has four major components: 1) a national media awareness campaign via independent radio and teenage magazines, 2) joined up action to ensure that ...

Precursor Mediated Synthesis of Nanostructured Silicas: From Precursor-Surfactant Ion Pairs to Structured Materials.

Science.gov (United States)

Hesemann, Peter; Nguyen, Thy Phung; Hankari, Samir El

2014-04-11

The synthesis of nanostructured anionic-surfactant-templated mesoporous silica (AMS) recently appeared as a new strategy for the formation of nanostructured silica based materials. This method is based on the use of anionic surfactants together with a co-structure-directing agent (CSDA), mostly a silylated ammonium precursor. The presence of this CSDA is necessary in order to create ionic interactions between template and silica forming phases and to ensure sufficient affinity between the two phases. This synthetic strategy was for the first time applied in view of the synthesis of surface functionalized silica bearing ammonium groups and was then extended on the formation of materials functionalized with anionic carboxylate and bifunctional amine-carboxylate groups. In the field of silica hybrid materials, the "anionic templating" strategy has recently been applied for the synthesis of silica hybrid materials from cationic precursors. Starting from di- or oligosilylated imidazolium and ammonium precursors, only template directed hydrolysis-polycondensation reactions involving complementary anionic surfactants allowed accessing structured ionosilica hybrid materials. The mechanistic particularity of this approach resides in the formation of precursor-surfactant ion pairs in the hydrolysis-polycondensation mixture. This review gives a systematic overview over the various types of materials accessed from this cooperative ionic templating approach and highlights the high potential of this original strategy for the formation of nanostructured silica based materials which appears as a complementary strategy to conventional soft templating approaches.

Neurosurgery Elective for Preclinical Medical Students: Early Exposure and Changing Attitudes.

Science.gov (United States)

Zuckerman, Scott L; Mistry, Akshitkumar M; Hanif, Rimal; Chambless, Lola B; Neimat, Joseph S; Wellons, John C; Mocco, J; Sills, Allen K; McGirt, Matthew J; Thompson, Reid C

2016-02-01

Exposure to surgical subspecialties is limited during the preclinical years of medical school. To offset this limitation, the authors created a neurosurgery elective for first- and second-year medical students. The objective was to provide each student with early exposure to neurosurgery by combining clinical experience with faculty discussions about the academic and personal realities of a career in neurosurgery. From 2012 to 2013, the authors offered a neurosurgery elective course to first- and second-year medical students. Each class consisted of the following: 1) peer-reviewed article analysis; 2) student presentation; 3) faculty academic lecture; 4) faculty personal lecture with question and answer period. Thirty-five students were enrolled over a 2-year period. After completing the elective, students were more likely to: consider neurosurgery as a future career (P life to be higher (P life, and family-work balance, while not altering the students' views about the difficulty of training. Adopting a neurosurgery elective geared towards preclinical medical students can significantly change attitudes about the field of neurosurgery and has potential to increase interest in pursuing a career in neurosurgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Regenerative medicine provides alternative strategies for the treatment of anal incontinence

DEFF Research Database (Denmark)

Gräs, Søren; Tolstrup, Cæcilie Krogsgaard; Lose, Gunnar

2017-01-01

of culture-expanded skeletal myogenic cells stimulates repair of both acute and 2 - 4-week-old anal sphincter injuries. The results from a small clinical trial with ten patients and a case report support the preclinical findings. Animal studies have also demonstrated that local injections of mesenchymal stem...... cells stimulate repair of sphincter injuries, and a complex bioengineering strategy for creation and implantation of an intrinsically innervated internal anal sphincter construct has been successfully developed in a series of animal studies. CONCLUSION: Cellular therapies with myogenic cells...... and mesenchymal stem cells and the use of bioengineering technology to create an anal sphincter are new potential strategies to treat anal incontinence caused by anal sphincter defects, but the clinical evidence is extremely limited. The use of culture-expanded autologous skeletal myogenic cells has been most...

A methodology for the sustainable design and implementation strategy of CO2 utilization processes

DEFF Research Database (Denmark)

Roh, Kosan; Frauzem, Rebecca; Nguyen, Tuan B. H.

2016-01-01

design and analysis is discussed as only limited amounts of process data is available for determining the optimal processing path and in the third stage the issue of implementation strategy is considered. As examples, two CO2 utilization methods for methanol production, combined reforming and direct...... synthesis are considered. Methanol plants employing such methods are developed using synthesis-design and simulation tools and their evaluation indicators are calculated under various implementation strategies. It is demonstrated that integrating or replacing an existing conventional methanol plant...

A General Strategy for Nanohybrids Synthesis via Coupled Competitive Reactions Controlled in a Hybrid Process

OpenAIRE

Wang, Rongming; Yang, Wantai; Song, Yuanjun; Shen, Xiaomiao; Wang, Junmei; Zhong, Xiaodi; Li, Shuai; Song, Yujun

2015-01-01

A new methodology based on core alloying and shell gradient-doping are developed for the synthesis of nanohybrids, realized by coupled competitive reactions, or sequenced reducing-nucleation and co-precipitation reaction of mixed metal salts in a microfluidic and batch-cooling process. The latent time of nucleation and the growth of nanohybrids can be well controlled due to the formation of controllable intermediates in the coupled competitive reactions. Thus, spatiotemporal-resolved synthesi...

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

Science.gov (United States)

Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

2016-01-01

Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

Design, Synthesis and Biological Evaluation of Quorum Sensing Modulators

DEFF Research Database (Denmark)

Hansen, Mette Reimert

to intercept the communication system by synthetic non-native ligands and thereby lower the pathogenesis and antibiotic tolerance of a bacterial biofilm. To identify new ligands with quorum sensing modulating activities, three types of AHL analogs were synthesized using different synthetic strategies....... Overall, 17 compounds were identified as quorum sensing activators with EC50 values in the low micromolar range. Two build/couple/pair strategies for the synthesis of structurally diverse small molecules are presented. In the first strategy, the Petasis 3-component reaction (Petasis 3-CR) of hydrazides...

Synthesis of sp3-rich scaffolds for molecular libraries through complexity-generating cascade reactions

DEFF Research Database (Denmark)

Flagstad, Thomas; Min, Geanna; Bonnet, K.

2016-01-01

An efficient strategy for the synthesis of complex small molecules from simple building blocks is presented. Key steps of the strategy include tandem Petasis and Diels–Alder reactions, and divergent complexity-generating cyclization cascades from a key dialdehyde intermediate. The methodology...

Preclinical diagnosis and emergency medical care in case of radiation accidents

International Nuclear Information System (INIS)

Ohlenschlaeger, L.

1990-01-01

Reference is made to preclinical diagnosis and emergency medical care at the site of a potential radiation accident. Possibilities and limits, respectively, of the medical measures are shown. Cooperation between the experts of the technical and medical rescue services is described. Exposition to radiation for the emergency medical staff resulting from the medical care of contaminated persons, is negligible if the personal precautions are observed. (orig.) [de

Fully automated synthesis of 11C-acetate as tumor PET tracer by simple modified solid-phase extraction purification

International Nuclear Information System (INIS)

Tang, Xiaolan; Tang, Ganghua; Nie, Dahong

2013-01-01

Introduction: Automated synthesis of 11 C-acetate ( 11 C-AC) as the most commonly used radioactive fatty acid tracer is performed by a simple, rapid, and modified solid-phase extraction (SPE) purification. Methods: Automated synthesis of 11 C-AC was implemented by carboxylation reaction of MeMgBr on a polyethylene Teflon loop ring with 11 C-CO 2 , followed by acidic hydrolysis with acid and SCX cartridge, and purification on SCX, AG11A8 and C18 SPE cartridges using a commercially available 11 C-tracer synthesizer. Quality control test and animals positron emission tomography (PET) imaging were also carried out. Results: A high and reproducible decay-uncorrected radiochemical yield of (41.0±4.6)% (n=10) was obtained from 11 C-CO 2 within the whole synthesis time about 8 min. The radiochemical purity of 11 C-AC was over 95% by high-performance liquid chromatography (HPLC) analysis. Quality control test and PET imaging showed that 11 C-AC injection produced by the simple SPE procedure was safe and efficient, and was in agreement with the current Chinese radiopharmaceutical quality control guidelines. Conclusion: The novel, simple, and rapid method is readily adapted to the fully automated synthesis of 11 C-AC on several existing commercial synthesis module. The method can be used routinely to produce 11 C-AC for preclinical and clinical studies with PET imaging. - Highlights: • A fully automated synthesis of 11 C-acetate by simple modified solid-phase extraction purification has been developed. • Typical non-decay-corrected yields were (41.0±4.6)% (n=10) • Radiochemical purity was determined by radio-HPLC analysis on a C18 column using the gradient program, instead of expensive organic acid column or anion column. • QC testing (RCP>99%)

Synthesis of Dendrimer Containing Carbazole Unit as a Core Chromophore

International Nuclear Information System (INIS)

Han, Seung Choul; Lee, Jae Wook; Jin, Sungho

2012-01-01

Dendrimers, which are prepared by repetition of a given set of reactions using either divergent or convergent strategies, are highly branched and regular macromolecules with well-defined structures and have served as functional objects in nanotechnology and nano-materials science. Following conventional organic small molecules and polymers, dendrimers are now regarded as the third class of materials for use in organic light-emitting diodes (OLEDs) and have attracted much attention due to their distinguished properties. Dendrimers contain three distinct structural parts that are the core, end-groups, and branched units connecting core and periphery. For light-emitting dendrimers, the core is usually selected as the luminescent chromophore, and the dendrons and their periphery are charge transporting units and can also tune the solubility. In contrast to linear polymers, dendrimers are sphere-like with dimensions of the order of nanometers depending on the generation number. By careful structural design, dendrimers combine the potential advantages of both small molecules and polymers. Therefore, the innovative strategy different from conventional convergent and divergent routes has been required to simplify dendrimer synthesis. Recent solid chemistry is the click chemistry which is the copper-catalyzed 1,3-dipolar cycloaddition reaction between alkyne and azide developed by Sharpless and Tornφe. This reaction has many advantages: very high yields, mild and simple reaction conditions, oxygen and water tolerance, and easy isolation of product. This reaction is clearly a breakthrough in the synthesis of dendrimers and dendritic and polymer materials. We have developed the fusion and stitching methods for the synthesis of various dendrimers using click chemistry between an alkyne and an azide. Overall, this method was found to be a straightforward strategy for the synthesis of triazole-based dendrimers. Taking advantage of this fact, herein we report a feasible route

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

Science.gov (United States)

Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

2013-01-01

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

Omics Meets Biology: Application to the Design and Preclinical Assessment of Antivenoms

Directory of Open Access Journals (Sweden)

Juan J. Calvete

2014-12-01

Full Text Available Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor availability of the only validated treatment for this disease, antivenoms. Antivenoms can be an efficacious treatment for snakebite envenoming, provided they are safe, effective, affordable, accessible and administered appropriately. The shortage of antivenoms in various regions, particularly in Sub-Saharan Africa and some parts of Asia, can be significantly alleviated by optimizing the use of current antivenoms and by the generation of novel polyspecific antivenoms having a wide spectrum of efficacy. Complementing preclinical testing of antivenom efficacy using in vivo and in vitro functional neutralization assays, developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by being able to test new antivenom preparations and to predict their paraspecific neutralization to the level of species-specific toxins.

Multimodal imaging of bone metastases: From preclinical to clinical applications

Directory of Open Access Journals (Sweden)

Stephan Ellmann

2015-10-01

Full Text Available Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

The predictive validity of the BioMedical Admissions Test for pre-clinical examination performance.

Science.gov (United States)

Emery, Joanne L; Bell, John F

2009-06-01

Some medical courses in the UK have many more applicants than places and almost all applicants have the highest possible previous and predicted examination grades. The BioMedical Admissions Test (BMAT) was designed to assist in the student selection process specifically for a number of 'traditional' medical courses with clear pre-clinical and clinical phases and a strong focus on science teaching in the early years. It is intended to supplement the information provided by examination results, interviews and personal statements. This paper reports on the predictive validity of the BMAT and its predecessor, the Medical and Veterinary Admissions Test. Results from the earliest 4 years of the test (2000-2003) were matched to the pre-clinical examination results of those accepted onto the medical course at the University of Cambridge. Correlation and logistic regression analyses were performed for each cohort. Section 2 of the test ('Scientific Knowledge') correlated more strongly with examination marks than did Section 1 ('Aptitude and Skills'). It also had a stronger relationship with the probability of achieving the highest examination class. The BMAT and its predecessor demonstrate predictive validity for the pre-clinical years of the medical course at the University of Cambridge. The test identifies important differences in skills and knowledge between candidates, not shown by their previous attainment, which predict their examination performance. It is thus a valid source of additional admissions information for medical courses with a strong scientific emphasis when previous attainment is very high.

Preclinical magnetic resonance imaging and systems biology in cancer research: current applications and challenges.

Science.gov (United States)

Albanese, Chris; Rodriguez, Olga C; VanMeter, John; Fricke, Stanley T; Rood, Brian R; Lee, YiChien; Wang, Sean S; Madhavan, Subha; Gusev, Yuriy; Petricoin, Emanuel F; Wang, Yue

2013-02-01

Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Evaluating the short-term effects of a communication skills program for preclinical medical students.

Science.gov (United States)

Lee, Young-Mee; Lee, Young Hee

2014-09-01

Regardless of the growing importance of communication skills as a core clinical competence, few studies have determined the effects of communication skills courses in undergraduate medical curricula in Asian medical schools. The purpose of this study was to examine the effectiveness of a communication skills program for preclinical medical students. A communication skills course was provided to 111 second-year medical students in a medical college in Korea. Students' self-assessed competency of communication skills was evaluated by a questionnaire survey. To examine the improvement in observed communication skills, the students' encounters with standardized patients (SPs) were assessed at the first session and at the final course assessment. A structured checklist, consisting of 25 communication skills items, was used for the assessment. Students' self-assessed competency of communication skills increased significantly after completion of the course (pcommunication skills scores also improved significantly at the end of the course; the mean scores of the first SPs encounters was 49.6 (standard deviation [SD], 11.1), and those of cases A and B at the final assessment were 61.5 (SD, 8.4) and 69.6 (SD, 7.8), respectively (F61=269.54, pcommunication skills course was beneficial in developing and improving communication skills competency in preclinical medical students. Further studies should be followed to examine whether the acquisition of communication skills during preclinical studies can be sustained into clerkship and actual practice.

Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

Science.gov (United States)

Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

2016-06-21

Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies.

Perceptions of preparedness for the first medical clerkship: a systematic review and synthesis.

Science.gov (United States)

Surmon, Laura; Bialocerkowski, Andrea; Hu, Wendy

2016-03-12

The transition from university-based to clerkship-based education can be challenging. Medical schools have introduced strategies to ease the transition, but there has been no systematic review synthesizing the evidence on the perceptions of preparedness of medical students for their first clerkship to support these interventions. This study therefore aimed to (1) identify and synthesize the published evidence on medical students' perceptions of preparedness for their first clerkship, and (2) identify factors that may impact on preparedness for clerkship, to better inform interventions aimed at easing this transition. Electronic databases (Medline, Journals@Ovid, CINAHL, ERIC, Web of Science, Embase) were searched without restriction and secondary searching of reference lists of included studies was also conducted. Included studies used quantitative or qualitative methodologies, involved medical students and addressed student/supervisor perceptions of preparedness for first clerkship. The first clerkship was defined as the first truly immersive educational experience during which the majority of learning was vocational and self-directed, as per the MeSH term 'clinical clerkship' and associated definition. Using an inductive thematic synthesis approach, 2 researchers independently extracted data, coded text (from results and discussion sections), and identified themes related to preparedness. Any disagreements were resolved by discussion and findings were then narratively synthesized. The initial search identified 1214 papers. After removing duplicates and assessing abstracts and full articles against the inclusion criteria, 8 articles were included in the review. In general, the body of evidence was of sound methodological quality. Ten themes relating to perceptions of preparedness of medical students for their first clerkship were identified; competence, disconnection, links to the future, uncertainty, part of the team, time/workload, adjustment, curriculum, prior

Educators' Perceptions on Bullying Prevention Strategies

Science.gov (United States)

de Wet, Corene

2017-01-01

I report on an investigation into a group of Free State educators' recognition of bullying, their reactions to incidences of bullying, and their perceptions of the effectiveness of a number of bullying prevention strategies. The research instrument was a synthesis of the Delaware Research Questionnaire and questions based on findings from previous…

A student-initiated and student-facilitated international health elective for preclinical medical students

Directory of Open Access Journals (Sweden)

Nirali Vora

2010-02-01

Full Text Available Introduction: Global health education is becoming more important for developing well-rounded physicians and may encourage students toward a career in primary care. Many medical schools, however, lack adequate and structured opportunities for students beginning the curriculum. Methods: Second-year medical students initiated, designed, and facilitated a pass–fail international health elective, providing a curricular framework for preclinical medical students wishing to gain exposure to the clinical and cultural practices of a developing country. Results: All course participants (N=30 completed a post-travel questionnaire within one week of sharing their experiences. Screening reflection essays for common themes that fulfill university core competencies yielded specific global health learning outcomes, including analysis of health care determinants. Conclusion: Medical students successfully implemented a sustainable global health curriculum for preclinical student peers. Financial constraints, language, and organizational burdens limit student participation. In future, long-term studies should analyze career impact and benefits to the host country.

Pre-clinical research in small animals using radiotherapy technology--a bidirectional translational approach.

Science.gov (United States)

Tillner, Falk; Thute, Prasad; Bütof, Rebecca; Krause, Mechthild; Enghardt, Wolfgang

2014-12-01

For translational cancer research, pre-clinical in-vivo studies using small animals have become indispensable in bridging the gap between in-vitro cell experiments and clinical implementation. When setting up such small animal experiments, various biological, technical and methodical aspects have to be considered. In this work we present a comprehensive topical review based on relevant publications on irradiation techniques used for pre-clinical cancer research in mice and rats. Clinical radiotherapy treatment devices for the application of external beam radiotherapy and brachytherapy as well as dedicated research irradiation devices are feasible for small animal irradiation depending on the animal model and the experimental goals. In this work, appropriate solutions for the technological transfer of human radiation oncology to small animal radiation research are summarised. Additionally, important information concerning the experimental design is provided such that reliable and clinically relevant results can be attained. Copyright © 2014. Published by Elsevier GmbH.

Pyro-Synthesis of Functional Nanocrystals

OpenAIRE

Gim, Jihyeon; Mathew, Vinod; Lim, Jinsub; Song, Jinju; Baek, Sora; Kang, Jungwon; Ahn, Docheon; Song, Sun-Ju; Yoon, Hyeonseok; Kim, Jaekook

2012-01-01

Despite nanomaterials with unique properties playing a vital role in scientific and technological advancements of various fields including chemical and electrochemical applications, the scope for exploration of nano-scale applications is still wide open. The intimate correlation between material properties and synthesis in combination with the urgency to enhance the empirical understanding of nanomaterials demand the evolution of new strategies to promising materials. Herein we introduce a ra...

Synthesis of an Orthogonal Topological Analogue of Helicene

DEFF Research Database (Denmark)

Wixe, Torbjörn; Wallentin, Carl‐Johan; Johnson, Magnus T.

2013-01-01

The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy r...

Synthesis and application of branched type II arabinogalactans

DEFF Research Database (Denmark)

Andersen, Mathias Christian Franch; Boos, Irene; Ruprecht, Colin

2017-01-01

The synthesis of linear- and (1→6)-branched β-(1→3)-D-galactans, structures found in plant arabinogalactan proteins (AGPs) is described. The synthetic strategy relies on iterative couplings of mono- and disaccharide thioglycoside donors, followed by a late stage glycosylation of heptagalactan bac...

Novel epigenetic target therapy for prostate cancer: a preclinical study.

Directory of Open Access Journals (Sweden)

Ilaria Naldi

Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

Novel epigenetic target therapy for prostate cancer: a preclinical study.

Science.gov (United States)

Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

2014-01-01

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

Micelle-Template Synthesis of Nitrogen-Doped Mesoporous Graphene as an Efficient Metal-Free Electrocatalyst for Hydrogen Production

Science.gov (United States)

Huang, Xiaodan; Zhao, Yufei; Ao, Zhimin; Wang, Guoxiu

2014-12-01

Synthesis of mesoporous graphene materials by soft-template methods remains a great challenge, owing to the poor self-assembly capability of precursors and the severe agglomeration of graphene nanosheets. Herein, a micelle-template strategy to prepare porous graphene materials with controllable mesopores, high specific surface areas and large pore volumes is reported. By fine-tuning the synthesis parameters, the pore sizes of mesoporous graphene can be rationally controlled. Nitrogen heteroatom doping is found to remarkably render electrocatalytic properties towards hydrogen evolution reactions as a highly efficient metal-free catalyst. The synthesis strategy and the demonstration of highly efficient catalytic effect provide benchmarks for preparing well-defined mesoporous graphene materials for energy production applications.

Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis

Science.gov (United States)

Lotesta, Stephen D.; Liu, Junjia; Yates, Emma V.; Krieger, Inna; Sacchettini, James C.; Freundlich, Joel S.; Sorensen, Erik J.

2011-01-01

New pleuromutilin-like compounds were synthesized in approximately 11 steps from 3-allylcyclopent-2-enone by a strategy featuring sequential carbonyl addition reactions. Several analogs possessing the C14 tiamulin ester side chain displayed activity in a Mycobacterium tuberculosis mc27000 assay. The results described herein provide a basis for further efforts to expand the structural and stereochemical diversity of the pleuromutilin class of bacterial protein synthesis inhibitors through advances in chemical synthesis. PMID:21874155

Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy.

Science.gov (United States)

Zhang, Sheng; Chen, Lan; Luo, Yong; Gunawan, Andrea; Lawrence, David S; Zhang, Zhong-Yin

2009-09-16

Protein tyrosine phosphatases (PTPs) regulate a broad range of cellular processes including proliferation, differentiation, migration, apoptosis, and immune responses. Dysfunction of PTP activity is associated with cancers, metabolic syndromes, and autoimmune disorders. Consequently, small molecule PTP inhibitors should serve not only as powerful tools to delineate the physiological roles of these enzymes in vivo but also as lead compounds for therapeutic development. We describe a novel stepwise fluorophore-tagged combinatorial library synthesis and competitive fluorescence polarization screening approach that transforms a weak and general PTP inhibitor into an extremely potent and selective TC-PTP inhibitor with highly efficacious cellular activity. The result serves as a proof-of-concept in PTP inhibitor development, as it demonstrates the feasibility of acquiring potent, yet highly selective, cell permeable PTP inhibitory agents. Given the general nature of the approach, this strategy should be applicable to other PTP targets.

Near-peers improve patient safety training in the preclinical curriculum.

Science.gov (United States)

Raty, Sally R; Teal, Cayla R; Nelson, Elizabeth A; Gill, Anne C

2017-01-01

Accrediting bodies require medical schools to teach patient safety and residents to develop teaching skills in patient safety. We created a patient safety course in the preclinical curriculum and used continuous quality improvement to make changes over time. To assess the impact of resident teaching on student perceptions of a Patient Safety course. Using the Institute for Healthcare Improvement patient safety curriculum as a frame, the course included the seven IHI modules, large group lectures and small group facilitated discussions. Applying a social action methodology, we evaluated the course for four years (Y1-Y4). In Y1, Y2, Y3 and Y4, we distributed a course evaluation to each student (n = 184, 189, 191, and 184, respectively) and the response rate was 96, 97, 95 and 100%, respectively. Overall course quality, clarity of course goals and value of small group discussions increased in Y2 after the introduction of residents as small group facilitators. The value of residents and the overall value of the course increased in Y3 after we provided residents with small group facilitation training. Preclinical students value the interaction with residents and may perceive the overall value of a course to be improved based on near-peer involvement. Residents gain valuable experience in small group facilitation and leadership.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

Science.gov (United States)

Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

2012-03-01

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Pre-clinical medical student experience in a pediatric pulmonary clinic

Directory of Open Access Journals (Sweden)

Thomas G. Saba

2015-11-01

Full Text Available Objective: Our objective was to evaluate the educational value of introducing pre-clinical medical students to pediatric patients and their families in a subspecialty clinic setting. Methods: First- and second-year medical students at the University of Michigan seeking clinical experience outside of the classroom attended an outpatient pediatric pulmonary clinic. Evaluation of the experience consisted of pre- and post-clinic student surveys and post-clinic parent surveys with statements employing a four-point Likert scale as well as open-ended questions. Results: Twenty-eight first-year students, 6 second-year students, and 33 parents participated in the study. Post-clinic statement scores significantly increased for statements addressing empathic attitudes, confidence communicating with children and families, comfort in the clinical environment, and social awareness. Scores did not change for statements addressing motivation, a sense of team membership, or confidence with career goals. Students achieved their goals of gaining experience interacting with patients, learning about pulmonary diseases, and observing clinic workflow. Parents felt that they contributed to student education and were not inconvenienced. Conclusions: Students identified several educational benefits of exposure to a single pediatric pulmonary clinic. Patients and families were not inconvenienced by the participation of a student. Additional studies are warranted to further investigate the value of this model of pre-clinical medical student exposure to subspecialty pediatrics.

Enantioselective Synthesis of (-)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation.

Science.gov (United States)

Antropow, Alyssa H; Garcia, Nicholas R; White, Kolby L; Movassaghi, Mohammad

2018-06-04

The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.

Eschenmoser Approach to Vitamin B by A/D Strategy

Indian Academy of Sciences (India)

IAS Admin

RB was brilliantly used by Eschenmoser for a correct photo-induced ... strategy, was based on Eschenmoser's east-west synthesis of an ...... [27] M O Benedyk, Fundamental Questions: An Interview with Professor Albert Eschenmoser, Bol. Soc.

Reaction mechanisms for on-surface synthesis of covalent nanostructures

International Nuclear Information System (INIS)

Björk, J

2016-01-01

In recent years, on-surface synthesis has become an increasingly popular strategy to form covalent nanostructures. The approach has great prospects for facilitating the manufacture of a range of fascinating materials with atomic precision. However, the on-surface reactions are enigmatic to control, currently restricting its bright perspectives and there is a great need to explore how the reactions are governed. The objective of this topical review is to summarize theoretical work that has focused on comprehending on-surface synthesis protocols through studies of reaction mechanisms. (topical review)

Local Strategy Improvement for Parity Game Solving

OpenAIRE

Friedmann, Oliver; Lange, Martin

2010-01-01

The problem of solving a parity game is at the core of many problems in model checking, satisfiability checking and program synthesis. Some of the best algorithms for solving parity game are strategy improvement algorithms. These are global in nature since they require the entire parity game to be present at the beginning. This is a distinct disadvantage because in many applications one only needs to know which winning region a particular node belongs to, and a witnessing winning strategy may...

Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Science.gov (United States)

Wood, Michael R; Noetzel, Meredith J; Melancon, Bruce J; Poslusney, Michael S; Nance, Kellie D; Hurtado, Miguel A; Luscombe, Vincent B; Weiner, Rebecca L; Rodriguez, Alice L; Lamsal, Atin; Chang, Sichen; Bubser, Michael; Blobaum, Anna L; Engers, Darren W; Niswender, Colleen M; Jones, Carrie K; Brandon, Nicholas J; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

2017-02-09

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M 4 ) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M 4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.

Science.gov (United States)

Hovens, Iris B; Schoemaker, Regien G; van der Zee, Eddy A; Heineman, Erik; Izaks, Gerbrand J; van Leeuwen, Barbara L

2012-10-01

Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. Copyright © 2012 Elsevier Inc. All rights reserved.

