Preclinical Animal Models for Temporomandibular Joint Tissue Engineering.

PubMed

Almarza, Alejandro J; Brown, Bryan N; Arzi, Boaz; Ângelo, David Faustino; Chung, William; Badylak, Stephen F; Detamore, Michael

2018-06-01

There is a paucity of in vivo studies that investigate the safety and efficacy of temporomandibular joint (TMJ) tissue regeneration approaches, in part due to the lack of established animal models. Review of disease models for study of TMJ is presented herein with an attempt to identify relevant preclinical animal models for TMJ tissue engineering, with emphasis on the disc and condyle. Although degenerative joint disease models have been mainly performed on mice, rats, and rabbits, preclinical regeneration approaches must employ larger animal species. There remains controversy regarding the preferred choice of larger animal models between the farm pig, minipig, goat, sheep, and dog. The advantages of the pig and minipig include their well characterized anatomy, physiology, and tissue properties. The advantages of the sheep and goat are their easier surgical access, low cost per animal, and its high tissue availability. The advantage of the dog is that the joint space is confined, so migration of interpositional devices should be less likely. However, each species has limitations as well. For example, the farm pig has continuous growth until about 18 months of age, and difficult surgical access due to the zygomatic arch covering the lateral aspect of joint. The minipig is not widely available and somewhat costly. The sheep and the goat are herbivores, and their TMJs mainly function in translation. The dog is a carnivore, and the TMJ is a hinge joint that can only rotate. Although no species provides the gold standard for all preclinical TMJ tissue engineering approaches, the goat and sheep have emerged as the leading options, with the minipig as the choice when cost is less of a limitation; and with the dog and farm pig serving as acceptable alternatives. Finally, naturally occurring TMJ disorders in domestic species may be harnessed on a preclinical trial basis as a clinically relevant platform for translation.

Methodological Rigor in Preclinical Cardiovascular Studies

PubMed Central

Ramirez, F. Daniel; Motazedian, Pouya; Jung, Richard G.; Di Santo, Pietro; MacDonald, Zachary D.; Moreland, Robert; Simard, Trevor; Clancy, Aisling A.; Russo, Juan J.; Welch, Vivian A.; Wells, George A.

2017-01-01

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in

Neuroinflammatory targets and treatments for epilepsy validated in experimental models.

PubMed

Aronica, Eleonora; Bauer, Sebastian; Bozzi, Yuri; Caleo, Matteo; Dingledine, Raymond; Gorter, Jan A; Henshall, David C; Kaufer, Daniela; Koh, Sookyong; Löscher, Wolfgang; Louboutin, Jean-Pierre; Mishto, Michele; Norwood, Braxton A; Palma, Eleonora; Poulter, Michael O; Terrone, Gaetano; Vezzani, Annamaria; Kaminski, Rafal M

2017-07-01

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

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

PubMed

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

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium.

PubMed

Knopp, K L; Stenfors, C; Baastrup, C; Bannon, A W; Calvo, M; Caspani, O; Currie, G; Finnerup, N B; Huang, W; Kennedy, J D; Lefevre, I; Machin, I; Macleod, M; Rees, H; Rice, A S C; Rutten, K; Segerdahl, M; Serra, J; Wodarski, R; Berge, O-G; Treedef, R-D

2017-12-29

Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of "negative" data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications

PubMed Central

Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong

2017-01-01

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. PMID:28515222

Zebrafish models for functional and toxicological screening of nanoscale drug delivery systems: promoting preclinical applications.

PubMed

Lee, Keon Yong; Jang, Gun Hyuk; Byun, Cho Hyun; Jeun, Minhong; Searson, Peter C; Lee, Kwan Hyi

2017-06-30

Preclinical screening with animal models is an important initial step in clinical translation of new drug delivery systems. However, establishing efficacy, biodistribution, and biotoxicity of complex, multicomponent systems in small animal models can be expensive and time-consuming. Zebrafish models represent an alternative for preclinical studies for nanoscale drug delivery systems. These models allow easy optical imaging, large sample size, and organ-specific studies, and hence an increasing number of preclinical studies are employing zebrafish models. In this review, we introduce various models and discuss recent studies of nanoscale drug delivery systems in zebrafish models. Also in the end, we proposed a guideline for the preclinical trials to accelerate the progress in this field. © 2017 The Author(s).

Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

DTIC Science & Technology

2014-09-01

AD_________________ Award Number: TITLE: Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...AUG 2013-7 Aug 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...a genetic mouse model of autism -like phenotypes, the Grin1 knockdown mouse. The Grin1 gene encodes the NR1 subunit of the NMDA receptor . In the

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

PubMed Central

Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew; Li, Tong; Worley, Paul F; Troncoso, Juan C; Wong, Phil C; Price, Don L

2012-01-01

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. PMID:21937983

Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis.

PubMed

Kitz, Jenna; Lowes, Lori E; Goodale, David; Allan, Alison L

2018-04-28

The majority of cancer deaths occur because of metastasis since current therapies are largely non-curative in the metastatic setting. The use of in vivo preclinical mouse models for assessing metastasis is, therefore, critical for developing effective new cancer biomarkers and therapies. Although a number of quantitative tools have been previously developed to study in vivo metastasis, the detection and quantification of rare metastatic events has remained challenging. This review will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer and the resulting lessons learned about CTC and metastasis biology. We will also discuss how the use of clinically-relevant CTC technologies such as the CellSearch ® and Parsortix™ platforms for preclinical CTC studies can serve to enhance the study of cancer biology, new biomarkers, and novel therapies from the bench to the bedside.

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

PubMed Central

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

Pharmacological enhancement of fear reduction: preclinical models

PubMed Central

Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

2011-01-01

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel.

PubMed

Zhou, X; Kurowski, S; Wu, W; Desai, K; Chu, L; Gutstein, D E; Seiffert, D; Wang, X

2016-09-01

Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals. Potential translational value of this preclinical model of MES was demonstrated. Objectives Cerebral microembolic signals (MESs) detected by transcranial Doppler (TCD) ultrasound constitute an independent predictor of stroke risk and prognosis. The aim of this study was to develop a novel preclinical model of MESs to facilitate translational research. Methods A clinical TCD ultrasound machine was used to detect MESs in the cerebral circulation of New Zealand White rabbits. Technical feasibility was assessed for the measurement of MESs in the middle cerebral artery (MCA) by TCD. FeCl3 -induced carotid arterial thrombosis was optimized for the generation of endogenous microemboli. Ascending doses of two antithrombotic agents (aspirin and clopidogrel) were evaluated individually and in combination for their effects on both arterial thrombosis and MESs in a 30% FeCl3 -induced carotid arterial thrombosis model, along with ex vivo functional assays. Results Dose-dependent FeCl3 -induced arterial thrombosis studies showed that 30% FeCl3 resulted in the most consistent and reproducible MESs in the MCA (3.3 ± 0.7 MESs h(-1) ). Ascending-dose studies showed that the effective doses for 50% inhibition (ED50 ) of thrombus formation, based on integrated blood flow and thrombus weight, respectively, were 3.1 mg kg(-1) and 4.2 mg kg(-1) orally for aspirin, and 0.3 mg kg(-1) and 0.28 mg kg(-1) orally for clopidogrel. The ED50 values for MES incidence were 12.7 mg kg(-1) orally for aspirin, and 0.25 mg kg(-1) orally for clopidogrel. Dual treatment with aspirin (5 mg kg(-1) ) and clopidogel (0.3 mg kg(-1) ) resulted in significant reductions in cerebral MESs (P < 0.05) as compared with monotherapy with either agent. Conclusions Our study

Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications.

PubMed

Rutter, Carolyn M; Knudsen, Amy B; Marsh, Tracey L; Doria-Rose, V Paul; Johnson, Eric; Pabiniak, Chester; Kuntz, Karen M; van Ballegooijen, Marjolein; Zauber, Ann G; Lansdorp-Vogelaar, Iris

2016-07-01

Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and treatment strategies. Because models often require assumptions about unobservable processes, assessing a model's predictive accuracy is important. We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 [0.44, 0.71], 0.63 [0.51, 0.75], 0.68 [0.53, 0.83]; estimated with 95% confidence interval: 0.56 [0.45, 0.69]). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications. © The

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

PubMed

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

2016-01-01

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.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

PubMed Central

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

Animal models of binge drinking, current challenges to improve face validity.

PubMed

Jeanblanc, Jérôme; Rolland, Benjamin; Gierski, Fabien; Martinetti, Margaret P; Naassila, Mickael

2018-05-05

Binge drinking (BD), i.e., consuming a large amount of alcohol in a short period of time, is an increasing public health issue. Though no clear definition has been adopted worldwide the speed of drinking seems to be a keystone of this behavior. Developing relevant animal models of BD is a priority for gaining a better characterization of the neurobiological and psychobiological mechanisms underlying this dangerous and harmful behavior. Until recently, preclinical research on BD has been conducted mostly using forced administration of alcohol, but more recent studies used scheduled access to alcohol, to model more voluntary excessive intakes, and to achieve signs of intoxications that mimic the human behavior. The main challenges for future research are discussed regarding the need of good face validity, construct validity and predictive validity of animal models of BD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Preclinical validation of a novel cocaine exposure therapy for relapse prevention.

PubMed

Mihindou, Claudia; Vouillac, Caroline; Koob, George F; Ahmed, Serge H

2011-09-15

Cocaine not only induces intense rewarding sensations but also craving for more cocaine, particularly during abstinence, an effect that contributes, together with other factors, to relapse. Here we sought to prevent this effect by extinguishing the conditioned interoceptive cues of cocaine that are thought to be acquired during repeated cocaine use. Cocaine-induced craving was studied in rats using the well-validated model of drug-primed reinstatement of cocaine seeking. To extinguish the conditioned interoceptive effects of cocaine, rats received daily repeated cocaine priming in the absence of drug reinforcement. Cocaine-primed reinstatement of cocaine seeking dramatically decreased with repeated cocaine priming regardless of the testing dose and even following a history of extended access to cocaine self-administration. The extinction of cocaine-primed reinstatement of cocaine seeking was enduring, generalized to stress-another major trigger of drug craving and relapse-and was context-dependent. These findings clearly show that it is feasible to prevent the ability of cocaine and stress to induce cocaine seeking using an approach designed to extinguish the drug's conditioned interoceptive cues. Although this preclinical extinction approach has limitations that need to be overcome in future research (i.e., its context-dependency), it may nevertheless represent a promising basis for the development of a novel exposure therapy against cocaine relapse. Copyright © 2011 Society of Biological Psychiatry. All rights reserved.

Excessive Aggression as Model of Violence: A Critical Evaluation of Current Preclinical Methods

PubMed Central

Miczek, Klaus A.; de Boer, Sietse F.; Haller, Jozsef

2013-01-01

Rationale Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area. Objectives How valid, reliable, productive and informative are the most frequently used animal models of excessive aggressive behavior? Methods The rationale, key methodological features, supporting data and arguments as well as their disadvantages and limitations of the most frequently used animal models for excessive aggressive behavior are summarized and their validity and reliability are evaluated. Results Excessive aggressive behavior is validly and reliably seen in (1) a proportion of feral-derived rats and selectively bred mice, (2) rats with compromised adrenal function resulting in a hypoglucocorticoid state, (3) a significant minority of mice, rats and monkeys after consumption of a moderate dose of alcohol, and (4) resident animals of various species after social instigation. Limitations of these procedures include restrictive animal research regulations, the requirement of expertise in surgical, pharmacological and behavioral techniques, and the behaviorally impoverished mouse strains that are used in molecular genetics research. Promising recent initiatives for novel experimental models include aggressive behaviors that are evoked by optogenetic stimulation and induced by the manipulation of early social experiences such as isolation rearing or social stress. Conclusions One of the most significant challenges for animal models of excessive, potentially abnormal aggressive behavior is the characterization of distinctive neurobiological mechanisms that differ from those governing species-typical aggressive behavior. Identifying novel targets for effective intervention requires increased understanding of the distinctive molecular, cellular and circuit mechanisms for each type of abnormal aggressive behavior. PMID:23430160

Models for preclinical studies in aging-related disorders: One is not for all

PubMed Central

Santulli, Gaetano; Borras, Consuelo; Bousquet, Jean; Calzà, Laura; Cano, Antonio; Illario, Maddalena; Franceschi, Claudio; Liotta, Giuseppe; Maggio, Marcello; Molloy, William D.; Montuori, Nunzia; O’Caoimh, Rónán; Orfila, Francesc; Rauter, Amelia P.; Santoro, Aurelia; Iaccarino, Guido

2015-01-01

Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical. PMID:27042427

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

PubMed

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.