In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

Directory of Open Access Journals (Sweden)

Christiane Broichhausen

2014-01-01

Full Text Available A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

Synthesis of benzimidazoles via iridium-catalyzed acceptorless dehydrogenative coupling.

Science.gov (United States)

Sun, Xiang; Lv, Xiao-Hui; Ye, Lin-Miao; Hu, Yu; Chen, Yan-Yan; Zhang, Xue-Jing; Yan, Ming

2015-07-21

Iridium-catalyzed acceptorless dehydrogenative coupling of tertiary amines and arylamines has been developed. A number of benzimidazoles were prepared in good yields. An iridium-mediated C-H activation mechanism is suggested. This finding represents a novel strategy for the synthesis of benzimidazoles.

Preclinical evaluation of radiolabeled DOTA-derivatized cyclic minigastrin analogs for targeting cholecystokinin receptor expressing malignancies.

NARCIS (Netherlands)

Guggenberg, E. von; Rangger, C.; Sosabowski, J.; Laverman, P.; Reubi, J.C.; Virgolini, I.J.; Decristoforo, C.

2012-01-01

PURPOSE: Targeting of cholecystokinin receptor expressing malignancies such as medullary thyroid carcinoma is currently limited by low in vivo stability of radioligands. To increase the stability, we have developed and preclinically evaluated two cyclic

SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

Energy Technology Data Exchange (ETDEWEB)

Hendrikx, Geert [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Voeoe, Stefan [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Bauwens, Matthias [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht (Netherlands); Post, Mark J. [Maastricht University, Department of Physiology, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); University Hospital, RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

2016-12-15

The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging. (orig.)

Preclinical detection of porcine circovirus type 2 infection using an ultrasensitive nanoparticle DNA probe-based PCR assay.

Directory of Open Access Journals (Sweden)

Yong Huang

Full Text Available Porcine circovirus type 2 (PCV2 has emerged as one of the most important pathogens affecting swine production globally. Preclinical identification of PCV2 is very important for effective prophylaxis of PCV2-associated diseases. In this study, we developed an ultrasensitive nanoparticle DNA probe-based PCR assay (UNDP-PCR for PCV2 detection. Magnetic microparticles coated with PCV2 specific DNA probes were used to enrich PCV2 DNA from samples, then gold nanoparticles coated with PCV2 specific oligonucleotides were added to form a sandwich nucleic acid-complex. After the complex was formed, the oligonucleotides were released and characterized by PCR. This assay exhibited about 500-fold more sensitive than conventional PCR, with a detection limit of 2 copies of purified PCV2 genomic DNA and 10 viral copies of PCV2 in serum. The assay has a wide detection range for all of PCV2 genotypes with reliable reproducibility. No cross-reactivity was observed from the samples of other related viruses including porcine circovirus type 1, porcine parvovirus, porcine pseudorabies virus, porcine reproductive and respiratory syndrome virus and classical swine fever virus. The positive detection rate of PCV2 specific UNDP-PCR in 40 preclinical field samples was 27.5%, which appeared greater than that by conventional and real-time PCR and appeared application potency in evaluation of the viral loads levels of preclinical infection samples. The UNDP-PCR assay reported here can reliably rule out false negative results from antibody-based assays, provide a nucleic acid extraction free, specific, ultrasensitive, economic and rapid diagnosis method for preclinical PCV2 infection in field, which may help prevent large-scale outbreaks.

Stable π-Extended p -Quinodimethanes: Synthesis and Tunable Ground States

KAUST Repository

Zeng, Zebing; Wu, Jishan

2014-01-01

in molecules with even larger biradical character and higher reactivity. Therefore, the synthesis of stable π-extended p-QDMs is very challenging. In this Personal Account we will briefly discuss different stabilizing strategies and synthetic methods towards

The CP molecule labyrinth: a paradigm of how endeavors in total synthesis lead to discoveries and inventions in organic synthesis.

Science.gov (United States)

Nicolaou, K C; Baran, Phil S

2002-08-02

Imagine an artist carving a sculpture from a marble slab and finding gold nuggets in the process. This thought is not a far-fetched description of the work of a synthetic chemist pursuing the total synthesis of a natural product. At the end of the day, he or she will be judged by the artistry of the final work and the weight of the gold discovered in the process. However, as colorful as this description of total synthesis may be, it does not entirely capture the essence of the endeavor, for there is much more to be told, especially with regard to the contrast of frustrating failures and exhilarating moments of discovery. To fully appreciate the often Herculean nature of the task and the rewards that accompany it, one must sense the details of the enterprise behind the scenes. A more vivid description of total synthesis as a struggle against a tough opponent is perhaps appropriate to dramatize these elements of the experience. In this article we describe one such endeavor of total synthesis which, in addition to reaching the target molecule, resulted in a wealth of new synthetic strategies and technologies for chemical synthesis. The total synthesis of the CP molecules is compared to Theseus' most celebrated athlos (Greek for exploit, accomplishment): the conquest of the dreaded Minotaur, which he accomplished through brilliance, skill, and bravery having traversed the famous labyrinth with the help of Ariadne. This story from Greek mythology comes alive in modern synthetic expeditions toward natural products as exemplified by the total synthesis of the CP molecules which serve as a paradigm for modern total synthesis endeavors, where the objectives are discovery and invention in the broader sense of organic synthesis.

Learning style preferences among pre-clinical medical students

Directory of Open Access Journals (Sweden)

Aye Aye Mon

2014-02-01

Full Text Available Generally, different students employ different learning styles dur-ing their studies and medical students are exposed to diverse methods of teaching. Therefore, understanding students’ learning style preference is an important consideration for a high quality and effective teaching and learning process.The aim of the study was to study the variation of learning styles among pre-clinical medical students of SEGi University, Malaysia. A cross-sectional study was performed by using VARK (Visual, Audio, Reading and Kinaesthetic questionnaire version 7.2 to assess the learning style preference of 98 (n=98 pre-clinical medical students in SEGi University. The questionnaire consists of 16 items which identify four different learning styles: visual, aural, reading/writing and kin-esthetic. Descriptive statistics were used to identify the learning styles of students. 61 students preferred multimodal as their learning style, out of which 43 (70% of them were female stu-dents and 18 (30% were male students. 37 students preferred unimodal as their learning style out of which 22 (59% of them were female students and 15 (41% were male students. In addi-tion, female students had more diverse preferences than male students by having 10 out of the other 11 possible combinations in multimodal learning style of preference, whereas the male stu-dents only had 5 out of the 11 combinations. In this study, there was no significant gender difference in the percentages of males and female students who preferred unimodal and multimodal styles of information presentation (P= 0.263; α=0.05. To con-clude, the majority of students of both genders had chosen quad-modal as their learning style preference. The results of this study can provide useful information for improving the quality of the teaching and learning experiences of students.

A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy

Directory of Open Access Journals (Sweden)

Leila Bond

2018-01-01

Full Text Available Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS. In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1 accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70–90% of cell death coincides to inducer exposure equivalent to 30–50% peak concentration (p < 0.05. A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs revealed HSP levels are 30% lower in muscle than spine (p < 0.1. Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05. Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001 but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature

Precursor Mediated Synthesis of Nanostructured Silicas: From Precursor-Surfactant Ion Pairs to Structured Materials

Directory of Open Access Journals (Sweden)

Peter Hesemann

2014-04-01

Full Text Available The synthesis of nanostructured anionic-surfactant-templated mesoporous silica (AMS recently appeared as a new strategy for the formation of nanostructured silica based materials. This method is based on the use of anionic surfactants together with a co-structure-directing agent (CSDA, mostly a silylated ammonium precursor. The presence of this CSDA is necessary in order to create ionic interactions between template and silica forming phases and to ensure sufficient affinity between the two phases. This synthetic strategy was for the first time applied in view of the synthesis of surface functionalized silica bearing ammonium groups and was then extended on the formation of materials functionalized with anionic carboxylate and bifunctional amine-carboxylate groups. In the field of silica hybrid materials, the “anionic templating” strategy has recently been applied for the synthesis of silica hybrid materials from cationic precursors. Starting from di- or oligosilylated imidazolium and ammonium precursors, only template directed hydrolysis-polycondensation reactions involving complementary anionic surfactants allowed accessing structured ionosilica hybrid materials. The mechanistic particularity of this approach resides in the formation of precursor-surfactant ion pairs in the hydrolysis-polycondensation mixture. This review gives a systematic overview over the various types of materials accessed from this cooperative ionic templating approach and highlights the high potential of this original strategy for the formation of nanostructured silica based materials which appears as a complementary strategy to conventional soft templating approaches.

Modulation Strategy of a 3 × 5 Modular Multilevel Matrix Converter

Directory of Open Access Journals (Sweden)

Rutian Wang

2018-02-01

Full Text Available In this paper, a modulation strategy of a 3 × 5 modular multilevel matrix converter (M3C is proposed. The circuit of 3 × 5 M3C is firstly introduced. Then, operation rules of 3 × 5 M3C are illustrated, and a connection pattern of branches is determined based on these rules. Different voltage states in the input and output side can be achieved by different connection patterns. These voltage states are represented in the form of vector. It is hard to synthesize five-phase output with the three-level synthesis method. Therefore, the five-level synthesis method is adopted in this paper; i.e., is the branch states have been increased. Ten effective vectors and a zero vector are selected based on the five-level synthesis method. With this modulation strategy, we achieve output line-to-line voltages that are in line with the trend of a sine wave. The segment division and duty cycle calculation are very simple, and the modulation strategy can be implemented easily. The simulation model of 3 × 5 M3C is constructed based on Matlab/Simulink, and the corresponding experimental platform is set up. The results of simulation and experiment show that the proposed method is reasonable and correct.

Economic evaluation of HIV pre-exposure prophylaxis strategies: protocol for a methodological systematic review and quantitative synthesis.

Science.gov (United States)

Thavorn, Kednapa; Kugathasan, Howsikan; Tan, Darrell H S; Moqueet, Nasheed; Baral, Stefan D; Skidmore, Becky; MacFadden, Derek; Simkin, Anna; Mishra, Sharmistha

2018-03-15

Pre-exposure prophylaxis (PrEP) with antiretrovirals is an efficacious and effective intervention to decrease the risk of HIV (human immunodeficiency virus) acquisition. Yet drug and delivery costs prohibit access in many jurisdictions. In the absence of guidelines for the synthesis of economic evaluations, we developed a protocol for a systematic review of economic evaluation studies for PrEP by drawing on best practices in systematic reviews and the conduct and reporting of economic evaluations. We aim to estimate the incremental cost per health outcome of PrEP compared with placebo, no PrEP, or other HIV prevention strategies; assess the methodological variability in, and quality of, economic evaluations of PrEP; estimate the incremental cost per health outcome of different PrEP implementation strategies; and quantify the potential sources of heterogeneity in outcomes. We will systematically search electronic databases (MEDLINE, Embase) and the gray literature. We will include economic evaluation studies that assess both costs and health outcomes of PrEP in HIV-uninfected individuals, without restricting language or year of publication. Two reviewers will independently screen studies using predefined inclusion criteria, extract data, and assess methodological quality using the Philips checklist, Second Panel on the Cost-effectiveness of Health and Medicines, and the International Society for Pharmacoeconomics and Outcomes Research recommendations. Outcomes of interest include incremental costs and outcomes in natural units or utilities, cost-effectiveness ratios, and net monetary benefit. We will perform descriptive and quantitative syntheses using sensitivity analyses of outcomes by population subgroups, HIV epidemic settings, study designs, baseline intervention contexts, key parameter inputs and assumptions, type of outcomes, economic perspectives, and willingness to pay values. Findings will guide future economic evaluation of PrEP strategies in terms of

78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

Science.gov (United States)

2013-11-25

...] Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products... Assessment of Investigational Cellular and Gene Therapy Products'' dated November 2013. The guidance document... products reviewed by the Office of Cellular, Tissue and Gene Therapies (OCTGT). The product areas covered...

Exploratory study of factors related to educational scores of first preclinical year medical students.

Science.gov (United States)

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

2014-03-01

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P satisfaction.

Influence of Teaching Strategies and its Order of Exposure on Pre-Clinical Teeth Arrangement - A Pilot Study.

Science.gov (United States)

Jeyapalan, Karthigeyan; Mani, Uma Maheswari; Christian, Jayanth; Seenivasan, Madhan Kumar; Natarajan, Parthasarathy; Vaidhyanathan, Anand Kumar

2016-10-01

Teeth arrangement is a vital skill for the undergraduate dental student. The attainment of skills depends largely on the methodology of teaching. In a dental curriculum, the students are exposed to a wide variety of inputs and teaching methodologies from different sources. The educational unit in dental school must identify the sequence of teaching methods that enhance the learning and practising ability of students. The aim of this study was to evaluate the effectiveness of three different teaching methodologies for teeth arrangement and compare the differences between the orders of exposure to each teaching methodology on the development of teeth arrangement skills. The first year B.D.S students were study participants and were divided into three groups A, B, C. They were exposed to three teaching patterns namely live demonstration with video assisted teaching, group discussion with hand-outs and lectures with power point presentation. After each teaching methodology, their skill was assessed. The groups were exposed to three methodologies in different order for three arrangements. The scores obtained were analysed using Kruskal Wallis rank sum test and Dunn test for statistical significance. Significantly higher scores in the teeth arrangement procedure were obtained by the Group A students who were exposed initially to live demonstration with video-assisted teaching. Difference in the scores was noted among and within the groups. The difference between Group A and Group C was statistically significant after both first and third teeth arrangement (p=0.0031, p=0.0057). The study suggests each pre-clinical practice should begin with a live demonstration to enhance immediate learning absorption followed by lectures with power point presentation and group discussion for retention of knowledge and memory retrieval.

Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs

Science.gov (United States)

Kusner, Linda L.; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

2015-01-01

Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID:25743217

Asymmetric Synthesis of Apratoxin E.