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

PubMed

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; Schroeder, Patricia; Schuck, Virna; Suryawanshi, Satyendra; Su, Yaming; Trapa, Patrick; Tsai, Alice; Vakilynejad, Majid; Wang, Shining; Wong, Harvey

2015-03-01

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 broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

Evaluation of a novel high-intensity focused ultrasound device: preclinical studies in a porcine model.

PubMed

Jewell, Mark L; Desilets, Charles; Smoller, Bruce R

2011-05-01

High-intensity focused ultrasound (HIFU) has been applied clinically for the noninvasive treatment of pathological conditions in various organs for over 50 years; however, there are little data describing the use of thermal HIFU to ablate fat for body contouring and treatment of collagen-rich layers. A novel device under clinical investigation (LipoSonix; Medicis Technologies Corporation, Bothell, Washington) uses HIFU to eliminate unwanted adipose tissue. The authors describe the results of HIFU treatment in a series of preclinical studies performed in a validated porcine model. Preclinical research included in vivo treatment of the abdominal subcutaneous adipose tissue of swine with transcutaneous HIFU therapy. Endpoint analyses included thermocouple temperature data, full-body necropsy, local pathology and histology studies, clinical hematology, urinalysis, and blood chemistry parameters, including lipid panels. The application of HIFU energy levels of 166 to 372 J/cm(2) generated tissue temperature approaching 70°C, which was restricted to the focal area (n = seven). Application of 68 and 86 J/cm(2) did not produce clinically-significant changes in serum liver function tests, free fatty acids, or cholesterol (n = eight). Gross examination of tissue from various organs showed no evidence of fat emboli or accumulation (n = two). Histology demonstrated well-preserved vasculature and intact nerve fibers within the HIFU focal area (n = three). Following treatment with 85.3 to 270 J/cm(2), normal healing response included the migration of macrophages into the damaged tissue and removal of disrupted cellular debris and lipids (n = 8). In a preclinical swine model, the controlled thermal effect of HIFU appears to provide a safe and effective means for ablating subcutaneous adipose tissue.

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

PubMed

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.

Preclinical models for obesity research

PubMed Central

Barrett, Perry; Morgan, Peter J.

2016-01-01

ABSTRACT 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. PMID:27821603

Porcine Tricuspid Valve Anatomy and Human Compatibility: Relevance for Preclinical Validation of Novel Valve Interventions.

PubMed

Waziri, Farhad; Lyager Nielsen, Sten; Michael Hasenkam, John

2016-09-01

Tricuspid regurgitation may be a precursor for heart failure, reduced functional capacity, and poor survival. A human compatible experimental model is required to understand the pathophysiology of the tricuspid valve disease as a basis for validating novel tricuspid valve interventions before clinical use. The study aim was to evaluate and compare the tricuspid valve anatomy of porcine and human hearts. The anatomy of the tricuspid valve and the surrounding structures that affect the valve during a cardiac cycle were examined in detail in 100 fresh and 19 formalin-fixed porcine hearts obtained from Danish Landrace pigs (body weight 80 kg). All valvular dimensions were compared with human data acquired from literature sources. No difference was seen in the tricuspid annulus circumference between porcine and human hearts (13.0 ± 1.2 cm versus 13.5 ± 1.5 cm; p = NS), or in valve area (5.7 ± 1.6 cm2 versus 5.6 ± 1.0 cm2; p = NS). The majority of chordae types exhibited a larger chordal length and thickness in human hearts compared to porcine hearts. In both species, the anterior papillary muscle (PM) was larger than other PMs in the right ventricle, but muscle length varied greatly (range: 5.2-40.3 mm) and was significantly different in pigs and in humans (12.2 ± 3.2 mm versus 19.2 mm; p <0.001). The porcine tricuspid valve was determined to be a valid model for preclinical animal studies, despite various anatomic differences being noted between porcine and human hearts.

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

PubMed

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.

Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

PubMed Central

Proetzel, Gabriele; Wiles, Michael V.; Roopenian, Derry C.

2015-01-01

The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID:24150980

Preclinical MR fingerprinting (MRF) at 7 T: effective quantitative imaging for rodent disease models.

PubMed

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

2015-03-01

High-field preclinical MRI scanners are now commonly used to quantitatively assess disease status and the 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 MR fingerprinting (MRF) methodology which has been described previously 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 min. 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 the quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. Copyright © 2015 John Wiley & Sons, Ltd.

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

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

Xie, Tianwu; Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch; Geneva Neuroscience Center, Geneva University, Geneva CH-1205

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 themore » 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.« less

Imaging technologies for preclinical models of bone and joint disorders

PubMed Central

2011-01-01

Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy. PMID:22214535

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

PubMed Central

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, <1 % had lesions resembling proximal MCA or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. Conclusions ICARE subjects are not representative of all 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

Reproducibility of preclinical animal research improves with heterogeneity of study samples

PubMed Central

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

Optimized design and analysis of preclinical intervention studies in vivo

PubMed Central

Laajala, Teemu D.; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

2016-01-01

Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions. PMID:27480578

Optimized design and analysis of preclinical intervention studies in vivo.

PubMed

Laajala, Teemu D; Jumppanen, Mikael; Huhtaniemi, Riikka; Fey, Vidal; Kaur, Amanpreet; Knuuttila, Matias; Aho, Eija; Oksala, Riikka; Westermarck, Jukka; Mäkelä, Sari; Poutanen, Matti; Aittokallio, Tero

2016-08-02

Recent reports have called into question the reproducibility, validity and translatability of the preclinical animal studies due to limitations in their experimental design and statistical analysis. To this end, we implemented a matching-based modelling approach for optimal intervention group allocation, randomization and power calculations, which takes full account of the complex animal characteristics at baseline prior to interventions. In prostate cancer xenograft studies, the method effectively normalized the confounding baseline variability, and resulted in animal allocations which were supported by RNA-seq profiling of the individual tumours. The matching information increased the statistical power to detect true treatment effects at smaller sample sizes in two castration-resistant prostate cancer models, thereby leading to saving of both animal lives and research costs. The novel modelling approach and its open-source and web-based software implementations enable the researchers to conduct adequately-powered and fully-blinded preclinical intervention studies, with the aim to accelerate the discovery of new therapeutic interventions.

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

PubMed Central

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 Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies

PubMed Central

Majumder, Kaustav; Arora, Nivedita; Modi, Shrey; Chugh, Rohit; Nomura, Alice; Giri, Bhuwan; Dawra, Rajinder; Ramakrishnan, Sundaram; Banerjee, Sulagna; Saluja, Ashok; Dudeja, Vikas

2017-01-01

A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as KrasG12D; Trp53R172H; Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies. PMID:26582596

Current preclinical models for the advancement of translational bladder cancer research.

PubMed

DeGraff, David J; Robinson, Victoria L; Shah, Jay B; Brandt, William D; Sonpavde, Guru; Kang, Yibin; Liebert, Monica; Wu, Xue-Ru; Taylor, John A

2013-02-01

Bladder cancer is a common disease representing the fifth most diagnosed solid tumor in the United States. Despite this, advances in our understanding of the molecular etiology and treatment of bladder cancer have been relatively lacking. This is especially apparent when recent advances in other cancers, such as breast and prostate, are taken into consideration. The field of bladder cancer research is ready and poised for a series of paradigm-shifting discoveries that will greatly impact the way this disease is clinically managed. Future preclinical discoveries with translational potential will require investigators to take full advantage of recent advances in molecular and animal modeling methodologies. We present an overview of current preclinical models and their potential roles in advancing our understanding of this deadly disease and for advancing care. ©2012 AACR.

A preclinical mouse model of invasive lobular breast cancer metastasis.

PubMed

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 breast cancer metastasis, which recapitulates key events in its formation and clinical course. Specifically, using the conditional K14cre;Cdh1(F/F);Trp53(F/F) model of de novo mammary tumor formation, we orthotopically transplanted invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once primary tumors were established in recipient mice, we mimicked the clinical course of treatment by conducting a mastectomy. After surgery, recipient mice succumbed to widespread overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Genomic profiling of paired mammary tumors and distant metastases showed that our model provides a unique tool to further explore the biology of metastatic disease. Neoadjuvant and adjuvant intervention studies using standard-of-care chemotherapeutics showed the value of this model in determining therapeutic agents that can target early- and late-stage metastatic disease. In obtaining a more accurate preclinical model of metastatic lobular breast cancer, our work offers advances supporting the development of more effective treatment strategies for metastatic disease.

Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse

PubMed Central

Carnicella, Sebastien; Ron, Dorit; Barak, Segev

2014-01-01

One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5–6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders. PMID:24721195

Biomarker validation of a decline in semantic processing in preclinical Alzheimer's disease.

PubMed

Papp, Kathryn V; Mormino, Elizabeth C; Amariglio, Rebecca E; Munro, Catherine; Dagley, Alex; Schultz, Aaron P; Johnson, Keith A; Sperling, Reisa A; Rentz, Dorene M

2016-07-01

Differentially worse performance on category versus letter fluency suggests greater semantic versus retrieval difficulties. This discrepancy, combined with reduced episodic memory, has widespread clinical utility in diagnosing Alzheimer's disease (AD). Our objective was to investigate whether changes in semantic processing, as measured by the discrepancy between category and letter fluency, was detectable in preclinical AD: in clinically normal older adults with abnormal β-amyloid (Aβ) deposition on positron emission tomography (PET) neuroimaging. Clinically normal older adults (mean Mini Mental State Exam (MMSE) score = 29) were classified as Aβ+ (n = 70) or Aβ- (n = 205) using Pittsburgh Compound B-(PET) imaging. Participants completed letter fluency (FAS; word generation to letters F-A-S) and category fluency (CAT; word generation to animals, vegetables, fruits) annually (mean follow-up = 2.42 years). The effect of Aβ status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) versus retrieval processes (CAT and FAS), we repeated models predicting CAT over time, controlling for FAS and likewise for CAT controlling for FAS. At baseline, the Aβ+ group performed better on FAS compared with the Aβ- group but comparably on CAT. Longitudinally, the Aβ+ group demonstrated greater decline on CAT compared with the Aβ- group (p = .0011). This finding remained significant even when covarying for FAS (p = .0107). Aβ+ participants similarly declined compared with Aβ- participants on FAS (p = .0112), but this effect became insignificant when covarying for CAT (p = .1607). These findings provide biomarker validation for the greater specificity of declines in category versus letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized. (PsycINFO Database Record (c

Improving the quality of preclinical research echocardiography: Observations, training and guidelines for measurement.

PubMed

Donner, Daniel G; Kiriazis, Helen; Du, Xiao-Jun; Marwick, Thomas H; McMullen, Julie R

2018-04-20

Informal training in preclinical research may be a contributor to the poor reproducibility of preclinical cardiology research and low rates of translation into clinical research and practice. Mouse echocardiography is a widely used technique to assess cardiac structure and function in drug intervention studies using disease models. The inter-observer variability (IOV) of clinical echocardiographic measurements has been shown to improve with formalized training, but preclinical echocardiography lacks similarly critical standardization of training. The aims of this investigation were to assess the IOV of echocardiographic measurements from studies in mice, and address any technical impediments to reproducibility by implementing standardized guidelines through formalized training. In this prospective, single-site, observational cohort study, 13 scientists performing preclinical echocardiographic image analysis were assessed for measurement of short-axis M-mode-derived dimensions and calculated left ventricular mass (LVMass). Ten M-mode images of mouse hearts acquired and analyzed by an expert researcher with a spectrum of LVMass were selected for assessment, and validated by autopsy weight. Following the initial observation, a structured formal training program was introduced, and accuracy and reproducibility were re-evaluated. Mean absolute percentage error (MAPE) for Expert-calculated LVMass was 6{plus minus}4% compared to autopsy LVMass, and 25{plus minus}21% for participants before training. Standardized formal training improved participant MAPE by approximately 30% relative to expert-calculated LVMass (p<0.001). Participants initially categorized with high-range error (25-45%) improved to low-moderate error ranges (<15-25%). This report reveals an example of technical skill training insufficiency likely endemic to preclinical research and provides validated guidelines for echocardiographic measurement for adaptation to formalized in-training programs.

A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation.

PubMed

Kleikers, Pamela W M; Hooijmans, Carlijn; Göb, Eva; Langhauser, Friederike; Rewell, Sarah S J; Radermacher, Kim; Ritskes-Hoitinga, Merel; Howells, David W; Kleinschnitz, Christoph; Schmidt, Harald H H W

2015-08-27

Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.

Predictive validity of behavioural animal models for chronic pain

PubMed Central

Berge, Odd-Geir

2011-01-01

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371010

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

PubMed

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.

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

PubMed Central

Ratajczak, Jessica; Gervois, Pascal; 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. PMID:29535784

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

PubMed

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.

How preclinical models evolved to resemble the diagnostic criteria of drug addiction

PubMed Central

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

2015-01-01

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. Despite extensive research, the pathophysiology and aetiology of addiction is only partially understood, due to the gap between current preclinical models of addiction and the clinical criteria of the disorder. Here we give a brief overview, based on selected methodologies, of how behavioral models have evolved over the last fifty years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. These new models will hopefully 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. Additional, 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. PMID:25747744

Challenges for Preclinical Investigations of Human Biofield Modalities

PubMed Central

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

Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse.

PubMed

Carnicella, Sebastien; Ron, Dorit; Barak, Segev

2014-05-01

One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5-6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Methodological Rigor in Preclinical Cardiovascular Studies: Targets to Enhance Reproducibility and Promote Research Translation.

PubMed

Ramirez, F Daniel; Motazedian, Pouya; Jung, Richard G; Di Santo, Pietro; MacDonald, Zachary D; Moreland, Robert; Simard, Trevor; Clancy, Aisling A; Russo, Juan J; Welch, Vivian A; Wells, George A; Hibbert, Benjamin

2017-06-09

Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and

The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation.

PubMed

Marshall, John C

2005-12-01

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. | Office of Cancer Genomics

Cancer.gov

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).

Insights from Preclinical Choice Models on Treating Drug Addiction

PubMed Central

Banks, Matthew L.; Negus, S. Stevens

2016-01-01

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food ‘choice’ procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. PMID:27916279

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

PubMed

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 < 0.001), psychological health (r = 0.29, p < 0.001), social relations (r = 0.11, p = 0.03) and environment (r = 0.23, p < 0.001). Male 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.

Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

Cancer.gov

The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

Arterial Calcification in Diabetes Mellitus: Preclinical Models and Translational Implications.

PubMed

Stabley, John N; Towler, Dwight A

2017-02-01

Diabetes mellitus increasingly afflicts our aging and dysmetabolic population. Type 2 diabetes mellitus and the antecedent metabolic syndrome represent the vast majority of the disease burden-increasingly prevalent in children and older adults. However, type 1 diabetes mellitus is also advancing in preadolescent children. As such, a crushing wave of cardiometabolic disease burden now faces our society. Arteriosclerotic calcification is increased in metabolic syndrome, type 2 diabetes mellitus, and type 1 diabetes mellitus-impairing conduit vessel compliance and function, thereby increasing the risk for dementia, stroke, heart attack, limb ischemia, renal insufficiency, and lower extremity amputation. Preclinical models of these dysmetabolic settings have provided insights into the pathobiology of arterial calcification. Osteochondrogenic morphogens in the BMP-Wnt signaling relay and transcriptional regulatory programs driven by Msx and Runx gene families are entrained to innate immune responses-responses activated by the dysmetabolic state-to direct arterial matrix deposition and mineralization. Recent studies implicate the endothelial-mesenchymal transition in contributing to the phenotypic drift of mineralizing vascular progenitors. In this brief overview, we discuss preclinical disease models that provide mechanistic insights-and point to challenges and opportunities to translate these insights into new therapeutic strategies for our patients afflicted with diabetes mellitus and its arteriosclerotic complications. © 2016 American Heart Association, Inc.

Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

PubMed Central

Cole, Banumathi K.; Issa, Danny; Feaver, Ryan E.

2018-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, affecting about 1/3 of the US general population and remaining as a significant cause of morbidity and mortality. The hallmark of the disease is the excessive accumulation of fat within the liver cells (hepatocytes), which eventually paves the way to cellular stress, injury and apoptosis. NAFLD is strongly associated with components of the metabolic syndrome and is fast emerging as a leading cause of liver transplant in the USA. Based on clinico-pathologic classification, NAFLD may present as isolated lipid collection (steatosis) within the hepatocytes (referred to as non-alcoholic fatty liver; NAFL); or as the more aggressive phenotype (known as non-alcoholic steatohepatitis; NASH). There are currently no regulatory agency-approved medication for NAFLD, despite the enormous work and resources that have gone into the study of this condition. Therefore, there remains a huge unmet need in developing and utilizing pre-clinical models that will recapitulate the disease condition in humans. In line with progress being made in developing appropriate disease models, this review highlights the cutting-edge preclinical in vitro and animal models that try to recapitulate the human disease pathophysiology and/or clinical manifestations. PMID:29299759

Insights from Preclinical Choice Models on Treating Drug Addiction.

PubMed

Banks, Matthew L; Negus, S Stevens

2017-02-01

Substance-use disorders are a global public health problem that arises from behavioral misallocation between drug use and more adaptive behaviors maintained by nondrug alternatives (e.g., food or money). Preclinical drug self-administration procedures that incorporate a concurrently available nondrug reinforcer (e.g., food) provide translationally relevant and distinct dependent measures of behavioral allocation (i.e., to assess the relative reinforcing efficacy of the drug) and behavioral rate (i.e., to assess motor competence). In particular, preclinical drug versus food 'choice' procedures have produced increasingly concordant results with both human laboratory drug self-administration studies and double-blind placebo-controlled clinical trials. Accordingly, here we provide a heuristic framework of substance-use disorders based on a behavioral-centric perspective and recent insights from these preclinical choice procedures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

PubMed

Arias, Jalayne J; Cummings, Jeffrey; Grant, Alexander Rae; Ford, Paul J

2015-01-01

Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Assessment of Spectral Doppler in Preclinical Ultrasound Using a Small-Size Rotating Phantom

PubMed Central

Yang, Xin; Sun, Chao; Anderson, Tom; Moran, Carmel M.; Hadoke, Patrick W.F.; Gray, Gillian A.; Hoskins, Peter R.

2013-01-01

Preclinical ultrasound scanners are used to measure blood flow in small animals, but the potential errors in blood velocity measurements have not been quantified. This investigation rectifies this omission through the design and use of phantoms and evaluation of measurement errors for a preclinical ultrasound system (Vevo 770, Visualsonics, Toronto, ON, Canada). A ray model of geometric spectral broadening was used to predict velocity errors. A small-scale rotating phantom, made from tissue-mimicking material, was developed. True and Doppler-measured maximum velocities of the moving targets were compared over a range of angles from 10° to 80°. Results indicate that the maximum velocity was overestimated by up to 158% by spectral Doppler. There was good agreement (<10%) between theoretical velocity errors and measured errors for beam-target angles of 50°–80°. However, for angles of 10°–40°, the agreement was not as good (>50%). The phantom is capable of validating the performance of blood velocity measurement in preclinical ultrasound. PMID:23711503

Validation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization.

PubMed

Braren, Rickmer; Altomonte, Jennifer; Settles, Marcus; Neff, Frauke; Esposito, Irene; Ebert, Oliver; Schwaiger, Markus; Rummeny, Ernst; Steingoetter, Andreas

2011-11-01

The hepatocellular carcinoma (HCC) exhibits varying degrees of vascularization with more poorly differentiated carcinoma commonly exhibiting high amounts of vascularization. Transcatheter arterial embolization (TAE) of HCC tumor nodules results in varying amounts of tumor necrosis. Reliable quantification of necrosis after TAE, would aid in treatment planning and testing of novel combinatorial treatment regimen. The aim of this work was to validate different imaging parameters as individual or combined predictors of tumor necrosis after TAE in an orthotopic rat HCC tumor model. Unifocal rat HCC was imaged by T(2)-weighted MRI, quantitative dynamic contrast enhanced (DCE) MRI, diffusion weighted MRI (DWI) and [(18)F]-FDG PET imaging before (day-1) and after (days 1 and 3) TAE. Univariate and multivariate regression analyses were carried out to analyze the ability of each imaging parameter to predict the percent residual vital tumor (vtu) and vital tissue (vti) as determined by quantitative histopathology. TAE induced a wide range of tumor necrosis. Tumor volume was the only parameter showing a correlation with vti (r(2) = 0.63) before TAE. After TAE, moderate correlations were found for FDG tracer uptake (r(2) = 0.56) and plasma tissue transfer constant (r(2) = 0.55). Correlations were higher for the extravascular extracellular volume fraction (v(e), r(2) = 0.68) and highest for the apparent diffusion coefficient (ADC, r(2) = 0.86). Multivariate analyses confirmed highest correlation of ADC and v(e) with vtu and vti. DWI and DCE-MRI with the respective parameters ADC (day 3) and v(e) (day 1) were identified as the most promising imaging techniques for the prediction of necrosis. This study validates a preclinical platform allowing for the improved tumor stratification after TAE and thus the testing of novel combinatorial therapy approaches in HCC. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

PubMed

Doncel, Gustavo F; Clark, Meredith R

2010-12-01

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

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

PubMed

Ogunlade, Olumide; Connell, John J; Huang, Jennifer L; Zhang, Edward; Lythgoe, Mark F; Long, David A; Beard, Paul

2018-06-01

Noninvasive imaging of the kidney vasculature in preclinical murine models is important for the assessment of renal development, studying 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 visualizing the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optical Fabry-Perot-based photoacoustic scanner was used to image the abdominal region of mice. High-resolution three-dimensional, noninvasive, label-free photoacoustic images of the mouse kidney and renal vasculature were acquired in vivo. The scanner was also used to visualize and quantify differences in the vascular architecture of the kidney in vivo due to polycystic kidney disease. This study suggests that photoacoustic imaging could be utilized as a novel preclinical imaging tool for studying the biology of renal disease.

Common pitfalls in preclinical cancer target validation.