Science.gov (United States)

Mao, Zhuo-Ya; Si, Chang-Mei; Liu, Yi-Wen; Dong, Han-Qing; Wei, Bang-Guo; Lin, Guo-Qiang

2016-10-21

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this "from nature to nature" strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

Environment and hydroelectricity colloquium - Synthesis

International Nuclear Information System (INIS)

Aelbrecht, Denis; Abadie, Marc; Baril, Dominique; Delacoux, Jean-Yves; Delaunay, Alexis; Loudiere, Daniel; Penalba, Anne; Pont, Didier; Rocq, Sylvie; Roult, Didier; Sheibani, Neda; Thevenet, Regis; Weisrock, Ghislain

2010-10-01

This document proposes a synthesis of a colloquium dedicated to the interactions between hydroelectric installations and the environment. The four sessions respectively addressed the impacts of hydroelectric installations on ecosystems and more particularly on pisciculture populations (strategies for migration restoration, development of fish-friendly turbines), the sedimentary management of hydroelectric installations, the implementation of the Water Framework European Directive (Austrian experience, biological assessment criteria), and examples of environmental integration of existing or projected installations

Preclinical evaluations of norcantharidin-loaded intravenous lipid microspheres with low toxicity.

Science.gov (United States)

Lin, Xia; Zhang, Bo; Zhang, Keru; Zhang, Yu; Wang, Juan; Qi, Na; Yang, Shenshen; He, Haibing; Tang, Xing

2012-12-01

The aim of this study was to perform a systematic preclinical evaluation of norcantharidin (NCTD)-loaded intravenous lipid microspheres (NLM). Pharmacokinetics, biodistribution, antitumor efficacy and drug safety assessment (including acute toxicity, subchronic toxicity, hemolysis testing, intravenous stimulation and injection anaphylaxis) of NLM were carried out in comparison with the commercial product disodium norcantharidate injection (NI). The pharmacokinetics of NLM in rats was similar to that of NI, and a non-linear correlation was observed between AUC and dose. A comparable antitumor efficacy of NLM and NI was observed in mice inoculated with A549, BEL7402 and BCAP-37 cell lines. It was worth noting that the NLM produced a lower drug concentration in heart compared with NI, and significantly reduced the cardiac and renal toxicity. The LD(50) of NLM was twice higher than that of NI. In NLM, over 80% of NCTD was loaded in the lipid phase or bound with phospholipids. Thus, NCTD was sequestered by direct contacting with body fluids and largely avoided distribution into tissues, consequently leading to significantly reduced cardiac and renal toxicity. These preclinical results suggested that NLM could be a useful potential carrier for parenteral administration of NCTD, while providing a superior safety profile.

Mediating Haptic Exploratory Strategies in Children Who Have Visual Impairment and Intellectual Disabilities

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McLinden, M.

2012-01-01

This article provides a synthesis of literature pertaining to the development of haptic exploratory strategies in children who have visual impairment and intellectual disabilities. The information received through such strategies assumes particular significance for these children, given the restricted information available through their visual…

Are study strategies related to medical licensing exam performance?

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West, Courtney; Kurz, Terri; Smith, Sherry; Graham, Lori

2014-11-02

To examine the relationship between study strategies and performance on a high stakes medical licensing exam entitled the United States Medical Licensing Examination Step 1. The action research project included seventy nine student participants at the Texas A & M Health Science Center College of Medicine during their pre-clinical education. Data collection included pre-matriculation and matriculation academic performance data, standardized exam data, and the Learning and Study Strategies Instrument. Multiple regression analyses were conducted. For both models, the dependent variable was the Step 1 score, and the independent variables included Medical College Admission Test, Undergraduate Grade Point Average, Year 1 Average, Year 2 Average, Customized National Board of Medical Examiners Average, Comprehensive Basic Science Exam score, and Learning and Study Strategy Instrument sub-scores. Model 2 added Comprehensive Basic Science Self-Assessment average. Concentration (Model 1 - β = .264; Model 2 - β = .254) was the only study strategy correlated with Step 1 performance. The other statistically significant predictors were Customized National Board of Medical Examiners Average (β = .315) and Year 2 Average (β = .280) in Model 1 and Comprehensive Basic Science Self-Assessment Average (β = .338) in Model 2. There does appear to be a relationship between the study strategy concentration and Step 1 licensing exam performance. Teaching students to practice and utilize certain techniques to improve concentration skills when preparing for and taking exams may help improve licensing exam scores.

Marketing: Exploring Applications for Educational Dissemination. Literature Synthesis.

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Reed, Linda

This synthesis of information about marketing and information dissemination of education-related products is divided into three parts: an overview of major writings, specific marketing strategies, and resources for further study. The first part opens with a definition of marketing as it relates to education. A review of the literature provides…

Strategies to reverse endothelial progenitor cell dysfunction in diabetes.

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Petrelli, Alessandra; Di Fenza, Raffaele; Carvello, Michele; Gatti, Francesca; Secchi, Antonio; Fiorina, Paolo

2012-01-01

Bone-marrow-derived cells-mediated postnatal vasculogenesis has been reported as the main responsible for the regulation of vascular homeostasis in adults. Since their discovery, endothelial progenitor cells have been depicted as mediators of postnatal vasculogenesis for their peculiar phenotype (partially staminal and partially endothelial), their ability to differentiate in endothelial cell line and to be incorporated into the vessels wall during ischemia/damage. Diabetes mellitus, a condition characterized by cardiovascular disease, nephropathy, and micro- and macroangiopathy, showed a dysfunction of endothelial progenitor cells. Herein, we review the mechanisms involved in diabetes-related dysfunction of endothelial progenitor cells, highlighting how hyperglycemia affects the different steps of endothelial progenitor cells lifetime (i.e., bone marrow mobilization, trafficking into the bloodstream, differentiation in endothelial cells, and homing in damaged tissues/organs). Finally, we review preclinical and clinical strategies that aim to revert diabetes-induced dysfunction of endothelial progenitor cells as a means of finding new strategies to prevent diabetic complications.

Strategies to Reverse Endothelial Progenitor Cell Dysfunction in Diabetes

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Alessandra Petrelli

2012-01-01

Full Text Available Bone-marrow-derived cells-mediated postnatal vasculogenesis has been reported as the main responsible for the regulation of vascular homeostasis in adults. Since their discovery, endothelial progenitor cells have been depicted as mediators of postnatal vasculogenesis for their peculiar phenotype (partially staminal and partially endothelial, their ability to differentiate in endothelial cell line and to be incorporated into the vessels wall during ischemia/damage. Diabetes mellitus, a condition characterized by cardiovascular disease, nephropathy, and micro- and macroangiopathy, showed a dysfunction of endothelial progenitor cells. Herein, we review the mechanisms involved in diabetes-related dysfunction of endothelial progenitor cells, highlighting how hyperglycemia affects the different steps of endothelial progenitor cells lifetime (i.e., bone marrow mobilization, trafficking into the bloodstream, differentiation in endothelial cells, and homing in damaged tissues/organs. Finally, we review preclinical and clinical strategies that aim to revert diabetes-induced dysfunction of endothelial progenitor cells as a means of finding new strategies to prevent diabetic complications.

Multicolour synthesis in lanthanide-doped nanocrystals through cation exchange in water

KAUST Repository

Han, Sanyang; Qin, Xian; An, Zhongfu; Zhu, Yihan; Liang, Liangliang; Han, Yu; Huang, Wei; Liu, Xiaogang

2016-01-01

lanthanide-doped luminescent nanomaterials have relied on direct synthesis requiring stringent controls over crystal nucleation and growth at elevated temperatures. Here we demonstrate the use of a cation exchange strategy for expeditiously accessing large

A computerized pre-clinical test for cemented hip prostheses based on finite element techniques

NARCIS (Netherlands)

Stolk, Jan

2003-01-01

Despite the success of cemented total hip replacement (THR), high failure rates are occasionally reported for cemented hip implants that are introduced on the orthopaedic market. Rigorous pre-clinical testing of hip implants could prevent these disasters, by detecting unsafe implant designs at a

Methodology for Knowledge Synthesis of the Management of Vaccination Pain and Needle Fear.

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Taddio, Anna; McMurtry, C Meghan; Shah, Vibhuti; Yoon, Eugene W; Uleryk, Elizabeth; Pillai Riddell, Rebecca; Lang, Eddy; Chambers, Christine T; Noel, Melanie; MacDonald, Noni E

2015-10-01

A knowledge synthesis was undertaken to inform the development of a revised and expanded clinical practice guideline about managing vaccination pain in children to include the management of pain across the lifespan and the management of fear in individuals with high levels of needle fear. This manuscript describes the methodological details of the knowledge synthesis and presents the list of included clinical questions, critical and important outcomes, search strategy, and search strategy results. The Grading of Assessments, Recommendations, Development and Evaluation (GRADE) and Cochrane methodologies provided the general framework. The project team voted on clinical questions for inclusion and critically important and important outcomes. A broad search strategy was used to identify relevant randomized-controlled trials and quasi-randomized-controlled trials. Quality of research evidence was assessed using the Cochrane risk of bias tool and quality across studies was assessed using GRADE. Multiple measures of the same construct within studies (eg, observer-rated and parent-rated infant distress) were combined before pooling. The standardized mean difference and 95% confidence intervals (CI) or relative risk and 95% CI was used to express the effects of an intervention. Altogether, 55 clinical questions were selected for inclusion in the knowledge synthesis; 49 pertained to pain management during vaccine injections and 6 pertained to fear management in individuals with high levels of needle fear. Pain, fear, and distress were typically prioritized as critically important outcomes across clinical questions. The search strategy identified 136 relevant studies. This manuscript describes the methodological details of a knowledge synthesis about pain management during vaccination and fear management in individuals with high levels of needle fear. Subsequent manuscripts in this series will present the results for the included questions.

Preclinical studies of dendrimer prodrugs.

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Kojima, Chie

2015-01-01

Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

Physiological remodeling of bifurcation aneurysms: preclinical results of the eCLIPs device.

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Marotta, Thomas R; Riina, Howard A; McDougall, Ian; Ricci, Donald R; Killer-Oberpfalzer, Monika

2018-02-01

OBJECTIVE Intracranial bifurcation aneurysms are complex lesions for which current therapy, including simple coiling, balloon- or stent-assisted coiling, coil retention, or intrasaccular devices, is inadequate. Thromboembolic complications due to a large burden of intraluminal metal, impedance of access to side branches, and a high recurrence rate, due largely to the unmitigated high-pressure flow into the aneurysm (water hammer effect), are among the limitations imposed by current therapy. The authors describe herein a novel device, eCLIPs, and its use in a preclinical laboratory study that suggests the device's design and functional features may overcome many of these limitations. METHODS A preclinical model of wide-necked bifurcation aneurysms in rabbits was used to assess functional features and efficacy of aneurysm occlusion by the eCLIPs device. RESULTS The eCLIPs device, in bridging the aneurysm neck, allows coil retention, disrupts flow away from the aneurysm, leaves the main vessel and side branches unencumbered by intraluminal metal, and serves as a platform for endothelial growth across the neck, excluding the aneurysm from the circulation. CONCLUSIONS The eCLIPs device permits physiological remodeling of the bifurcation.

Strategies to initiate and control the nucleation behavior of bimetallic nanoparticles.

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Krishnan, Gopi; de Graaf, Sytze; Ten Brink, Gert H; Persson, Per O Å; Kooi, Bart J; Palasantzas, George

2017-06-22

In this work we report strategies to nucleate bimetallic nanoparticles (NPs) made by gas phase synthesis of elements showing difficulty in homogeneous nucleation. It is shown that the nucleation assisted problem of bimetallic NP synthesis can be solved via the following pathways: (i) selecting an element which can itself nucleate and act as a nucleation center for the synthesis of bimetallic NPs; (ii) introducing H 2 or CH 4 as an impurity/trace gas to initiate nucleation during the synthesis of bimetallic NPs. The latter can solve the problem if none of the elements in a bimetallic NP can initiate nucleation. We illustrate the abovementioned strategies for the case of Mg based bimetallic NPs, which are interesting as hydrogen storage materials and exhibit both nucleation and oxidation issues even under ultra-high vacuum conditions. In particular, it is shown that adding H 2 in small proportions favors the formation of a solid solution/alloy structure even in the case of immiscible Mg and Ti, where normally phase separation occurs during synthesis. In addition, we illustrate the possibility of improving the nucleation rate, and controlling the structure and size distribution of bimetallic NPs using H 2 /CH 4 as a reactive/nucleating gas. This is shown to be associated with the dimer bond energies of the various formed species and the vapor pressures of the metals, which are key factors for NP nucleation.

Rapid and accurate synthesis of TALE genes from synthetic oligonucleotides.

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Wang, Fenghua; Zhang, Hefei; Gao, Jingxia; Chen, Fengjiao; Chen, Sijie; Zhang, Cuizhen; Peng, Gang

2016-01-01

Custom synthesis of transcription activator-like effector (TALE) genes has relied upon plasmid libraries of pre-fabricated TALE-repeat monomers or oligomers. Here we describe a novel synthesis method that directly incorporates annealed synthetic oligonucleotides into the TALE-repeat units. Our approach utilizes iterative sets of oligonucleotides and a translational frame check strategy to ensure the high efficiency and accuracy of TALE-gene synthesis. TALE arrays of more than 20 repeats can be constructed, and the majority of the synthesized constructs have perfect sequences. In addition, this novel oligonucleotide-based method can readily accommodate design changes to the TALE repeats. We demonstrated an increased gene targeting efficiency against a genomic site containing a potentially methylated cytosine by incorporating non-conventional repeat variable di-residue (RVD) sequences.