PubMed

Kaelin, William G

2017-07-01

An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

From Bench to Bedside: Utility of the Rabbit Elastase Aneurysm Model in Pre-Clinical Studies of Intracranial Aneurysm Treatment

PubMed Central

Brinjikji, Waleed; Ding, Yong H; Kallmes, David F; Kadirvel, Ramanathan

2016-01-01

Summary Pre-clinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus, an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss 1) various techniques used to create the aneurysm, 2) complications of aneurysm creation, 3) natural history of the arterial aneurysm, 4) histopathologic and hemodynamic features of the aneurysm 5) devices tested using this model and 6) weaknesses of the model. We demonstrate how pre-clinical studies using this model are applied in treatment of intracranial aneurysms in humans. The model has a similar hemodynamic, morphological and histologic characteristics to human aneurysms and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths however, the model does have many weaknesses including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore the model’s extracranial location affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms however further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms. PMID:25904642

Sex-related responses after traumatic brain injury: Considerations for preclinical modeling.

PubMed

Späni, Claudia B; Braun, David J; Van Eldik, Linda J

2018-05-18

Traumatic brain injury (TBI) has historically been viewed as a primarily male problem, since men are more likely to experience a TBI because of more frequent participation in activities that increase risk of head injuries. This male bias is also reflected in preclinical research where mostly male animals have been used in basic and translational science. However, with an aging population in which TBI incidence is increasingly sex-independent due to falls, and increasing female participation in high-risk activities, the attention to potential sex differences in TBI responses and outcomes will become more important. These considerations are especially relevant in designing preclinical animal models of TBI that are more predictive of human responses and outcomes. This review characterizes sex differences following TBI with a special emphasis on the contribution of the female sex hormones, progesterone and estrogen, to these differences. This information is potentially important in developing and customizing TBI treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

Silencing of Tuberin Enhances Photoreceptor Survival and Function in a Preclinical Model of Retinitis Pigmentosa (An American Ophthalmological Society Thesis)

PubMed Central

Tsang, Stephen H.; Chan, Lawrence; Tsai, Yi-Ting; Wu, Wen-Hsuan; Hsu, Chun-Wei; Yang, Jin; Tosi, Joaquin; Wert, Katherine J.; Davis, Richard J.; Mahajan, Vinit B.

2014-01-01

Purpose: To assess the functional consequences of silencing of tuberin, an inhibitor of the mTOR signaling pathway, in a preclinical model of retinitis pigmentosa (RP) in order to test the hypothesis that insufficient induction of the protein kinase B (PKB)-regulated tuberin/mTOR self-survival pathway initiates apoptosis. Methods: In an unbiased genome-scale approach, kinase peptide substrate arrays were used to analyze self-survival pathways at the onset of photoreceptor degeneration. The mutant Pde6bH620Q/Pde6bH620Q at P14 and P18 photoreceptor outer segment (OS) lysates were labeled with P-ATP and hybridized to an array of 1,164 different synthetic peptide substrates. At this stage, OS of Pde6bH620Q/Pde6bH620Q rods are morphologically normal. In vitro kinase assays and immunohistochemistry were used to validate phosphorylation. Short hairpin RNA (shRNA) gene silencing was used to validate tuberin’s role in regulating survival. Results: At the onset of degeneration, 162 peptides were differentially phosphorylated. Protein kinases A, G, C (AGC kinases), and B exhibited increased activity in both peptide array and in vitro kinase assays. Immunohistochemical data confirmed altered phosphorylation patterns for phosphoinositide-dependent kinase-1 (PDK1), ribosomal protein S6 (RPS6), and tuberin. Tuberin gene silencing rescued photoreceptors from degeneration. Conclusions: Phosphorylation of tuberin and RPS6 is due to the upregulated activity of PKB. PKB/tuberin cell growth/survival signaling is activated before the onset of degeneration. Substrates of the AGC kinases in the PKB/tuberin pathway are phosphorylated to promote cell survival. Knockdown of tuberin, the inhibitor of the mTOR pathway, increased photoreceptor survival and function in a preclinical model of RP. PMID:25646031

A Validated Open-Source Multisolver Fourth-Generation Composite Femur Model.

PubMed

MacLeod, Alisdair R; Rose, Hannah; Gill, Harinderjit S

2016-12-01

Synthetic biomechanical test specimens are frequently used for preclinical evaluation of implant performance, often in combination with numerical modeling, such as finite-element (FE) analysis. Commercial and freely available FE packages are widely used with three FE packages in particular gaining popularity: abaqus (Dassault Systèmes, Johnston, RI), ansys (ANSYS, Inc., Canonsburg, PA), and febio (University of Utah, Salt Lake City, UT). To the best of our knowledge, no study has yet made a comparison of these three commonly used solvers. Additionally, despite the femur being the most extensively studied bone in the body, no freely available validated model exists. The primary aim of the study was primarily to conduct a comparison of mesh convergence and strain prediction between the three solvers (abaqus, ansys, and febio) and to provide validated open-source models of a fourth-generation composite femur for use with all the three FE packages. Second, we evaluated the geometric variability around the femoral neck region of the composite femurs. Experimental testing was conducted using fourth-generation Sawbones® composite femurs instrumented with strain gauges at four locations. A generic FE model and four specimen-specific FE models were created from CT scans. The study found that the three solvers produced excellent agreement, with strain predictions being within an average of 3.0% for all the solvers (r2 > 0.99) and 1.4% for the two commercial codes. The average of the root mean squared error against the experimental results was 134.5% (r2 = 0.29) for the generic model and 13.8% (r2 = 0.96) for the specimen-specific models. It was found that composite femurs had variations in cortical thickness around the neck of the femur of up to 48.4%. For the first time, an experimentally validated, finite-element model of the femur is presented for use in three solvers. This model is freely available online along with all the supporting validation data.

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson's disease.

PubMed

Paris, Irmgard; Cardenas, Sergio; Lozano, Jorge; Perez-Pastene, Carolina; Graumann, Rebecca; Riveros, Alejandra; Caviedes, Pablo; Segura-Aguilar, Juan

2007-09-01

Four decades after L-dopa introduction to PD therapy, the cause of Parkinson's disease (PD) remains unknown despite the intensive research and the discovery of a number of gene mutations and deletions in the pathogenesis of familial PD. Different model neurotoxins have been used as preclinical experimental models to study the neurodegenerative process in PD, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone. The lack of success in identifying the molecular mechanism for the degenerative process in PD opens the question whether the current preclinical experimental models are suitable to understand the degeneration of neuromelanin-containing dopaminergic neurons in PD. We propose aminochrome as a model neurotoxin to study the neurodegenerative processes occurring in neuromelanin-containing dopaminergic neurons in PD. Aminochrome is an endogenous compound formed during dopamine oxidation and it is the precursor of neuromelanin, a substance whose formation is a normal process in mesencephalic dopaminergic neurons. However, aminochrome itself can induce neurotoxicity under certain aberrant conditions such as (i) one-electron reduction of aminochrome catalyzed by flavoenzymes to leukoaminochrome o-semiquinone radical, which is a highly reactive neurotoxin; or (ii) the formation of aminochrome adducts with alpha-synuclein, enhancing and stabilizing the formation of neurotoxic protofibrils. These two neurotoxic pathways of aminochrome are prevented by DT-diaphorase, an enzyme that effectively reduces aminochrome with two-electrons preventing both aminochrome one-electron reduction or formation alpha synuclein protofibrils. We propose to use aminochrome as a preclinical experimental model to study the neurodegenerative process of neuromelanin containing dopaminergic neurons in PD.

Assessing Risk/Benefit for Trials Using Preclinical Evidence: A Proposal

PubMed Central

Kimmelman, Jonathan; Henderson, Valerie C.

2015-01-01

Abstract Moral evaluation of risk/benefit in early phase studies requires assessing the clinical promise of a candidate intervention using preclinical evidence. Yet there is little to guide ethics committees, investigators, sponsors or other stakeholders morally charged with making these assessments (“evaluators”). In what follows, we draw on published guidelines for preclinical study design to develop a structured process for assessing the clinical promise of new interventions. In the first step, evaluators gather all relevant preclinical studies, assess the magnitude of treatment effects, and determine clinical promise in light of various threats to valid clinical inference. In the second step, evaluators adjust assessments of clinical promise from preclinical studies by examining how other agents in the same reference class-and supported by similar evidence- have fared in clinical development. Assessments of clinical promise can then be fed into moral evaluation of risk and benefit in early phase trials. Though our approach has limitations, it offers a systematic and transparent method for assessing risk/benefit in early phase trials of novel interventions. PMID:26463620

NEMA NU 4-2008 validation and applications of the PET-SORTEO Monte Carlo simulations platform for the geometry of the Inveon PET preclinical scanner

NASA Astrophysics Data System (ADS)

Boisson, F.; Wimberley, C. J.; Lehnert, W.; Zahra, D.; Pham, T.; Perkins, G.; Hamze, H.; Gregoire, M.-C.; Reilhac, A.

2013-10-01

Monte Carlo-based simulation of positron emission tomography (PET) data plays a key role in the design and optimization of data correction and processing methods. Our first aim was to adapt and configure the PET-SORTEO Monte Carlo simulation program for the geometry of the widely distributed Inveon PET preclinical scanner manufactured by Siemens Preclinical Solutions. The validation was carried out against actual measurements performed on the Inveon PET scanner at the Australian Nuclear Science and Technology Organisation in Australia and at the Brain & Mind Research Institute and by strictly following the NEMA NU 4-2008 standard. The comparison of simulated and experimental performance measurements included spatial resolution, sensitivity, scatter fraction and count rates, image quality and Derenzo phantom studies. Results showed that PET-SORTEO reliably reproduces the performances of this Inveon preclinical system. In addition, imaging studies showed that the PET-SORTEO simulation program provides raw data for the Inveon scanner that can be fully corrected and reconstructed using the same programs as for the actual data. All correction techniques (attenuation, scatter, randoms, dead-time, and normalization) can be applied on the simulated data leading to fully quantitative reconstructed images. In the second part of the study, we demonstrated its ability to generate fast and realistic biological studies. PET-SORTEO is a workable and reliable tool that can be used, in a classical way, to validate and/or optimize a single PET data processing step such as a reconstruction method. However, we demonstrated that by combining a realistic simulated biological study ([11C]Raclopride here) involving different condition groups, simulation allows one also to assess and optimize the data correction, reconstruction and data processing line flow as a whole, specifically for each biological study, which is our ultimate intent.

Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

PubMed Central

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. PMID:24128326

Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation

NASA Astrophysics Data System (ADS)

Bass, Christopher Paul

registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

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

PubMed Central

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

2018-01-01

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

Naturally Occurring Disk Herniation in Dogs: An Opportunity for Pre-Clinical Spinal Cord Injury Research

PubMed Central

Levine, Gwendolyn J.; Porter, Brian F.; Topp, Kimberly; Noble-Haeusslein, Linda J.

2011-01-01

Abstract Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation. PMID:21438715

Preclinical fluorescent mouse models of pancreatic cancer

NASA Astrophysics Data System (ADS)

Bouvet, Michael; Hoffman, Robert M.

2007-02-01

Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

PubMed

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.

Development and validation of an LC-MS method for determination of Karanjin in rat plasma: application to preclinical pharmacokinetics.

PubMed

Yi, Deliang; Wang, Zhihua; Yi, Longzhi

2015-04-01

A selective and sensitive liquid chromatography-mass spectrometry (MS) method was developed and validated for the determination of karanjin in rat plasma. The target analyte, together with the internal standard (warfarin), was extracted from rat plasma by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a ZORBAX SB-C18 column using a mixture of acetonitrile and 0.1% aqueous formic acid as the mobile phase with linear gradient elution. MS detection was performed on a single quadrupole MS by selected ion monitoring mode via a positive electrospray ionization source. The assay exhibited a linear dynamic range of 2.50-3,000 ng/mL for karanjin. The intra- and inter-day precision was <10.8%, and the intra- and inter-day accuracy was <9.2%. The validated method has been applied to the preclinical pharmacokinetic studies of karanjin following oral administration of 5, 10 and 20 mg/kg karanjin to rats. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Minnelide reduces tumor burden in preclinical models of osteosarcoma.