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

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Kothe, Christian

2014-05-01

Full Text Available [english] Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

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Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-03-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase

Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

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Poirier, Nicolas; Mary, Caroline; Le Bas-Bernardet, Stephanie; Daguin, Veronique; Belarif, Lyssia; Chevalier, Melanie; Hervouet, Jeremy; Minault, David; Ville, Simon; Charpy, Vianney; Blancho, Gilles; Vanhove, Bernard

2014-01-01

Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo. PMID:24598534

Alternating skills training and clerkships to ease the transition from preclinical to clinical training

NARCIS (Netherlands)

Van Hell, E.A.; Kuks, J.B.; Borleffs, J.C.; Cohen-Schotanus, J.

2011-01-01

Background: The transition from preclinical to clinical training is perceived as stressful with a high workload being the main difficulty. To ease this transition, we implemented a dual learning year, where just-in-time skills training and clerkships alternated. Aims: To examine the effect of the

Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges.

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Roland R Regoes

2005-08-01

Full Text Available Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against "real life" exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses.Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success.Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions.

Potential bias factors that affect the course evaluation of students in preclinical courses

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Su Jin Chae

2017-06-01

Full Text Available Purpose We aim to identify what potential bias factors affected students’ overall course evaluation, and to observe what factors should be considered in the curriculum evaluation system of medical schools. Methods This study analyzed students’ ratings of preclinical instructions at the Ajou University School of Medicine. The ratings of instructions involved 41 first-year and 45 second-year medical students. Results There was a statistically significant difference between years of study and ratings’ scoring. Learning difficulty, learning amount, student assessment, and teacher preparation from second-year students were significantly higher than first-year students (p<0.05. The analysis results revealed that student assessment was the predictor of ratings from first-year students, while teacher preparation was the predictor of ratings from second-year students. Conclusion We found significant interactions between year of study and the students’ rating results. We were able to confirm that satisfaction of instructions factors perceived by medical students were different for the characteristics of courses. Our results may be an important resource for evaluating preclinical curriculums.

Growing assisted migration: Synthesis of a climate change adaptation strategy

Science.gov (United States)

Mary I. Williams; R. Kasten Dumroese

2013-01-01

Assisted migration may be necessary as a climate change adaptation strategy for native plant species that are less adaptive or mobile. Moving plants has been practiced a long time in human history, but movement of species in response to climate change is a new context. First proposed in 1985, assisted migration has gained attention since 2007 as a strategy to prevent...

The Flipped Classroom for pre-clinical dental skills teaching - a reflective commentary.

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Crothers, A J; Bagg, J; McKerlie, R

2017-05-12

A Flipped Classroom method for teaching of adult practical pre-clinical dental skills was introduced to the BDS curriculum in Glasgow during the 2015/2016 academic session. This report provides a commentary of the first year of employing this method - from the identification of the need to optimise teaching resources, through the planning, implementation and development of the method, with an early indication of performance.

Selenium nanoparticles: potential in cancer gene and drug delivery.

Science.gov (United States)

Maiyo, Fiona; Singh, Moganavelli

2017-05-01

In recent decades, colloidal selenium nanoparticles have emerged as exceptional selenium species with reported chemopreventative and therapeutic properties. This has sparked widespread interest in their use as a carrier of therapeutic agents with results displaying synergistic effects of selenium with its therapeutic cargo and improved anticancer activity. Functionalization remains a critical step in selenium nanoparticles' development for application in gene or drug delivery. In this review, we highlight recent developments in the synthesis and functionalization strategies of selenium nanoparticles used in cancer drug and gene delivery systems. We also provide an update of recent preclinical studies utilizing selenium nanoparticles in cancer therapeutics.

Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery.

Science.gov (United States)

Brothers, John F; Ung, Matthew; Escalante-Chong, Renan; Ross, Jermaine; Zhang, Jenny; Cha, Yoonjeong; Lysaght, Andrew; Funt, Jason; Kusko, Rebecca

2018-06-01

The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data. Copyright © 2018 Elsevier Inc. All rights reserved.

Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic Diseases and Pregnancy Outcome.

Science.gov (United States)

Spinillo, Arsenio; Beneventi, Fausta; Locatelli, Elena; Ramoni, Vèronique; Caporali, Roberto; Alpini, Claudia; Albonico, Giulia; Cavagnoli, Chiara; Montecucco, Carlomaurizio

2016-10-01

To evaluate the impact of preclinical systemic autoimmune rheumatic disorders on pregnancy outcome. In this longitudinal cohort study, patients were enrolled during the first trimester of pregnancy if they reported having had connective tissue disorder symptoms, were found to be positive for circulating autoantibodies, and on clinical evaluation were judged to have a preclinical or incomplete rheumatic disorder. The incidence of fetal growth restriction (FGR), preeclampsia, and adverse pregnancy outcomes in patients with preclinical rheumatic disorders was compared with that in selected controls, after adjustment for confounders by penalized logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Of 5,232 women screened, 150 (2.9%) were initially diagnosed as having a suspected rheumatic disorder. After a mean ± SD postpartum follow-up of 16.7 ± 5.5 months, 64 of these women (42.7%) had no clinically apparent rheumatic disease and 86 (57.3%) had persistent symptoms and positive autoantibody results, including 10 (6.7%) who developed a definitive rheumatic disease. The incidences of preeclampsia/FGR and of small for gestational age (SGA) infants were 5.1% (23 of 450) and 9.3% (42 of 450), respectively, among controls, 12.5% (8 of 640) (OR 2.7 [95% CI 1.1-6.4]) and 18.8% (12 of 64) (OR 2.2 [95% CI 1.1-4.5]), respectively, among women with no clinically apparent disease, and 16.3% (14 of 86) (OR 3.8 [95% CI 1.9-7.7]) and 18.6% (16 of 86) (OR 2.3 [95% CI 1.2-4.3]), respectively, among those with persisting symptoms at follow-up. Mean ± SD umbilical artery Doppler pulsatility indices were higher among women with no clinically apparent disease (0.95 ± 0.2) and those with persisting symptoms (0.96 ± 0.21) than in controls (0.89 ± 0.12) (P = 0.01 and P rheumatic disorders were associated with an increased risk of FGR/preeclampsia and SGA. The impact of these findings and their utility in screening

Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

Energy Technology Data Exchange (ETDEWEB)

Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfizer.com [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States); Ramaiah, Shashi K. [Drug Safety, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139 (United States); Whiteley, Laurence O. [Drug Safety, Pfizer Worldwide Research and Development, 1 Burtt Rd, Andover, MA 01810 (United States)

2016-12-01

Drug-induced nephrotoxicity is a common drug development complication for pharmaceutical companies. Sensitive, specific, translatable and non-invasive biomarkers of renal toxicity are urgently needed to diagnose nephron segment specific injury. The currently available gold standard biomarkers for nephrotoxicity are not kidney-specific, lack sensitivity for early detection, and are not suitable for renal damage localization (glomerular vs tubulointerstitial injury). MicroRNAs (miRNAs) are increasingly gaining momentum as promising biomarkers of various organ toxicities, including drug induced renal injury. This is mostly due to their stability in easily accessible biofluids, ease of developing nucleic acids detection compared to protein detection assays, as well as their interspecies translatability. Increasing concordance of miRNA findings by standardizing methodology most suitable for their detection and quantitation, as well as characterization of their expression pattern in a cell type specific manner, will accelerate progress toward validation of these miRNAs as biomarkers in pre-clinical, and clinical settings. This review aims to highlight the current pre-clinical findings surrounding miRNAs as biomarkers in two important segments of the nephron, the glomerulus and tubules. - Highlights: • miRNAs are promising biomarkers of drug-induced kidney injury. • Summarized pre-clinical miRNA biomarkers of drug-induced nephrotoxicity. • Described the strengths and challenges associated with miRNAs as biomarkers.

Cued memory decline in biomarker-defined preclinical Alzheimer disease.

Science.gov (United States)

Papp, Kathryn V; Rentz, Dorene M; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Quiroz, Yakeel; Johnson, Keith A; Sperling, Reisa A

2017-04-11

To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging. Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ +/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education. A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ + participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ - peers. Furthermore, Aβ + participants who scored ≤46/48 had smaller hippocampal volumes ( t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ 2 = 14.30, p recall. Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ + clinically normal individuals at greatest risk of short-term clinical progression. © 2017 American Academy of Neurology.

Effective treatment strategies against Ebola virus

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Amina Yaqoob

2015-08-01

Full Text Available Ebola virus (EBOV, a member of order Mononegavirales is most famous for causing the endemics of hemorrhagic fever in different countries of the world. Various effective treatment for EBOV are available presently but different clinical trials and experimental studies on animal models are ongoing for this purpose. Results from different studies showed that selective vaccines and therapeutic drugs have potential to interfere the viral life events within host cell in order to inhibit its replication. Various pre-clinical trials in this regard are proved successful on non-human primates (NHPs and found to be significant in inhibiting EBOV infections. It is the need of hour to develop effective vaccines against Ebola virus to combat this problem as soon as possible. The present article is a brief review on potential treatment strategies against Ebola virus.

[DIFFERENCE IN THE PREVALENCE OF BURNOUT SYNDROME IN PRECLINICAL AND CLINICAL TEACHING DOCTORS OF MOSTAR SCHOOL OF MEDICINE].

Science.gov (United States)

Vukojevič, Mladenka; Antunovič, Andelka; Petrov, Božo

2015-01-01

The aim of this study was to determine the difference in the prevalence of burnout syndrome in preclinical and clinical teaching doctors of Mostar School of Medicine in the academic year 2011/2012. Special attention was also focused on finding out the possible difference between the syndrome incidence that was correlated to gender and years of service. The main hypothesis was that the probability of burnout syndrome incidence was higher in the group of female clinical teaching doctors having more years of service. The study involved 62 people with high academic education employed at Mostar School of Medicine who were surveyed during a randomly selected consecutive 3-month period (February to May) of the academic year 2011/2012. The data were prospectively collected through a standardized questionnaire survey. The studied parameters were gender, years of work experience and the engagement in preclinical or clinical departments of the Medical School. The survey showed that 43 out of 62 (69.4%) respondents did not suffer the burnout syndrome, while moderate syndrome was recodred in 19 (30.6%) of them. No person had serious symptoms of the syndrome. The difference between the respondents who suffered the syndrome and those who did not was not statistically significant (P=0.002). Considering the gender of respondents, statistically significant differences were not confirmed (P=0.444). Considering the years of service, the highest incidence of the syndrome was found in people with more work experience (in the group of 21-25 years), but the difference between the groups was not statistically significant (P=0.271). Observing the work in preclinical and clinical departments, because of the limited number of patients we could not confirm the hypothesis. The syndrome had affected 13 (21%) clinical teaching doctors and 6 (9,7%) preclinical doctors, while the differenece between them was not statistically significant (P=0.054). Considering the results of this research, it has

Novel Microwave-Assisted Synthesis of the Immunomodulator Organotellurium Compound Ammonium Trichloro(dioxoethylene-O,O'tellurate (AS101

Directory of Open Access Journals (Sweden)

M. Pilar Vázquez-Tato

2014-02-01

Full Text Available Ammonium trichloro[1,2-ethanediolato-O,O']-tellurate (AS101 is the most important synthetic Te compound from the standpoint of its biological activity. It is a potent immunomodulator with a variety of potential therapeutic applications and antitumoral action in several preclinical and clinical studies. An experimental design has been used to develop and optimize a novel microwave-assisted synthesis (MAOS of the AS101. In comparison to the results observed in the literature, refluxing Te(IV chloride and ethylene glycol in acetonitrile (Method A, or by refluxing Te(IV chloride and ammonium chloride in ethylene glycol (Method B, it was found that the developed methods in the present work are an effective alternative, because although performance slightly decreases compared to conventional procedures (75% vs. 79% by Method A, and 45% vs. 51% by Method B, reaction times decreased from 4 h to 30 min and from 4 h to 10 min, by Methods A and B respectively. MAOS is proving to be of value in the rapid synthesis of compounds with new and improved biological activities, specially based on the benefit of its shorter reaction times.

Verification and Performance Evaluation of Timed Game Strategies

DEFF Research Database (Denmark)

David, Alexandre; Fang, Huixing; Larsen, Kim Guldstrand

2014-01-01

Control synthesis techniques, based on timed games, derive strategies to ensure a given control objective, e.g., time-bounded reachability. Model checking verifies correctness properties of systems. Statistical model checking can be used to analyse performance aspects of systems, e.g., energy...... consumption. In this work, we propose to combine these three techniques. In particular, given a strategy synthesized for a timed game and a given control objective, we want to make a deeper examination of the consequences of adopting this strategy. Firstly, we want to apply model checking to the timed game...... under the synthesized strategy in order to verify additional correctness properties. Secondly, we want to apply statistical model checking to evaluate various performance aspects of the synthesized strategy. For this, the underlying timed game is extended with relevant price and stochastic information...

Synthesis of hydrophobic peptides : An Fmoc “Solubilising Tail” method

NARCIS (Netherlands)

Choma, Christin T.; Robillard, George T.; Englebretsen, Darren R.

1998-01-01

The development of an Fmoc method for synthesis and purification of hydrophobic peptides using a “solubihsing tail” strategy is described. Peptide-constructs of the form hydrophobic peptide-[CHmb ester]-solubilising peptide were synthesised. Procedures for forming the 4-Hmb ester linkage, and

Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk.

Science.gov (United States)

Gintant, Gary A

2008-08-01

The successful development of novel drugs requires the ability to detect (and avoid) compounds that may provoke Torsades-de-Pointes (TdeP) arrhythmia while endorsing those compounds with minimal torsadogenic risk. As TdeP is a rare arrhythmia not readily observed during clinical or post-marketing studies, numerous preclinical models are employed to assess delayed or altered ventricular repolarization (surrogate markers linked to enhanced proarrhythmic risk). This review evaluates the advantages and limitations of selected preclinical models (ranging from the simplest cellular hERG current assay to the more complex in vitro perfused ventricular wedge and Langendorff heart preparations and in vivo chronic atrio-ventricular (AV)-node block model). Specific attention is paid to the utility of concentration-response relationships and "risk signatures" derived from these studies, with the intention of moving beyond predicting clinical QT prolongation and towards prediction of TdeP risk. While the more complex proarrhythmia models may be suited to addressing questionable or conflicting proarrhythmic signals obtained with simpler preclinical assays, further benchmarking of proarrhythmia models is required for their use in the robust evaluation of safety margins. In the future, these models may be able to reduce unwarranted attrition of evolving compounds while becoming pivotal in the balanced integrated risk assessment of advancing compounds.

Scalable synthesis of sequence-defined, unimolecular macromolecules by Flow-IEG

Science.gov (United States)

Leibfarth, Frank A.; Johnson, Jeremiah A.; Jamison, Timothy F.

2015-01-01

We report a semiautomated synthesis of sequence and architecturally defined, unimolecular macromolecules through a marriage of multistep flow synthesis and iterative exponential growth (Flow-IEG). The Flow-IEG system performs three reactions and an in-line purification in a total residence time of under 10 min, effectively doubling the molecular weight of an oligomeric species in an uninterrupted reaction sequence. Further iterations using the Flow-IEG system enable an exponential increase in molecular weight. Incorporating a variety of monomer structures and branching units provides control over polymer sequence and architecture. The synthesis of a uniform macromolecule with a molecular weight of 4,023 g/mol is demonstrated. The user-friendly nature, scalability, and modularity of Flow-IEG provide a general strategy for the automated synthesis of sequence-defined, unimolecular macromolecules. Flow-IEG is thus an enabling tool for theory validation, structure–property studies, and advanced applications in biotechnology and materials science. PMID:26269573

Synthesis and binding studies of Alzheimer ligands on solid support.

Science.gov (United States)

Rzepecki, Petra; Geib, Nina; Peifer, Manuel; Biesemeier, Frank; Schrader, Thomas

2007-05-11

Aminopyrazole derivatives constitute the first class of nonpeptidic rationally designed beta-sheet ligands. Here we describe a double solid-phase protocol for both synthesis and affinity testing. The presented solid-phase synthesis of four types of hybrid compounds relies on the Fmoc strategy and circumvents subsequent HPLC purification by precipitating the final product from organic solution in pure form. Hexa- and octapeptide pendants with internal di- and tetrapeptide bridges are now amenable in high yields to combinatorial synthesis of compound libraries for high-throughput screening purposes. Solid-phase peptide synthesis (SPPS) on an acid-resistant PAM allows us, after PMB deprotection, to subject the free aminopyrazole binding sites in an immobilized state to on-bead assays with fluorescence-labeled peptides. From the fluorescence emission intensity decrease, individual binding constants can be calculated via reference curves by simple application of the law of mass action. Gratifyingly, host/guest complexation can be monitored quantitatively even for those ligands, which are almost insoluble in water.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

Science.gov (United States)

Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L; Albert, Marylin; Weintraub, S; Fortin, Norbert J; Cotman, Carl W

2013-07-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

Directory of Open Access Journals (Sweden)

Julia L. Hurwitz

2010-02-01

Full Text Available Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans.

Peer-mentoring Program during the Preclinical Years of Medical School at Bonn University: a Project Description.

Science.gov (United States)

Lapp, Hendrik; Makowka, Philipp; Recker, Florian

2018-01-01

Introduction: To better prepare young medical students in a thorough and competent manner for the ever increasing clinical, scientific, as well as psychosocial requirements, universities should enable a close, personal transfer of experience and knowledge. Structured mentoring programs are a promising approach to incorporate clinical subjects earlier into the preclinical training. Such a mentoring program facilitates the prioritization of concepts from a broad, theory-heavy syllabus. Here we report the experiences and results of the preclinical mentoring program of Bonn University, which was introduced in the winter semester of 2012/2013. Project desciption: The program is characterized by the concept of peer-to-peer teaching during the preclinical semesters of medical school. Regular, voluntary course meetings with different clinical case examples provide students the opportunity to apply knowledge acquired from the basic science curricula; furthermore, a personal contact for advice and support is ensured. Thus, an informal exchange of experiences is made possible, which provides to the students motivational and learning aids, in particular for the oral examination at the end of the premedical semesters as well as for other examinations during medical school. Results: Over the course of the preceding three years the number of participants and the interest in the program grew steadily. The analysis of collected evaluations confirms very good communication between mentors and students (>80%), as well as consistently good to very good quality and usefulness in terms of the mentors' subject-specific and other advice. The overall final evaluation of the mentoring program was always good to very good (winter semester: very good 64.8±5.0%, good 35.2±5.0%, summer semester: very good 83.9±7.5%, good 16.1±7.5%) Summary: In summary, it has been shown that the mentoring program had a positive impact on the development, education and satisfaction of students beginning

Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma

International Nuclear Information System (INIS)

Wang, Weining; Iyer, N. Gopalakrishna; Tay, Hsien Ts’ung; Wu, Yonghui; Lim, Tony K. H.; Zheng, Lin; Song, In Chin; Kwoh, Chee Keong; Huynh, Hung; Tan, Patrick O. B.; Chow, Pierce K. H.

2015-01-01

Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long

Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

DEFF Research Database (Denmark)

Pedersen, Torben Møller; Hansen, E. Louise; Kane, John

2001-01-01

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different $alpha@-oxygen-substituted, racemic aldehydes were initially transformed by asy...... the allylic stereocenter and the alkene geometry. Thus, a single $gamma@-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.......A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different $alpha@-oxygen-substituted, racemic aldehydes were initially transformed...... by asymmetric HWE reactions into mixtures of two major $alpha@,$beta@-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution...

Total Synthesis of Hyperforin.

Science.gov (United States)

Ting, Chi P; Maimone, Thomas J

2015-08-26

A 10-step total synthesis of the polycyclic polyprenylated acylphloroglucinol (PPAP) natural product hyperforin from 2-methylcyclopent-2-en-1-one is reported. This route was enabled by a diketene annulation reaction and an oxidative ring expansion strategy designed to complement the presumed biosynthesis of this complex meroterpene. The described work enables the preparation of a highly substituted bicyclo[3.3.1]nonane-1,3,5-trione motif in only six steps and thus serves as a platform for the construction of easily synthesized, highly diverse PPAPs modifiable at every position.

Development of the Vinylogous Pictet-Spengler Cyclization and Total Synthesis of (±)-Lundurine A.

Science.gov (United States)

Nash, Aaron; Qi, Xiangbing; Maity, Pradip; Owens, Kyle; Tambar, Uttam K

2018-04-16

A novel vinylogous Pictet-Spengler cyclization has been developed for the generation of indole-annulated medium-sized rings. The method enables the synthesis of tetrahydroazocinoindoles with a fully substituted carbon center, a prevalent structural motif in many biologically active alkaloids. The strategy has been applied to the total synthesis of (±)-lundurine A. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the N-Terminal Amino Acid of Aculeine B.

Science.gov (United States)

Shiozaki, Hiroki; Miyahara, Masayoshi; Otsuka, Kazunori; Miyako, Kei; Honda, Akito; Takasaki, Yuichi; Takamizawa, Satoshi; Tukada, Hideyuki; Ishikawa, Yuichi; Sakai, Ryuichi; Oikawa, Masato

2018-05-23

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.

Synthesis, structural characterization and selectively catalytic properties of metal-organic frameworks with nano-sized channels: A modular design strategy

International Nuclear Information System (INIS)

Qiu Lingguang; Gu Lina; Hu Gang; Zhang Lide

2009-01-01

Modular design method for designing and synthesizing microporous metal-organic frameworks (MOFs) with selective catalytical activity was described. MOFs with both nano-sized channels and potential catalytic activities could be obtained through self-assembly of a framework unit and a catalyst unit. By selecting hexaaquo metal complexes and the ligand BTC (BTC=1,3,5-benzenetricarboxylate) as framework-building blocks and using the metal complex [M(phen) 2 (H 2 O) 2 ] 2+ (phen=1,10-phenanthroline) as a catalyst unit, a series of supramolecular MOFs 1-7 with three-dimensional nano-sized channels, i.e. [M 1 (H 2 O) 6 ].[M 2 (phen) 2 (H 2 O) 2 ] 2 .2(BTC).xH 2 O (M 1 , M 2 =Co(II), Ni(II), Cu(II), Zn(II), or Mn(II), phen=1,10-phenanthroline, BTC=1,3,5-benzenetricarboxylate, x=22-24), were synthesized through self-assembly, and their structures were characterized by IR, elemental analysis, and single-crystal X-ray diffraction. These supramolecular microporous MOFs showed significant size and shape selectivity in the catalyzed oxidation of phenols, which is due to catalytic reactions taking place in the channels of the framework. Design strategy, synthesis, and self-assembly mechanism for the construction of these porous MOFs were discussed. - Grapical abstract: A modular design strategy has been developed to synthesize microporous metal-organic frameworks with potential catalytic activity by self-assembly of the framework-building blocks and the catalyst unit

An energy strategy for France; Une strategie energetique pour la France

Energy Technology Data Exchange (ETDEWEB)

Fontaine, N.

2003-10-01

The present report endeavors tpo make a synthesis of the debate about energy to deduce numerous measures devoted to define the French energy strategy for the short, middle and long term. Two parts are studied in this report. In the first one, the landscape of energy is set, the market is tackled, the energy supply and demand are object of controversy. In the second part, the objective for an energy policy are summarized, elements for the control of energy demand are studied, the energy supply is equally tackled. (N.C.)

Multicolour synthesis in lanthanide-doped nanocrystals through cation exchange in water

KAUST Repository

Han, Sanyang

2016-10-04

Meeting the high demand for lanthanide-doped luminescent nanocrystals across a broad range of fields hinges upon the development of a robust synthetic protocol that provides rapid, just-in-time nanocrystal preparation. However, to date, almost all lanthanide-doped luminescent nanomaterials have relied on direct synthesis requiring stringent controls over crystal nucleation and growth at elevated temperatures. Here we demonstrate the use of a cation exchange strategy for expeditiously accessing large classes of such nanocrystals. By combining the process of cation exchange with energy migration, the luminescence properties of the nanocrystals can be easily tuned while preserving the size, morphology and crystal phase of the initial nanocrystal template. This post-synthesis strategy enables us to achieve upconversion luminescence in Ce3+ and Mn2+-activated hexagonal-phased nanocrystals, opening a gateway towards applications ranging from chemical sensing to anti-counterfeiting.

Development of multimodal imaging strategies for the pharmacology of anticancer agents

International Nuclear Information System (INIS)

Brulle, Laura

2012-01-01

Preclinical imaging in oncology is booming. It allows, using representative animal models of human cancers, to understand the mechanisms of development of pathologies and to assess the therapeutic efficiency of a new treatment. The main objective of this work was to develop two ortho-topic models of cancer (pancreas and colon) and to assess on them the reference treatments as well as a new therapeutic strategy by non-thermal plasma so called Plasma Gun. The two cancer models developed showed good representation in relation to human cancers, with the appearance of distant metastases and hypoxia. 5-fluorouracil for the HCT116-luc ortho-topic model of colorectal carcinoma and gemcitabine for the MIA PaCa2-luc pancreatic adenocarcinoma model, have induced discrete effects at low dose which can be detected thanks imaging modalities. After validation of our experimental steps, a new therapeutic strategy, Plasma Gun was evaluated and showed significant effects on tumor growth inhibition. The second objective was to carry out tools for the induction and the characterization of bone metastases and for high resolution imaging of the vasculature. On the one hand, bone metastases obtained by injection of PC3M-luc cells intracardially, was evaluated and quantified with different imaging modalities (bioluminescence, scintigraphy and Computed Tomography). And the other hand, the achievement of a high resolution imaging of vascularization, was possible by the casting method that restores the 3D structure of the vascular architecture following injection of a resin in the circulation. Developments makes during this thesis are new tools for preclinical evaluation of novel anticancer therapies. (author) [fr

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | FNLCR Staging

Science.gov (United States)

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. Th

A multi-paradigm language for reactive synthesis

Directory of Open Access Journals (Sweden)

Ioannis Filippidis

2016-02-01

Full Text Available This paper proposes a language for describing reactive synthesis problems that integrates imperative and declarative elements. The semantics is defined in terms of two-player turn-based infinite games with full information. Currently, synthesis tools accept linear temporal logic (LTL as input, but this description is less structured and does not facilitate the expression of sequential constraints. This motivates the use of a structured programming language to specify synthesis problems. Transition systems and guarded commands serve as imperative constructs, expressed in a syntax based on that of the modeling language Promela. The syntax allows defining which player controls data and control flow, and separating a program into assumptions and guarantees. These notions are necessary for input to game solvers. The integration of imperative and declarative paradigms allows using the paradigm that is most appropriate for expressing each requirement. The declarative part is expressed in the LTL fragment of generalized reactivity(1, which admits efficient synthesis algorithms, extended with past LTL. The implementation translates Promela to input for the Slugs synthesizer and is written in Python. The AMBA AHB bus case study is revisited and synthesized efficiently, identifying the need to reorder binary decision diagrams during strategy construction, in order to prevent the exponential blowup observed in previous work.

Strategies for microbial synthesis of high-value phytochemicals

Science.gov (United States)

Li, Sijin; Li, Yanran; Smolke, Christina D.

2018-03-01

Phytochemicals are of great pharmaceutical and agricultural importance, but often exhibit low abundance in nature. Recent demonstrations of industrial-scale production of phytochemicals in yeast have shown that microbial production of these high-value chemicals is a promising alternative to sourcing these molecules from native plant hosts. However, a number of challenges remain in the broader application of this approach, including the limited knowledge of plant secondary metabolism and the inefficient reconstitution of plant metabolic pathways in microbial hosts. In this Review, we discuss recent strategies to achieve microbial biosynthesis of complex phytochemicals, including strategies to: (1) reconstruct plant biosynthetic pathways that have not been fully elucidated by mining enzymes from native and non-native hosts or by enzyme engineering; (2) enhance plant enzyme activity, specifically cytochrome P450 activity, by improving efficiency, selectivity, expression or electron transfer; and (3) enhance overall reaction efficiency of multi-enzyme pathways by dynamic control, compartmentalization or optimization with the host's metabolism. We also highlight remaining challenges to — and future opportunities of — this approach.