PubMed

Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

2013-07-28

Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Novel System for Real-Time Integration of 3-D Echocardiography and Fluoroscopy for Image-Guided Cardiac Interventions: Preclinical Validation and Clinical Feasibility Evaluation.

PubMed

Arujuna, Aruna V; Housden, R James; Ma, Yingliang; Rajani, Ronak; Gao, Gang; Nijhof, Niels; Cathier, Pascal; Bullens, Roland; Gijsbers, Geert; Parish, Victoria; Kapetanakis, Stamatis; Hancock, Jane; Rinaldi, C Aldo; Cooklin, Michael; Gill, Jaswinder; Thomas, Martyn; O'neill, Mark D; Razavi, Reza; Rhode, Kawal S

2014-01-01

Real-time imaging is required to guide minimally invasive catheter-based cardiac interventions. While transesophageal echocardiography allows for high-quality visualization of cardiac anatomy, X-ray fluoroscopy provides excellent visualization of devices. We have developed a novel image fusion system that allows real-time integration of 3-D echocardiography and the X-ray fluoroscopy. The system was validated in the following two stages: 1) preclinical to determine function and validate accuracy; and 2) in the clinical setting to assess clinical workflow feasibility and determine overall system accuracy. In the preclinical phase, the system was assessed using both phantom and porcine experimental studies. Median 2-D projection errors of 4.5 and 3.3 mm were found for the phantom and porcine studies, respectively. The clinical phase focused on extending the use of the system to interventions in patients undergoing either atrial fibrillation catheter ablation (CA) or transcatheter aortic valve implantation (TAVI). Eleven patients were studied with nine in the CA group and two in the TAVI group. Successful real-time view synchronization was achieved in all cases with a calculated median distance error of 2.2 mm in the CA group and 3.4 mm in the TAVI group. A standard clinical workflow was established using the image fusion system. These pilot data confirm the technical feasibility of accurate real-time echo-fluoroscopic image overlay in clinical practice, which may be a useful adjunct for real-time guidance during interventional cardiac procedures.

Application of advanced preclinical models and methods in anesthetic neurotoxicity research.

PubMed

Wang, Cheng; Zhang, Xuan; Liu, Fang

2017-05-01

Recently, there has been increasing concern regarding the potential of anesthetics to disturb the long-term function of the central nervous system (CNS). The field of anesthesia-related toxicology, therefore, has engaged multiple scientific disciplines and utilized a variety of pre-clinical research models in an attempt to identify the basic characteristics of the anesthetic agents that may produce acute and/or chronic adverse effects on the CNS. This review discusses how the application of advanced research approaches and models, such as the nonhuman primate, neural stem cell-derived organotypic slice cultures and/or organs-on-chips systems, can serve as translational models of infantile anesthetic exposure. Utilization of these models may expeditiously decrease the uncertainty in the risk posed to children by postnatal anesthetic exposure. Copyright © 2017. Published by Elsevier Inc.

Four dimensional optoacoustic imaging of perfusion in preclinical breast tumor model in vivo (Conference Presentation)

NASA Astrophysics Data System (ADS)

Deán-Ben, Xosé Luís.; Ermolayev, Vladimir; Mandal, Subhamoy; Ntziachristos, Vasilis; Razansky, Daniel

2016-03-01

Imaging plays an increasingly important role in clinical management and preclinical studies of cancer. Application of optical molecular imaging technologies, in combination with highly specific contrast agent approaches, eminently contributed to understanding of functional and histological properties of tumors and anticancer therapies. Yet, optical imaging exhibits deterioration in spatial resolution and other performance metrics due to light scattering in deep living tissues. High resolution molecular imaging at the whole-organ or whole-body scale may therefore bring additional understanding of vascular networks, blood perfusion and microenvironment gradients of malignancies. In this work, we constructed a volumetric multispectral optoacoustic tomography (vMSOT) scanner for cancer imaging in preclinical models and explored its capacity for real-time 3D intravital imaging of whole breast cancer allografts in mice. Intrinsic tissue properties, such as blood oxygenation gradients, along with the distribution of externally administered liposomes carrying clinically-approved indocyanine green dye (lipo-ICG) were visualized in order to study vascularization, probe penetration and extravasation kinetics in different regions of interest within solid tumors. The use of v-MSOT along with the application of volumetric image analysis and perfusion tracking tools for studies of pathophysiological processes within microenvironment gradients of solid tumors demonstrated superior volumetric imaging system performance with sustained competitive resolution and imaging depth suitable for investigations in preclinical cancer models.

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

PubMed Central

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

Groundwater Model Validation

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

Ahmed E. Hassan

2006-01-24

Models have an inherent uncertainty. The difficulty in fully characterizing the subsurface environment makes uncertainty an integral component of groundwater flow and transport models, which dictates the need for continuous monitoring and improvement. Building and sustaining confidence in closure decisions and monitoring networks based on models of subsurface conditions require developing confidence in the models through an iterative process. The definition of model validation is postulated as a confidence building and long-term iterative process (Hassan, 2004a). Model validation should be viewed as a process not an end result. Following Hassan (2004b), an approach is proposed for the validation process ofmore » stochastic groundwater models. The approach is briefly summarized herein and detailed analyses of acceptance criteria for stochastic realizations and of using validation data to reduce input parameter uncertainty are presented and applied to two case studies. During the validation process for stochastic models, a question arises as to the sufficiency of the number of acceptable model realizations (in terms of conformity with validation data). Using a hierarchical approach to make this determination is proposed. This approach is based on computing five measures or metrics and following a decision tree to determine if a sufficient number of realizations attain satisfactory scores regarding how they represent the field data used for calibration (old) and used for validation (new). The first two of these measures are applied to hypothetical scenarios using the first case study and assuming field data consistent with the model or significantly different from the model results. In both cases it is shown how the two measures would lead to the appropriate decision about the model performance. Standard statistical tests are used to evaluate these measures with the results indicating they are appropriate measures for evaluating model realizations. The use of

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

PubMed

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.

Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts

PubMed Central

George, Steven Z.; Wallace, Margaret R.; Wu, Samuel S.; Moser, Michael W.; Wright, Thomas W.; Farmer, Kevin W.; Borsa, Paul A.; Parr, Jeffrey J.; Greenfield, Warren H.; Dai, Yunfeng; Li, Hua; Fillingim, Roger B.

2016-01-01

Tailored treatment based on individual risk factors is an area with promise to improve options for pain relief. Musculoskeletal pain has a biopsychosocial nature, and multiple factors should be considered when determining risk for chronic pain. This study investigated whether subgroups comprised genetic and psychological factors predicted outcomes in preclinical and clinical models of shoulder pain. Classification and regression tree analysis was performed for an exercise-induced shoulder injury cohort (n = 190) to identify high-risk subgroups, and a surgical pain cohort (n = 150) was used for risk validation. Questionnaires for fear of pain and pain catastrophizing were administered before injury and preoperatively. DNA collected from saliva was genotyped for a priori selected genes involved with pain modulation (COMT and AVPR1A) and inflammation (IL1B and TNF/LTA). Recovery was operationalized as a brief pain inventory rating of 0/10 for current pain intensity and <2/10 for worst pain intensity. Follow-up for the preclinical cohort was in daily increments, whereas follow-up for the clinical cohort was at 3, 6, and 12 months postoperatively. Risk subgroups comprised the COMT high pain sensitivity variant and either pain catastrophizing or fear of pain were predictive of heightened shoulder pain responses in the preclinical model. Further analysis in the clinical model identified the COMT high pain sensitivity variant and pain catastrophizing subgroup as the better predictor. Future studies will determine whether these findings can be replicated in other anatomical regions and whether personalized medicine strategies can be developed for this risk subgroup. PMID:25599310

Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

PubMed Central

Lalu, Manoj M; Sullivan, Katrina J; Mei, Shirley HJ; Moher, David; Straus, Alexander; Fergusson, Dean A; Stewart, Duncan J; Jazi, Mazen; MacLeod, Malcolm; Winston, Brent; Marshall, John; Hutton, Brian; Walley, Keith R; McIntyre, Lauralyn

2016-01-01

Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18–0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies. DOI: http://dx.doi.org/10.7554/eLife.17850.001 PMID:27870924

A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam.

PubMed

Cifani, Carlo; Polidori, Carlo; Melotto, Sergio; Ciccocioppo, Roberto; Massi, Maurizio

2009-05-01

Preclinical models are needed to investigate the neurobiology and psychobiology of binge eating and to identify innovative pharmacotherapeutic strategies. A modification of the model based on the combination of cyclic caloric restrictions and acute stress was developed to further increase its face validity and reliability and, for the first time, to assess its predictive value. Four groups of female rats were employed: group 1 was normally fed and not stressed on the test day (25th); group 2 was fed normally but was exposed to an acute stress on day 25; group 3 was exposed to three cycles (4 days 66% of chow intake + 4 days food ad libitum) of yo-yo dieting but not stressed; and group 4 was exposed to cyclic yo-yo dieting and then stressed. All groups were fed highly palatable food (HPF) for 2 h on days 5-6 and 13-14. Acute stress was elicited by exposing rats to HPF, but preventing them from access to it for 15 min. The combination of cyclic food restriction and stressful exposure to food markedly increased HPF intake. Sibutramine and fluoxetine inhibited food intake in all conditions. Topiramate selectively inhibited compulsive HPF intake in rats submitted to caloric restriction and stress. Midazolam increased HPF intake. Pharmacological results suggest that this model, in addition to face validity as an isomorphic model of human binge eating, is endowed with good predictive validity.

Guidelines for standard preclinical experiments in the mouse model of myasthenia gravis induced by acetylcholine receptor immunization.

PubMed

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.

Pica in Rats as a Preclinical Model of Emesis.

PubMed

Davis, T Gregg

2016-10-03

The ability to assess the potential for gastrointestinal adverse events in a preclinical setting is a challenge in the development of new drugs, as the vast majority of in vivo research is conducted in rodent species lacking a vomiting reflex. The use of higher species capable of emesis is often limited by cost, technical experience, and relevant efficacy models to define a therapeutic index. Additionally, investigators should be mindful of ethical considerations when using more sentient species when an alternative in lower species is available. This unit describes the use of pica behavior in rodents as an alternative for evaluating emetic potential in vivo. After an acclimation period, the incidence of rats engaging in pica following the administration of a test article can be used to generate a dose-response curve of the pica behavior. When linked with an appropriate efficacy model, this allows compounds to be ranked based on therapeutic index. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension.

PubMed

Budas, Grant R; Boehm, Mario; Kojonazarov, Baktybek; Viswanathan, Gayathri; Tian, Xia; Veeroju, Swathi; Novoyatleva, Tatyana; Grimminger, Friedrich; Hinojosa-Kirschenbaum, Ford; Ghofrani, Hossein A; Weissmann, Norbert; Seeger, Werner; Liles, John T; Schermuly, Ralph T

2018-02-01

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.