Mapping student thinking in chemical synthesis

Science.gov (United States)

Weinrich, Melissa

In order to support the development of learning progressions about central ideas and practices in different disciplines, we need detailed analyses of the implicit assumptions and reasoning strategies that guide students' thinking at different educational levels. In the particular case of chemistry, understanding how new chemical substances are produced (chemical synthesis) is of critical importance. Thus, we have used a qualitative research approach based on individual interviews with first semester general chemistry students (n = 16), second semester organic chemistry students (n = 15), advanced undergraduates (n = 9), first year graduate students (n = 15), and PhD candidates (n = 16) to better characterize diverse students' underlying cognitive elements (conceptual modes and modes of reasoning) when thinking about chemical synthesis. Our results reveal a great variability in the cognitive resources and strategies used by students with different levels of training in the discipline to make decisions, particularly at intermediate levels of expertise. The specific nature of the task had a strong influence on the conceptual sophistication and mode of reasoning that students exhibited. Nevertheless, our data analysis has allowed us to identify common modes of reasoning and assumptions that seem to guide students' thinking at different educational levels. Our results should facilitate the development of learning progressions that help improve chemistry instruction, curriculum, and assessment.

Fluorescent Nanoprobes Dedicated to in Vivo Imaging: From Preclinical Validations to Clinical Translation

Directory of Open Access Journals (Sweden)

Isabelle Texier

2012-05-01

Full Text Available With the fast development, in the last ten years, of a large choice of set-ups dedicated to routine in vivo measurements in rodents, fluorescence imaging techniques are becoming essential tools in preclinical studies. Human clinical uses for diagnostic and image-guided surgery are also emerging. In comparison to low-molecular weight organic dyes, the use of fluorescent nanoprobes can improve both the signal sensitivity (better in vivo optical properties and the fluorescence biodistribution (passive “nano” uptake in tumours for instance. A wide range of fluorescent nanoprobes have been designed and tested in preclinical studies for the last few years. They will be reviewed and discussed considering the obstacles that need to be overcome for their potential everyday use in clinics. The conjugation of fluorescence imaging with the benefits of nanotechnology should open the way to new medical applications in the near future.

Eco-friendly Synthesis of Organics and Nanomaterials ...

Science.gov (United States)

The presentation summarizes our recent activity in chemical synthesis involving benign alternatives, such as the use of supported reagents, and greener reaction medium in aqueous or solvent-free conditions.1 The synthesis of heterocyclic compounds, coupling reactions, and a variety of name reactions2 are the primary beneficiaries as exemplified by the synthesis of N-aryl azacycloalkanes, isoindoles, and dihydropyrazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,3-dioxanes, pyrazoles, catalyzed by basic water or polystyrene sulfonic acid (PSSA) in conjunction with microwave (MW) irradiation.2 Vitamins B1, B2, C, and tea and wine polyphenols which function both as reducing and capping agents, provide extremely simple, one-pot, green synthetic methods to bulk quantities of nanomaterials in water.3a Shape-controlled synthesis of noble nanostructures via MW-assisted spontaneous reduction of noble metal salts using sugars will be presented.3b A general method has been developed for the cross-linking reaction of poly (vinyl alcohol) (PVA) with metallic systems; bimetallic systems,3c and SWNT, MWNT, and C-60.3d The strategy is extended to the formation of biodegradable carboxymethylcellulose (CMC) composite films with noble nanometals;3e such metal decoration and alignment of carbon nanotubes in CMC is possible using MW approach3f which also enables the shape-controlled bulk synthesis of Ag and Fe nanorods in poly (ethylene glycol).3g MW hydrothermal process delivers m

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.

Science.gov (United States)

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Caciagli, Valerio; Catrambone, Fernando; D'Andrea, Piero; Felicetti, Patrizia; Gensini, Martina; Marastoni, Elena; Nannicini, Rossano; Paris, Marielle; Terracciano, Rosa; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2007-02-08

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Quetiapine: recent developments in preclinical research

Directory of Open Access Journals (Sweden)

Marco Orsetti

2010-03-01

Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

Strategies to inhibit the lipid oxidation in the enzymatic synthesis of monoglycerides by glycerolysis of Babassu oil - doi: 10.4025/actascitechnol.v35i3.14187

Directory of Open Access Journals (Sweden)

Larissa Freitas

2013-06-01

Full Text Available Different strategies to avoid the lipid feedstock oxidation in the enzymatic synthesis of monoglycerides (MAG from glycerolysis of babassu oil were tested. The reactions were catalyzed by Burkholderia cepacia lipase immobilized on SiO2-PVA and the tests carried out in batchwise. The best strategy was tested in a continuous packed-bed reactor. Different antioxidants and emulsifiers were used, including: Buthyl-hydroxy-toluene (BHT, tocopherol, soy lecithin and Triton X-100. The influence of inert atmosphere (N2 on the MAG production was also investigated. Results were compared with those attaining in the control reaction. The best performance was obtained using N2 in the reaction medium, preventing the oxidation of babassu oil. MAG concentrations were 60 and 24% in batch and continuous mode, respectively. Among the tested antioxidant and emulsifying agents, only soy lecithin was found to be efficient but its application showed limit performance to be used in continuous runs.  

Preclinical incorporation dosimetry of (+)-[18F) flubatine in piglets

International Nuclear Information System (INIS)

Sattler, B.; Patt, M.; Sabri, O.; Kranz, M.; Donat, C.K.; Deuther-Conrad, W.; Fischer, S.; Brust, P.; Sattler, T.; Smits, R.; Hoepping, A.; Steinbach, J.

2015-01-01

Full text of publication follows. Aim: (+)-[ 18 F] flubatine is the mirror image isomer of (-)-[ 18 F] flubatine, which is successfully used for neuroimaging of alpha4beta2 nAChRs with PET. To assess the radiation risk by this new radiotracer, biodistribution, organ doses (OD) and the effective dose (ED) were investigated in a preclinical trials using piglets. Method: whole body dosimetry of (+)-[ 18 F] flubatine was performed in 3 female piglets (age: 43 ± 1.2 days, weight: 14 ± 1.0 kg). The animals were narcotized using 20 mg/kg Ketamine, 2 mg/kg Azaperone; 1.5% Isoflurane in 70% N 2 O/30% O 2 and sequentially PET-imaged up to 5 hours post i.v. injection of 183.5 ± 9.0 MBq on a SIEMENS Biograph16 PET/CT-system on 7 bed positions (BP) per frame, 1.5 to 6 min/BP, CT-attenuation correction (AC) and iterative reconstruction. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (%ID/g, and %ID/organ). Time- and mass-scales were adapted to the human order of magnitude. The ODs were calculated using the adult male model with OLINDA. The ED was calculated using tissue weighting factors as published in the ICRP103. Results: The highest OD was received by the urinary bladder (71.7 ± 26.3 μSv/MBq), the kidneys (45.1 ± 6.5 μSv/MBq) and the brain (32.3 ± 3.24 μSv/MBq). The highest contribution to the ED was by the urinary bladder (2.9 ± 1.1 μSv/MBq), the lungs (1.7 ± 0.02 μSv/MBq) and the red marrow (1.4 ± 0.1μSv/MBq). According to this data, the ED to humans is 14.3 ± 0.3 μSv/MBq. Conclusion: considering 40% underestimation of the ED to humans by preclinical dosimetry [1] the expected ED to humans after 300 MBq i.v. is 7.2 mSv, which is about the ED by (-)-[ 18 F]flubatine (6.8 mSv/300 MBq) and well within the range of what other 18 F-labeled compounds cause to humans. This risk assessment encourages to transfer (+)-[F 18 ] flubatine from preclinical to clinical study phases and to further develop

Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update

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Wen-Hao Zhang

2016-01-01

Full Text Available Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is are the first-line therapy for erectile dysfunction (ED. The constant discoveries of nitric oxide (NO/cyclic guanosine monophosphate (cGMP cell-signaling pathway for smooth muscle (SM control in other urogenital tracts (UGTs make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH except on maximum urinary flow rate (Q max with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie′s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required.

High-resolution mutational profiling suggests the genetic validity of glioblastoma patient-derived pre-clinical models.

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Shawn E Yost

Full Text Available Recent advances in the ability to efficiently characterize tumor genomes is enabling targeted drug development, which requires rigorous biomarker-based patient selection to increase effectiveness. Consequently, representative DNA biomarkers become equally important in pre-clinical studies. However, it is still unclear how well these markers are maintained between the primary tumor and the patient-derived tumor models. Here, we report the comprehensive identification of somatic coding mutations and copy number aberrations in four glioblastoma (GBM primary tumors and their matched pre-clinical models: serum-free neurospheres, adherent cell cultures, and mouse xenografts. We developed innovative methods to improve the data quality and allow a strict comparison of matched tumor samples. Our analysis identifies known GBM mutations altering PTEN and TP53 genes, and new actionable mutations such as the loss of PIK3R1, and reveals clear patient-to-patient differences. In contrast, for each patient, we do not observe any significant remodeling of the mutational profile between primary to model tumors and the few discrepancies can be attributed to stochastic errors or differences in sample purity. Similarly, we observe ∼96% primary-to-model concordance in copy number calls in the high-cellularity samples. In contrast to previous reports based on gene expression profiles, we do not observe significant differences at the DNA level between in vitro compared to in vivo models. This study suggests, at a remarkable resolution, the genome-wide conservation of a patient's tumor genetics in various pre-clinical models, and therefore supports their use for the development and testing of personalized targeted therapies.

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

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Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Comparative assessment of the diets of healthy individuals, subjects with preclinical coronary heart disease and patients with severe heart diseases

International Nuclear Information System (INIS)

Aronov, D.M.; Eganyan, R.A.; Kovaleva, O.F.; Zhidko, N.I.; Danielov, G.Eh.; Rozhnov, A.V.; Shcherbakova, I.A.

1991-01-01

92 males aged 26 to 55 (28 healthy individuals, 45 persons with preclinical coronary heart disease and 19 patients with functional class 1-2 coronary heart disease) were examined to study the peculiarities and dietary patterns of persons with a high physical working capacity and having no typical clinical signs of the disease. All persons were subjected to a complex examination which included questionnarire, myocardial scintigraphy with 201 Tl at a maximum physical loading, echocardiography, coronaroangiography. Certain dietary peculiarities are established in persons with preclinical coronary heart disease

Beyond “implementation strategies”: classifying the full range of strategies used in implementation science and practice

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Jennifer Leeman

2017-11-01

Full Text Available Abstract Background Strategies are central to the National Institutes of Health’s definition of implementation research as “the study of strategies to integrate evidence-based interventions into specific settings.” Multiple scholars have proposed lists of the strategies used in implementation research and practice, which they increasingly are classifying under the single term “implementation strategies.” We contend that classifying all strategies under a single term leads to confusion, impedes synthesis across studies, and limits advancement of the full range of strategies of importance to implementation. To address this concern, we offer a system for classifying implementation strategies that builds on Proctor and colleagues’ (2013 reporting guidelines, which recommend that authors not only name and define their implementation strategies but also specify who enacted the strategy (i.e., the actor and the level and determinants that were targeted (i.e., the action targets. Main body We build on Wandersman and colleagues’ Interactive Systems Framework to distinguish strategies based on whether they are enacted by actors functioning as part of a Delivery, Support, or Synthesis and Translation System. We build on Damschroder and colleague’s Consolidated Framework for Implementation Research to distinguish the levels that strategies target (intervention, inner setting, outer setting, individual, and process. We then draw on numerous resources to identify determinants, which are conceptualized as modifiable factors that prevent or enable the adoption and implementation of evidence-based interventions. Identifying actors and targets resulted in five conceptually distinct classes of implementation strategies: dissemination, implementation process, integration, capacity-building, and scale-up. In our descriptions of each class, we identify the level of the Interactive System Framework at which the strategy is enacted (actors, level and

Learning Grasp Strategies Composed of Contact Relative Motions

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Platt, Robert, Jr.

2007-01-01

Of central importance to grasp synthesis algorithms are the assumptions made about the object to be grasped and the sensory information that is available. Many approaches avoid the issue of sensing entirely by assuming that complete information is available. In contrast, this paper proposes an approach to grasp synthesis expressed in terms of units of control that simultaneously change the contact configuration and sense information about the object and the relative manipulator-object pose. These units of control, known as contact relative motions (CRMs), allow the grasp synthesis problem to be recast as an optimal control problem where the goal is to find a strategy for executing CRMs that leads to a grasp in the shortest number of steps. An experiment is described that uses Robonaut, the NASA-JSC space humanoid, to show that CRMs are a viable means of synthesizing grasps. However, because of the limited amount of information that a single CRM can sense, the optimal control problem may be partially observable. This paper proposes expressing the problem as a k-order Markov Decision Process (MDP) and solving it using Reinforcement Learning. This approach is tested in a simulation of a two-contact manipulator that learns to grasp an object. Grasp strategies learned in simulation are tested on the physical Robonaut platform and found to lead to grasp configurations consistently.

Image Retargeting by Content-Aware Synthesis

OpenAIRE

Dong, Weiming; Wu, Fuzhang; Kong, Yan; Mei, Xing; Lee, Tong-Yee; Zhang, Xiaopeng

2014-01-01

Real-world images usually contain vivid contents and rich textural details, which will complicate the manipulation on them. In this paper, we design a new framework based on content-aware synthesis to enhance content-aware image retargeting. By detecting the textural regions in an image, the textural image content can be synthesized rather than simply distorted or cropped. This method enables the manipulation of textural & non-textural regions with different strategy since they have different...

Degenerated human articular cartilage at autopsy represents preclinical osteoarthritic cartilage: comparison with clinically defined osteoarthritic cartilage

NARCIS (Netherlands)

van Valburg, A. A.; Wenting, M. J.; Beekman, B.; te Koppele, J. M.; Lafeber, F. P.; Bijlsma, J. W.

1997-01-01

To investigate whether macroscopically fibrillated human articular knee cartilage observed at autopsy can be considered an early, preclinical phase of osteoarthritis (OA). Histological and biochemical characteristics of 3 types of articular knee cartilage were compared: macroscopically degenerated

Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

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Iwaniec, U T; Philbrick, K A; Wong, C P; Gordon, J L; Kahler-Quesada, A M; Olson, D A; Branscum, A J; Sargent, J L; DeMambro, V E; Rosen, C J; Turner, R T

2016-10-01

Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies

VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

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Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

2016-01-01

Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

Core@shell Nanoparticles: Greener Synthesis Using Natural Plant Products

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Mehrdad Khatami

2018-03-01

Full Text Available Among an array of hybrid nanoparticles, core-shell nanoparticles comprise of two or more materials, such as metals and biomolecules, wherein one of them forms the core at the center, while the other material/materials that were located around the central core develops a shell. Core-shell nanostructures are useful entities with high thermal and chemical stability, lower toxicity, greater solubility, and higher permeability to specific target cells. Plant or natural products-mediated synthesis of nanostructures refers to the use of plants or its extracts for the synthesis of nanostructures, an emerging field of sustainable nanotechnology. Various physiochemical and greener methods have been advanced for the synthesis of nanostructures, in contrast to conventional approaches that require the use of synthetic compounds for the assembly of nanostructures. Although several biological resources have been exploited for the synthesis of core-shell nanoparticles, but plant-based materials appear to be the ideal candidates for large-scale green synthesis of core-shell nanoparticles. This review summarizes the known strategies for the greener production of core-shell nanoparticles using plants extract or their derivatives and highlights their salient attributes, such as low costs, the lack of dependence on the use of any toxic materials, and the environmental friendliness for the sustainable assembly of stabile nanostructures.

Multifaceted Strategy for the Synthesis of Diverse 2,2'-Bithiophene Derivatives

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Stanisław Krompiec

2015-03-01

Full Text Available New catalytically or high pressure activated reactions and routes, including coupling, double bond migration in allylic systems, and various types of cycloaddition and dihydroamination have been used for the synthesis of novel bithiophene derivatives. Thanks to the abovementioned reactions and routes combined with non-catalytic ones, new acetylene, butadiyne, isoxazole, 1,2,3-triazole, pyrrole, benzene, and fluoranthene derivatives with one, two or six bithiophenyl moieties have been obtained. Basic sources of crucial substrates which include bithiophene motif for catalytic reactions were 2,2'-bithiophene, gaseous acetylene and 1,3-butadiyne.

Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer.

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McKeage, Mark J; Baguley, Bruce C

2010-04-15

The unique characteristics of tumor vasculature represent an attractive target that may be exploited by vascular-targeting anticancer agents. A promising strategy involves the selective disruption of established tumor blood vessels by tumor-vascular disrupting agents (tumor-VDAs), which exhibit antivascular activity, resulting in inhibition of tumor blood flow and extensive necrosis within the tumor core. The tumor-VDA class can be subdivided into flavonoid compounds, which are related to flavone acetic acid, and tubulin-binding compounds. ASA404, of the flavonoid class, is the most advanced tumor-VDA in clinical development and has been evaluated preclinically and in several phase 1 and phase 2 studies. Preclinical studies have demonstrated the selective apoptosis of tumor endothelial cells and the inhibition of tumor blood flow. Synergistic activity was observed with ASA404 and with several chemotherapeutic agents, particularly taxanes. In clinical trials, compared with chemotherapy alone, ASA404 was tolerated well and produced improved activity in patients with nonsmall cell lung cancer when combined with paclitaxel and carboplatin. Phase 3 clinical trials are ongoing. Selectively targeting established tumor vasculature with tumor-VDAs represents a promising and innovative approach to improving the efficacy of standard anticancer therapies. (c) 2010 American Cancer Society.

Synthesis of Renewable meta-Xylylenediamine from Biomass-Derived Furfural.

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Scodeller, Ivan; Mansouri, Samir; Morvan, Didier; Muller, Eric; de Oliveira Vigier, Karine; Wischert, Raphael; Jérôme, François

2018-04-30

We report the synthesis of biomass-derived functionalized aromatic chemicals from furfural, a building block nowadays available in large scale from low-cost biomass. The scientific strategy relies on a Diels-Alder/aromatization sequence. By controlling the rate of each step, it was possible to produce exclusively the meta aromatic isomer. In particular, through this route, we describe the synthesis of renewably sourced meta-xylylenediamine (MXD). Transposition of this work to other furfural-derived chemicals is also discussed and reveals that functionalized biomass-derived aromatics (benzaldehyde, benzylamine, etc.) can be potentially produced, according to this route. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pre-clinical MR elastography: Principles, techniques, and applications

Science.gov (United States)

Bayly, P. V.; Garbow, J. R.

2018-06-01

Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

Radiochemistry, pre-clinical studies and first clinical investigation of 90Y-labeled hydroxyapatite (HA) particles prepared utilizing 90Y produced by (n,γ) route

International Nuclear Information System (INIS)

Vimalnath, K.V.; Chakraborty, Sudipta; Rajeswari, A.; Sarma, H.D.; Nuwad, Jitendra; Pandey, Usha; Kamaleshwaran, K.; Shinto, Ajit; Dash, Ashutosh

2015-01-01

Introduction: The scope of using no carrier added (NCA) 90 Y [T 1/2 = 64.1 h, E β(max) = 2.28 MeV] obtained from 90 Sr/ 90 Y generator in radiation synovectomy (RSV) is widely accepted. In the present study, the prospect of using 90 Y produced by (n,γ) route in a medium flux research reactor for use in RSV was explored. Methods: Yttrium-90 was produced by thermal neutron irradiation of Y 2 O 3 target at a neutron flux of ~ 1 × 10 14 n/cm 2 .s for 14 d. The influence of various experimental parameters were systematically investigated and optimized to arrive at the most favorable conditions for the formulation of 90 Y labeled hydroxyapatite (HA) using HA particles of 1–10 μm size range. An optimized kit formulation strategy was developed for convenient one-step compounding of 90 Y-HA, which is easily adaptable at hospital radiopharmacy. The pre-clinical biological evaluation of 90 Y-HA particles was studied by carrying out biodistribution and bioluminiscence imaging studies in Wistar rats. The first clinical investigation using the radiolabeled preparation was performed on a patient suffering from chronic arthritis in knee joint by administering 185 MBq 90 Y-HA formulated at the hospital radiopharmacy deploying the proposed strategy. Results: Yttrium-90 was produced with a specific activity of 851 ± 111 MBq/mg and radionuclidic purity of 99.95 ± 0.02%. 90 Y-labeled HA particles (185 ± 10 MBq doses) were formulated in high radiochemical purity (> 99%) and excellent in vitro stability. The preparation showed promising results in pre-clinical studies carried out in Wistar rats. The preliminary results of the first clinical investigation of 90 Y-HA preparation in a patient with rheumatoid arthritis in knee joints demonstrated the effectiveness of the formulation prepared using 90 Y produced via (n,γ) route in the management of the disease. Conclusion: The studies revealed that effective utilization of 90 Y produced via (n,γ) route in a medium flux research

Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma.

Science.gov (United States)

Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

2014-01-01

Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. © 2013 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

Long-term impact of a preclinical endovascular skills course on medical student career choices.

Science.gov (United States)

Lee, Jason T; Son, Ji H; Chandra, Venita; Lilo, Emily; Dalman, Ronald L

2011-10-01

Surging interest in the 0 + 5 integrated vascular surgery (VS) residency and successful recruitment of the top students in medical school requires early exposure to the field. We sought to determine the impact of a high-fidelity simulation-based preclinical endovascular skills course on medical student performance and ultimate career specialty choices. Fifty-two preclinical medical students enrolled in an 8-week VS elective course from 2007 to 2009. Students completed a baseline and postcourse survey and performed a renal angioplasty/stent procedure on an endovascular simulator (pretest). A curriculum consisting of didactic teaching covering peripheral vascular disease and weekly mentored simulator sessions concluded with a final graded procedure (posttest). Long-term follow-up surveys 1 to 3 years after course completion were administered to determine ultimate career paths of participants as well as motivating factors for career choice. Objective and subjective performance measured on the simulator and through structured global assessment scales improved in all students from pre- to posttest, particularly with regard to technical skill and overall procedural competency (P choices including surgical subspecialties (64%), radiology (10%), and cardiology (6%). Most respondents indicated major reasons for continued interest in VS were the ability to practice endovascular procedures on the simulator (92%) and mentorship from VS faculty (70%). Basic endovascular skills can be efficiently introduced through a simulation-based curriculum and lead to improved novice performance. Early exposure of preclinical medical students provides an effective teaching and recruitment tool for procedural-based fields, particularly surgical subspecialties. Mentored exposure to endovascular procedures on the simulator positively impacts long-term medical student attitudes toward vascular surgery and ultimate career choices. Copyright © 2011 Society for Vascular Surgery. Published by

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Science.gov (United States)

Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

2017-08-01

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma

International Nuclear Information System (INIS)

Tagde, A; Singh, H; Kang, M H; Reynolds, C P

2014-01-01

Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM

SYNTHETIC STRATEGY FOR THE PREPARATION OF BIOACTIVE GALACTOGLYCEROLIPIDS

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Emiliano Manzo

2011-12-01

Full Text Available The current communication represents an extended abstract of the presentation delivered on the joint Moldo-Italian seminar “New frontiers in natural product chemistry”, held in the Institute of Chemistry, Academy of Sciences of Moldova on 30 September. A simple and efficient strategy for the synthesis of galactoglycerolipids is provided.

Value of Entheseal Ultrasonography and Serum Cartilage Oligomeric Matrix Protein in the Preclinical Diagnosis of Psoriatic Arthritis

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Moataz Mohammed Samy Elbeblawy

2010-03-01

Full Text Available Objective: To evaluate the utility of entheseal ultrasonography and serum COMP in the preclinical diagnosis of psoriatic arthritis. Methods: 60 psoriatic patients were divided into: 30 patients with psoriasis (group I and 30 patients with psoriatic arthritis as control (group II. They underwent independent clinical and ultrasonographic examination of both lower limbs at the calcaneal insertions of Achilles tendons. Psoriatic arthritis disease activity and severity was assessed by modified DAS28 and Steinbrockers scores. Serum levels of COMP were measured for all patients by ELISA. Results: On clinical examination, no entheseal abnormalities were detected in group I while they were present in 23.3% of group II with statistically significant difference between them (P 0.05. Serum COMP were significantly elevated in group I and II with no statistically significant difference between them (mean ± SD 5.9 ± 3 and 6.8 ± 12 respectively, P > 0.05. Entheseal ultrasound was more specific (67% while serum COMP was more sensitive (87% in the preclinical diagnosis of psoriatic arthritis. Serum COMP levels were significantly correlated with CRP in both groups and with DAS28 and Steinbrockers scores in group II (P < 0.01. Conclusion: Entheseal ultrasonography and serum COMP levels may be used complementary to each other for preclinical diagnosis of psoriatic arthritis. Serum COMP seems to be promising prognostic marker for psoriatic arthritis patients.

Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization.

Science.gov (United States)

Tuzun, Erdem; Berrih-Aknin, Sonia; Brenner, Talma; Kusner, Linda L; Le Panse, Rozen; Yang, Huan; Tzartos, Socrates; Christadoss, Premkumar

2015-08-01

Myasthenia gravis (MG) is an autoimmune disorder characterized by generalized muscle weakness due to neuromuscular junction (NMJ) dysfunction brought by acetylcholine receptor (AChR) antibodies in most cases. Although steroids and other immunosuppressants are effectively used for treatment of MG, these medications often cause severe side effects and a complete remission cannot be obtained in many cases. For pre-clinical evaluation of more effective and less toxic treatment methods for MG, the experimental autoimmune myasthenia gravis (EAMG) induced by Torpedo AChR immunization has become one of the standard animal models. Although numerous compounds have been recently proposed for MG mostly by using the active immunization EAMG model, only a few have been proven to be effective in MG patients. The variability in the experimental design, immunization methods and outcome measurements of pre-clinical EAMG studies make it difficult to interpret the published reports and assess the potential for application to MG patients. In an effort to standardize the active immunization EAMG model, we propose standard procedures for animal care conditions, sampling and randomization of mice, experimental design and outcome measures. Utilization of these standard procedures might improve the power of pre-clinical EAMG experiments and increase the chances for identifying promising novel treatment methods that can be effectively translated into clinical trials for MG. Copyright © 2015 Elsevier Inc. All rights reserved.

The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

NARCIS (Netherlands)

D. Martins-de-Souza (Daniel); M. Alsaif (Murtada); A. Ernst (Agnes); L.W. Harris (Laura); N. Aerts (Nancy); I. Lenaerts (Ilse); P.J. Peeters (Pieter); K. Amess (Kevin); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)

2012-01-01

textabstractBackground: Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore,

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

Energy Technology Data Exchange (ETDEWEB)

Grant, Claire, E-mail: claire.grant@astrazeneca.com [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Ewart, Lorna [Drug Safety and Metabolism, AstraZeneca, Da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston SG8 6HB (United Kingdom); Muthas, Daniel [Respiratory, Inflammation and Autoimmunity iMED, AstraZeneca, Pepparedsleden 1, 431 83 Mölndal (Sweden); Deavall, Damian [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Smith, Simon A. [Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Royston SG8 6HB (United Kingdom); Clack, Glen [Translational Medicine Unit, Early Clinical Development, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Newham, Pete [Drug Safety and Metabolism, AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG (United Kingdom)

2016-04-01

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used