Model Validation Status Review

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

E.L. Hardin

The primary objective for the Model Validation Status Review was to perform a one-time evaluation of model validation associated with the analysis/model reports (AMRs) containing model input to total-system performance assessment (TSPA) for the Yucca Mountain site recommendation (SR). This review was performed in response to Corrective Action Request BSC-01-C-01 (Clark 2001, Krisha 2001) pursuant to Quality Assurance review findings of an adverse trend in model validation deficiency. The review findings in this report provide the following information which defines the extent of model validation deficiency and the corrective action needed: (1) AMRs that contain or support models are identified,more » and conversely, for each model the supporting documentation is identified. (2) The use for each model is determined based on whether the output is used directly for TSPA-SR, or for screening (exclusion) of features, events, and processes (FEPs), and the nature of the model output. (3) Two approaches are used to evaluate the extent to which the validation for each model is compliant with AP-3.10Q (Analyses and Models). The approaches differ in regard to whether model validation is achieved within individual AMRs as originally intended, or whether model validation could be readily achieved by incorporating information from other sources. (4) Recommendations are presented for changes to the AMRs, and additional model development activities or data collection, that will remedy model validation review findings, in support of licensing activities. The Model Validation Status Review emphasized those AMRs that support TSPA-SR (CRWMS M&O 2000bl and 2000bm). A series of workshops and teleconferences was held to discuss and integrate the review findings. The review encompassed 125 AMRs (Table 1) plus certain other supporting documents and data needed to assess model validity. The AMRs were grouped in 21 model areas representing the modeling of processes affecting the natural

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

PubMed

Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

2011-03-01

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A

Preclinical experimental stress studies: protocols, assessment and comparison.

PubMed

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.

Gene expression profile of mouse prostate tumors reveals dysregulations in major biological processes and identifies potential murine targets for preclinical development of human prostate cancer therapy.

PubMed

Haram, Kerstyn M; Peltier, Heidi J; Lu, Bin; Bhasin, Manoj; Otu, Hasan H; Choy, Bob; Regan, Meredith; Libermann, Towia A; Latham, Gary J; Sanda, Martin G; Arredouani, Mohamed S

2008-10-01

Translation of preclinical studies into effective human cancer therapy is hampered by the lack of defined molecular expression patterns in mouse models that correspond to the human counterpart. We sought to generate an open source TRAMP mouse microarray dataset and to use this array to identify differentially expressed genes from human prostate cancer (PCa) that have concordant expression in TRAMP tumors, and thereby represent lead targets for preclinical therapy development. We performed microarrays on total RNA extracted and amplified from eight TRAMP tumors and nine normal prostates. A subset of differentially expressed genes was validated by QRT-PCR. Differentially expressed TRAMP genes were analyzed for concordant expression in publicly available human prostate array datasets and a subset of resulting genes was analyzed by QRT-PCR. Cross-referencing differentially expressed TRAMP genes to public human prostate array datasets revealed 66 genes with concordant expression in mouse and human PCa; 56 between metastases and normal and 10 between primary tumor and normal tissues. Of these 10 genes, two, Sox4 and Tubb2a, were validated by QRT-PCR. Our analysis also revealed various dysregulations in major biologic pathways in the TRAMP prostates. We report a TRAMP microarray dataset of which a gene subset was validated by QRT-PCR with expression patterns consistent with previous gene-specific TRAMP studies. Concordance analysis between TRAMP and human PCa associated genes supports the utility of the model and suggests several novel molecular targets for preclinical therapy.

Vascular physiology and protein disposition in a preclinical model of neurodegeneration.

PubMed

Boswell, C Andrew; Mundo, Eduardo E; Johnstone, Bernadette; Ulufatu, Sheila; Schweiger, Michelle G; Bumbaca, Daniela; Fielder, Paul J; Prabhu, Saileta; Khawli, Leslie A

2013-05-06

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently

Prediction of practical performance in preclinical laboratory courses - the return of wire bending for admission of dental students in Hamburg.

PubMed

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

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.

Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

PubMed Central

Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

2008-01-01

This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

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

PubMed

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.

Strengths and Weaknesses of Pre-Clinical Models for Human Melanoma Treatment: Dawn of Dogs’ Revolution for Immunotherapy

PubMed Central

Barutello, Giuseppina; Rolih, Valeria; Arigoni, Maddalena; Tarone, Lidia; Conti, Laura

2018-01-01

Despite several therapeutic advances, malignant melanoma still remains a fatal disease for which novel and long-term curative treatments are needed. The successful development of innovative therapies strongly depends on the availability of appropriate pre-clinical models. For this purpose, several mouse models holding the promise to provide insight into molecular biology and clinical behavior of melanoma have been generated. The most relevant ones and their contribution for the advancement of therapeutic approaches for the treatment of human melanoma patients will be here summarized. However, as models, mice do not recapitulate all the features of human melanoma, thus their strengths and weaknesses need to be carefully identified and considered for the translation of the results into the human clinics. In this panorama, the concept of comparative oncology acquires a priceless value. The revolutionary importance of spontaneous canine melanoma as a translational model for the pre-clinical investigation of melanoma progression and treatment will be here discussed, with a special consideration to the development of innovative immunotherapeutic approaches. PMID:29534457

Preclinical restorative training.

PubMed

Ferguson, Michael B; Sobel, Morton; Niederman, Richard

2002-10-01

In conjunction with its problem-based learning curriculum, Harvard School of Dental Medicine (HSDM) developed a shortened preclinical restorative training curriculum. This study compared our curriculum with those in other dental schools and examined student reaction to it. Twenty-nine U.S. dental schools responded to a survey regarding the length of their preclinical course in Operative Dentistry. Nationally, preclinical courses ranged from 179 hours to 280 hours (mean +/- SEM = 193 +/- 9 hours; n = 29). In marked contrast, the new seventy-five-hour preclinical curriculum at Harvard was the lowest of any school, and significantly lower than the U.S. average (p < 0.01). In Harvard's previous curriculum, students spent 232 curriculum hours. Reactions of Harvard students to this compact preclinical curriculum were surveyed using a three-topic, three-category survey instrument. Results indicated that, prior to beginning clinical patient care, approximately 80 percent of students felt that the course was too short and 20 percent just right. Conversely, and retrospectively, after completing their dental school training, only 35 percent felt it was too short, and 65 percent felt it was just right. Retrospectively, in terms of clinical preparedness, 55 percent felt adequately prepared and 35 percent felt well prepared to treat their patients. No significant change was noted between Part II National Board scores following the change to the reduced curricula time. The average National Board Part II scores prior to initiating the new curriculum was 86.3, and afterwards, it was 86.2. Further, for the North East Regional Board, HSDM students in the past four years demonstrated a 98 percent overall success rate with 100 percent primary pass in the operative dentistry part of the examination. These results suggest that an abbreviated preclinical training is not only possible, but may make time available for training opportunities in other areas, such as aesthetic dental

Experimental validation of finite element modelling of a modular metal-on-polyethylene total hip replacement.

PubMed

Hua, Xijin; Wang, Ling; Al-Hajjar, Mazen; Jin, Zhongmin; Wilcox, Ruth K; Fisher, John

2014-07-01

Finite element models are becoming increasingly useful tools to conduct parametric analysis, design optimisation and pre-clinical testing for hip joint replacements. However, the verification of the finite element model is critically important. The purposes of this study were to develop a three-dimensional anatomic finite element model for a modular metal-on-polyethylene total hip replacement for predicting its contact mechanics and to conduct experimental validation for a simple finite element model which was simplified from the anatomic finite element model. An anatomic modular metal-on-polyethylene total hip replacement model (anatomic model) was first developed and then simplified with reasonable accuracy to a simple modular total hip replacement model (simplified model) for validation. The contact areas on the articulating surface of three polyethylene liners of modular metal-on-polyethylene total hip replacement bearings with different clearances were measured experimentally in the Leeds ProSim hip joint simulator under a series of loading conditions and different cup inclination angles. The contact areas predicted from the simplified model were then compared with that measured experimentally under the same conditions. The results showed that the simplification made for the anatomic model did not change the predictions of contact mechanics of the modular metal-on-polyethylene total hip replacement substantially (less than 12% for contact stresses and contact areas). Good agreements of contact areas between the finite element predictions from the simplified model and experimental measurements were obtained, with maximum difference of 14% across all conditions considered. This indicated that the simplification and assumptions made in the anatomic model were reasonable and the finite element predictions from the simplified model were valid. © IMechE 2014.

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

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. PMID:24872857

Preclinical animal anxiety research - flaws and prejudices.

PubMed

Ennaceur, Abdelkader; Chazot, Paul L

2016-04-01

The current tests of anxiety in mice and rats used in preclinical research include the elevated plus-maze (EPM) or zero-maze (EZM), the light/dark box (LDB), and the open-field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a source of their inconsistent and contradictory results. These constraints are very costly, and they are in most cases useless as they originate from flawed methodologies. In the present report, we argue that the EPM or EZM, LDB, and OF do not provide unequivocal measures of anxiety; that there is no evidence of motivation conflict involved in these tests. They can be considered at best, tests of natural preference for unlit and/or enclosed spaces. We also argued that pharmacological validation of a behavioral test is an inappropriate approach; it stems from the confusion of animal models of human behavior with animal models of pathophysiology. A behavioral test is developed to detect not to produce symptoms, and a drug is used to validate an identified physiological target. In order to overcome the major methodological flaws in animal anxiety studies, we proposed an open space anxiety test, a 3D maze, which is described here with highlights of its various advantages over to the traditional tests.

ABBV-105, a selective and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK), is efficacious in multiple preclinical models of inflammation.

PubMed

Goess, Christian; Harris, Christopher M; Murdock, Sara; McCarthy, Richard W; Sampson, Erik; Twomey, Rachel; Mathieu, Suzanne; Mario, Regina; Perham, Matthew; Goedken, Eric R; Long, Andrew J

2018-06-02

Bruton's Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker. ABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis (CIA), and reduced disease in an IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy. ABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

The impact of preclinical irreproducibility on drug development.

PubMed

Freedman, L P; Gibson, M C

2015-01-01

The development of novel therapeutics depends and builds upon the validity and reproducibility of previously published data and findings. Yet irreproducibility is pervasive in preclinical life science research and can be traced to cumulative errors or flaws in several areas, including reference materials, study design, laboratory protocols, and data collection and analysis. The expanded development and use of consensus-based standards and well-documented best practices is needed to both enhance reproducibility and drive therapeutic innovations. © 2014 ASCPT.

Rational Design of Mouse Models for Cancer Research.

PubMed

Landgraf, Marietta; McGovern, Jacqui A; Friedl, Peter; Hutmacher, Dietmar W

2018-03-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models. Nevertheless, most preclinical studies in mice suffer from insufficient predictive value when compared with cancer biology and therapy response of human patients. We propose an innovative strategy to improve the predictive power of preclinical cancer models. Combining (i) genomic, tissue engineering and regenerative medicine approaches for rational design of mouse models with (ii) rapid prototyping and computational benchmarking against human clinical data will enable fast and nonbiased validation of newly generated models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models.

PubMed

St Clair, Joshua R; Ramirez, David; Passman, Samantha; Benninger, Richard K P

2018-05-01

In type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and β-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and β-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast-enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre-symptomatic T1D and therapeutic reversal.

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

PubMed

El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

2015-01-01

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. © 2015. Published by The Company of Biologists Ltd.

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

PubMed Central

El Meskini, Rajaa; Iacovelli, Anthony J.; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L.; Baran, Maureen; Householder, Deborah B.; Van Dyke, Terry; Weaver Ohler, Zoë

2015-01-01

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. PMID:25431423

Quality Assurance in Biobanking for Pre-Clinical Research

PubMed Central

Simeon-Dubach, Daniel; Zeisberger, Steffen M.; Hoerstrup, Simon P.

2016-01-01

It is estimated that not less than USD 28 billion are spent each year in the USA alone on irreproducible pre-clinical research, which is not only a fundamental loss of investment and resources but also a strong inhibitor of efficiency for upstream processes regarding the translation towards clinical applications and therapies. The issues and cost of irreproducibility has mainly been published on pre-clinical research. In contrast to pre-clinical research, test material is often being transferred into humans in clinical research. To protect treated human subjects and guarantee a defined quality standard in the field of clinical research, the manufacturing and processing infrastructures have to strictly follow and adhere to certain (inter-)national quality standards. It is assumed and suggested by the authors that by an implementation of certain quality standards within the area of pre-clinical research, billions of USD might be saved and the translation phase of promising pre-clinical results towards clinical applications may substantially be improved. In this review, we discuss how an implementation of a quality assurance (QA) management system might positively improve sample quality and sustainability within pre-clinically focused biobank infrastructures. Biobanks are frequently positioned at the very beginning of the biomedical research value chain, and, since almost every research material has been stored in a biobank during the investigated life cycle, biobanking seems to be of substantial importance from this perspective. The role model of a QA-regulated biobank structure can be found in biobanks within the context of clinical research organizations such as in regenerative medicine clusters. PMID:27781023

Identification of new epilepsy treatments: issues in preclinical methodology.

PubMed

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.

Dissolution DNP for in vivo preclinical studies

NASA Astrophysics Data System (ADS)

Comment, Arnaud

2016-03-01

The tremendous polarization enhancement afforded by dissolution dynamic nuclear polarization (DNP) can be taken advantage of to perform preclinical in vivo molecular and metabolic imaging. Following the injection of molecules that are hyperpolarized via dissolution DNP, real-time measurements of their biodistribution and metabolic conversion can be recorded. This technology therefore provides a unique and invaluable tool for probing cellular metabolism in vivo in animal models in a noninvasive manner. It gives the opportunity to follow and evaluate disease progression and treatment response without requiring ex vivo destructive tissue assays. Although its considerable potential has now been widely recognized, hyperpolarized magnetic resonance by dissolution DNP remains a challenging method to implement for routine in vivo preclinical measurements. The aim of this article is to provide an overview of the current state-of-the-art technology for preclinical applications and the challenges that need to be addressed to promote it and allow its wider dissemination in the near future.

Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

PubMed Central

Antonello, ZA; Nucera, C

2015-01-01

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

PubMed

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.

Better Utilization of Mouse Models of Neurodegenerative Diseases in Preclinical Studies: From the Bench to the Clinic.

PubMed

Janus, Christopher; Hernandez, Carolina; deLelys, Victoria; Roder, Hanno; Welzl, Hans

2016-01-01

The major symptom of Alzheimer's disease is dementia progressing with age. Its clinical diagnosis is preceded by a long prodromal period of brain pathology that encompasses both formation of extracellular amyloid and intraneuronal tau deposits in the brain and widespread neuronal death. At present, familial cases of dementia provide the most promising foundation for modeling neurodegenerative tauopathies, a group of heterogeneous disorders characterized by prominent intracellular accumulation of hyperphosphorylated tau protein. In this chapter, we describe major behavioral hallmarks of tauopathies, briefly outline the genetics underlying familial cases, and discuss the arising implications for modeling the disease in transgenic mouse systems. The selection of tests performed to evaluate the phenotype of a model should be guided by the key behavioral hallmarks that characterize human disorder and their homology to mouse cognitive systems. We attempt to provide general guidelines and establish criteria for modeling dementia in a mouse; however, interpretations of obtained results should avoid a reductionist "one gene, one disease" explanation of model characteristics. Rather, the focus should be directed to the question of how the mouse genome can cope with the over-expression of the protein coded by transgene(s). While each model is valuable within its own constraints and the experiments performed are guided by specific hypotheses, we seek to expand upon their methodology by offering guidance spanning from issues of mouse husbandry to choices of behavioral tests and routes of drug administration that might increase the external validity of studies and consequently optimize the translational aspect of preclinical research.

Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

PubMed

Hennika, Tammy; Hu, Guo; Olaciregui, Nagore G; Barton, Kelly L; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J; Tsoli, Maria; Ziegler, David S; Carcaboso, Angel M; Becher, Oren J

2017-01-01

Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective

PubMed Central

Tan, Hor-Yue; San-Marina, Serban; Wang, Ning; Hong, Ming; Li, Sha; Li, Lei; Cheung, Fan; Wen, Xiao-Yan; Feng, Yibin

2016-01-01

Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field. PMID:26941826

Validation of the Filovirus Plaque Assay for Use in Preclinical Studies

DTIC Science & Technology

2016-09-02

filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for...and robust for filovirus titration in samples associated with the performance of GLP animal model studies. Keywords: Plaque assay; filovirus; Ebola...ebolavirus; marburgvirus; Marburg virus; Vero E6 cells; GLP compliant; validation; animal rule DISTRIBUTION STATEMENT A: Approved for public

Human genetics as a model for target validation: finding new therapies for diabetes.

PubMed

Thomsen, Soren K; Gloyn, Anna L

2017-06-01

Type 2 diabetes is a global epidemic with major effects on healthcare expenditure and quality of life. Currently available treatments are inadequate for the prevention of comorbidities, yet progress towards new therapies remains slow. A major barrier is the insufficiency of traditional preclinical models for predicting drug efficacy and safety. Human genetics offers a complementary model to assess causal mechanisms for target validation. Genetic perturbations are 'experiments of nature' that provide a uniquely relevant window into the long-term effects of modulating specific targets. Here, we show that genetic discoveries over the past decades have accurately predicted (now known) therapeutic mechanisms for type 2 diabetes. These findings highlight the potential for use of human genetic variation for prospective target validation, and establish a framework for future applications. Studies into rare, monogenic forms of diabetes have also provided proof-of-principle for precision medicine, and the applicability of this paradigm to complex disease is discussed. Finally, we highlight some of the limitations that are relevant to the use of genome-wide association studies (GWAS) in the search for new therapies for diabetes. A key outstanding challenge is the translation of GWAS signals into disease biology and we outline possible solutions for tackling this experimental bottleneck.

Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model.

PubMed

Rawas-Qalaji, Mutasem; Rachid, Ousama; Mendez, Belacryst A; Losada, Annette; Simons, F Estelle R; Simons, Keith J

2015-01-01

For anaphylaxis treatment in community settings, adrenaline (epinephrine) administration using an auto-injector in the thigh is universally recommended. Despite this, many people at risk of anaphylaxis in community settings do not carry their prescribed auto-injectors consistently and hesitate to use them when anaphylaxis occurs.The objective of this research was to study the effect of a substantial reduction in adrenaline (Epi) particle size to a few micrometres (Epi microcrystals (Epi-MC)) on enhancing adrenaline dissolution and increasing the rate and extent of sublingual absorption from a previously developed rapidly disintegrating sublingual tablet (RDST) formulation in a validated preclinical model. The in-vivo absorption of Epi-MC 20 mg RDSTs and Epi 40 mg RDSTs was evaluated in rabbits. Epi 0.3 mg intramuscular (IM) injection in the thigh and placebo RDSTs were used as positive and negative controls, respectively. Epimean (standard deviation) area under the plasma concentration vs time curves up to 60 min and Cmax from Epi-MC 20 mg and Epi 40 mg RDSTs did not differ significantly (P > 0.05) from Epi 0.3 mg IM injection. After adrenaline, regardless of route of administration, pharmacokinetic parameters were significantly higher (P < 0.05) than after placebo RDSTs administration (reflecting endogenous adrenaline levels). Epi-MC RDSTs facilitated a twofold increase in Epi absorption and a 50% reduction in the sublingual dose. This novel sublingual tablet formulation is potentially useful for the first-aid treatment of anaphylaxis in community settings. © 2014 Royal Pharmaceutical Society.

EDRN Breast and Ovary Cancer CVC, Study 3: Phase 3 Validation of screening decision rules in preclinical UKCTOCS serial samples — EDRN Public Portal

Cancer.gov

We will collaborate with investigators from University College London to test a screening decision rule in preclinical serial samples from the U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to learn if the panel can do better than CA125 alone. The UKCTOCS is an ideal setting for retrospective validation of an early detection marker panel and decision rule because it offers serial samples collected annually and use of imaging in women with rising CA125. Multi-modal strategies using serum markers HE4, MSLN, MMP7, and CA125 will be compared to strategies relying exclusively on CA125 and transvaginal sonography (TVS).

Preliminary study for small animal preclinical hadrontherapy facility

NASA Astrophysics Data System (ADS)

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

Preclinical Imaging for the Study of Mouse Models of Thyroid Cancer

PubMed Central

Greco, Adelaide; Orlandella, Francesca Maria; Iervolino, Paola Lucia Chiara; Klain, Michele; Salvatore, Giuliana

2017-01-01

Thyroid cancer, which represents the most common tumors among endocrine malignancies, comprises a wide range of neoplasms with different clinical aggressiveness. One of the most important challenges in research is to identify mouse models that most closely resemble human pathology; other goals include finding a way to detect markers of disease that common to humans and mice and to identify the most appropriate and least invasive therapeutic strategies for specific tumor types. Preclinical thyroid imaging includes a wide range of techniques that allow for morphological and functional characterization of thyroid disease as well as targeting and in most cases, this imaging allows quantitative analysis of the molecular pattern of the thyroid cancer. The aim of this review paper is to provide an overview of all of the imaging techniques used to date both for diagnosis and theranostic purposes in mouse models of thyroid cancer. PMID:29258188

Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

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

Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov; Cross, Kevin P.

Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describemore » the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ► We characterize a new in silico model to predict mutagenicity of drug impurities. ► The model predicts Salmonella mutagenicity and will be useful for safety assessment. ► We examine toxicity fingerprints and toxicophores of this Ames assay model. ► We compare these attributes to those found in drug impurities known to FDA/CDER. ► We validate the model and find it has a desired predictive performance.« less

Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models

PubMed Central

Báez-Díaz, Claudia; Sánchez-Margallo, Francisco Miguel

2017-01-01

Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans. PMID:28725598

Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

PubMed

Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

2013-03-01

Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted

Non-invasive molecular imaging for preclinical cancer therapeutic development

PubMed Central

O'Farrell, AC; Shnyder, SD; Marston, G; Coletta, PL; Gill, JH

2013-01-01

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development. PMID:23488622

Subchondroplasty for the Treatment of Post-Traumatic Bone Marrow Lesions of the Medial Femoral Condyle in a Pre-Clinical Canine Model.

PubMed

Brimmo, Olubusola A; Bozynski, Chantelle C; Cook, Cristi R; Kuroki, Keiichi; Sherman, Seth L; Pfeiffer, Ferris M; Stoker, Aaron M; Cook, James L

2018-05-10

This study characterizes long-term outcomes associated with subchondroplasty (SCP) treatment for impact-induced subchondral bone marrow lesions (BML) using a validated pre-clinical canine model. With IACUC approval, purpose-bred research hounds (n = 16) underwent arthroscopic impact injury (40N) to both medial femoral condyles. At 3 months, functional assessments, arthroscopy and MRI were performed and knees (n = 32) were randomly assigned to SCP (3 mL fluoroscopically guided percutaneous injection of AccuFill BSM into BML bone defects) or sham injection (Control). Dogs were assessed at 3, 6, 12, and 24 months after treatment using functional assessments, radiographic evaluation, arthroscopy, and MRI. Dogs were humanely euthanatized at 3, 6, 12, or 24 months after treatment for gross, microCT, and histologic assessments. All knees had focal articular cartilage defects with associated subchondral BMLs, as well as clinical dysfunction, 3 months after injury. At the 3- and 6-months, SCP knees showed more functional impairment than Control knees, however, these differences were not statistically significant. At 1 and 2 years post-treatment, function in SCP knees was better than in Control knees with range of motion being significantly (p < 0.05) better for SCP. Radiographic, arthroscopic, MRI, gross, microCT, and histologic findings matched the functional assessments well with Control being associated with better results at the 2 early time points and SCP being associated with better results at 1 and 2 years. SCP treatment using calcium phosphate bone void filler was associated with an initial increase in pain and dysfunction followed by symptomatic benefits for up to 2 years after treatment for post-traumatic femoral condyle BMLs in a preclinical canine model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Power Plant Model Validation Tool

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

The PPMV is used to validate generator model using disturbance recordings. The PPMV tool contains a collection of power plant models and model validation studies, as well as disturbance recordings from a number of historic grid events. The user can import data from a new disturbance into the database, which converts PMU and SCADA data into GE PSLF format, and then run the tool to validate (or invalidate) the model for a specific power plant against its actual performance. The PNNL PPMV tool enables the automation of the process of power plant model validation using disturbance recordings. The tool usesmore » PMU and SCADA measurements as input information. The tool automatically adjusts all required EPCL scripts and interacts with GE PSLF in the batch mode. The main tool features includes: The tool interacts with GE PSLF; The tool uses GE PSLF Play-In Function for generator model validation; Database of projects (model validation studies); Database of the historic events; Database of the power plant; The tool has advanced visualization capabilities; and The tool automatically generates reports« less

Identification of new treatments for epilepsy: issues in preclinical methodology

PubMed Central

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

Long-term tolerance to kidney allografts in a preclinical canine model.

PubMed

Kuhr, Christian S; Yunusov, Murad; Sale, George; Loretz, Carol; Storb, Rainer

2007-08-27

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

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

PubMed

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.

Rat animal model for preclinical testing of microparticle urethral bulking agents.

PubMed

Mann-Gow, Travis K; Blaivas, Jerry G; King, Benjamin J; El-Ghannam, Ahmed; Knabe, Christine; Lam, Michael K; Kida, Masatoshi; Sikavi, Cameron S; Plante, Mark K; Krhut, Jan; Zvara, Peter

2015-04-01

To develop an economic, practical and readily available animal model for preclinical testing of urethral bulking therapies, as well as to establish feasible experimental methods that allow for complete analysis of hard microparticle bulking agents. Alumina ceramic beads suspended in hyaluronic acid were injected into the proximal urethra of 15 female rats under an operating microscope. We assessed overall lower urinary tract function, bulking material intraurethral integrity and local host tissue response over time. Microphotographs were taken during injection and again 6 months postoperatively, before urethral harvest. Urinary flow rate and voiding frequency were assessed before and after injection. At 6 months, the urethra was removed and embedded in resin. Hard tissue sections were cut using a sawing microtome, and processed for histological analysis using scanning electron microscopy, light microscopy and immunohistochemistry. Microphotographs of the urethra showed complete volume retention of the bulking agent at 6 months. There was no significant difference between average urinary frequency and mean urinary flow rate at 1 and 3 months postinjection as compared with baseline. Scanning electron microscopy proved suitable for evaluation of microparticle size and integrity, as well as local tissue remodeling. Light microscopy and immunohistochemistry allowed for evaluation of an inflammatory host tissue reaction to the bulking agent. The microsurgical injection technique, in vivo physiology and novel hard tissue processing for histology, described in the present study, will allow for future comprehensive preclinical testing of urethral bulking therapy agents containing microparticles made of a hard material. © 2015 The Japanese Urological Association.

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

PubMed

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.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

PubMed

Teuns, Greet B A; Geys, Helena M; Geuens, Sonja M A; Stinissen, Piet; Meert, Theo F

2014-01-01

Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the

Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

PubMed Central

Dohmen, Amy J. C.; Swartz, Justin E.; Van Den Brekel, Michiel W. M.; Willems, Stefan M.; Spijker, René; Neefjes, Jacques; Zuur, Charlotte L.

2015-01-01

Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well. PMID:26343729

Feasibility of spatial frequency domain imaging (SFDI) for optically characterizing a preclinical oncology model.

PubMed

Tabassum, Syeda; Zhao, Yanyu; Istfan, Raeef; Wu, Junjie; Waxman, David J; Roblyer, Darren

2016-10-01

Determination of chemotherapy efficacy early during treatment would provide more opportunities for physicians to alter and adapt treatment plans. Diffuse optical technologies may be ideally suited to track early biological events following chemotherapy administration due to low cost and high information content. We evaluated the use of spatial frequency domain imaging (SFDI) to characterize a small animal tumor model in order to move towards the goal of endogenous optical monitoring of cancer therapy in a controlled preclinical setting. The effects of key measurement parameters including the choice of imaging spatial frequency and the repeatability of measurements were evaluated. The precision of SFDI optical property extractions over repeat mouse measurements was determined to be within 3.52% for move and replace experiments. Baseline optical properties and chromophore values as well as intratumor heterogeneity were evaluated over 25 tumors. Additionally, tumor growth and chemotherapy response were monitored over a 45 day longitudinal study in a small number of mice to demonstrate the ability of SFDI to track treatment effects. Optical scattering and oxygen saturation increased as much as 70% and 25% respectively in treated tumors, suggesting SFDI may be useful for preclinical tracking of cancer therapies.

Quantum-dot-based suspension microarray for multiplex detection of lung cancer markers: preclinical validation and comparison with the Luminex xMAP® system

NASA Astrophysics Data System (ADS)

Bilan, Regina; Ametzazurra, Amagoia; Brazhnik, Kristina; Escorza, Sergio; Fernández, David; Uríbarri, María; Nabiev, Igor; Sukhanova, Alyona

2017-03-01

A novel suspension multiplex immunoassay for the simultaneous specific detection of lung cancer markers in bronchoalveolar lavage fluid (BALF) clinical samples based on fluorescent microspheres having different size and spectrally encoded with quantum dots (QDEM) was developed. The designed suspension immunoassay was validated for the quantitative detection of three lung cancer markers in BALF samples from 42 lung cancer patients and 10 control subjects. Tumor markers were detected through simultaneous formation of specific immune complexes consisting of a capture molecule, the target antigen, and biotinylated recognition molecule on the surface of the different QDEM in a mixture. The immune complexes were visualized by fluorescently labeled streptavidin and simultaneously analyzed using a flow cytometer. Preclinical validation of the immunoassay was performed and results were compared with those obtained using an alternative 3-plex immunoassay based on Luminex xMAP® technology, developed on classical organic fluorophores. The comparison showed that the QDEM and xMAP® assays yielded almost identical results, with clear discrimination between control and clinical samples. Thus, developed QDEM technology can become a good alternative to xMAP® assays permitting analysis of multiple protein biomarkers using conventional flow cytometers.

Quantum-dot-based suspension microarray for multiplex detection of lung cancer markers: preclinical validation and comparison with the Luminex xMAP® system

PubMed Central

Bilan, Regina; Ametzazurra, Amagoia; Brazhnik, Kristina; Escorza, Sergio; Fernández, David; Uríbarri, María; Nabiev, Igor; Sukhanova, Alyona

2017-01-01

A novel suspension multiplex immunoassay for the simultaneous specific detection of lung cancer markers in bronchoalveolar lavage fluid (BALF) clinical samples based on fluorescent microspheres having different size and spectrally encoded with quantum dots (QDEM) was developed. The designed suspension immunoassay was validated for the quantitative detection of three lung cancer markers in BALF samples from 42 lung cancer patients and 10 control subjects. Tumor markers were detected through simultaneous formation of specific immune complexes consisting of a capture molecule, the target antigen, and biotinylated recognition molecule on the surface of the different QDEM in a mixture. The immune complexes were visualized by fluorescently labeled streptavidin and simultaneously analyzed using a flow cytometer. Preclinical validation of the immunoassay was performed and results were compared with those obtained using an alternative 3-plex immunoassay based on Luminex xMAP® technology, developed on classical organic fluorophores. The comparison showed that the QDEM and xMAP® assays yielded almost identical results, with clear discrimination between control and clinical samples. Thus, developed QDEM technology can become a good alternative to xMAP® assays permitting analysis of multiple protein biomarkers using conventional flow cytometers. PMID:28300171

N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

PubMed

Polyak, Erzsebet; Ostrovsky, Julian; Peng, Min; Dingley, Stephen D; Tsukikawa, Mai; Kwon, Young Joon; McCormack, Shana E; Bennett, Michael; Xiao, Rui; Seiler, Christoph; Zhang, Zhe; Falk, Marni J

2018-04-01

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major

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

PubMed

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.

Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury.

PubMed

Fiorentino, Marco; Kellum, John A

2018-05-23

Several cellular and molecular targets and mechanisms have been investigated in preclinical studies of acute kidney injury (AKI), but translation in successful clinical studies has failed to date. This article reviews many issues that have limited this and the potential future perspectives in AKI prevention and treatment. Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success. © 2018 S. Karger AG, Basel.

Preclinical Magnetic Resonance Imaging and Systems Biology in Cancer Research

PubMed Central

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

2014-01-01

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. PMID:23219428

Experimental psychiatric illness and drug abuse models: from human to animal, an overview.

PubMed

Edwards, Scott; Koob, George F

2012-01-01

Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

Rapid identification and validation of novel targeted approaches for Glioblastoma: A combined ex vivo-in vivo pharmaco-omic model.

PubMed

Daher, Ahmad; de Groot, John

2018-01-01

Tumor heterogeneity is a major factor in glioblastoma's poor response to therapy and seemingly inevitable recurrence. Only two glioblastoma drugs have received Food and Drug Administration approval since 1998, highlighting the urgent need for new therapies. Profiling "omics" analyses have helped characterize glioblastoma molecularly and have thus identified multiple molecular targets for precision medicine. These molecular targets have influenced clinical trial design; many "actionable" mutation-focused trials are underway, but because they have not yet led to therapeutic breakthroughs, new strategies for treating glioblastoma, especially those with a pharmacological functional component, remain in high demand. In that regard, high-throughput screening that allows for expedited preclinical drug testing and the use of GBM models that represent tumor heterogeneity more accurately than traditional cancer cell lines is necessary to maximize the successful translation of agents into the clinic. High-throughput screening has been successfully used in the testing, discovery, and validation of potential therapeutics in various cancer models, but it has not been extensively utilized in glioblastoma models. In this report, we describe the basic aspects of high-throughput screening and propose a modified high-throughput screening model in which ex vivo and in vivo drug testing is complemented by post-screening pharmacological, pan-omic analysis to expedite anti-glioma drugs' preclinical testing and develop predictive biomarker datasets that can aid in personalizing glioblastoma therapy and inform clinical trial design. Copyright © 2017 Elsevier Inc. All rights reserved.

Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts.

PubMed

Ambrogio, Chiara; Carmona, Francisco J; Vidal, August; Falcone, Mattia; Nieto, Patricia; Romero, Octavio A; Puertas, Sara; Vizoso, Miguel; Nadal, Ernest; Poggio, Teresa; Sánchez-Céspedes, Montserrat; Esteller, Manel; Mulero, Francisca; Voena, Claudia; Chiarle, Roberto; Barbacid, Mariano; Santamaría, David; Villanueva, Alberto

2014-11-01

Cancer evolution is a process that is still poorly understood because of the lack of versatile in vivo longitudinal studies. By generating murine non-small cell lung cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations, and the appearance of naturally occurring intratumor heterogeneity, thus recapitulating the stochastic nature of human cancer development. This approach combines the robustness of genetically engineered cancer models with the flexibility of allograft methodology. We have applied this tool for the preclinical evaluation of therapeutic approaches. This system can be implemented to improve the design of future treatments for patients with NSCLC. ©2014 American Association for Cancer Research.

Formulation, stability study, and pre-clinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis.

PubMed

de Souza Fernandes, Lígia; Amorim, Yuri Martins; Silva, Elton Libério da; Silva, Samuel Calixto; Santos, Alécia Junia Aparecida; Peixoto, Franciele Natália; Pires, Luara Moniele Neves; Sakamoto, Raquel Yumi; Pinto, Flávia do Carmo Horta; Scarpa, Maria Virgínia Costa; Gonzaga de Freitas Araújo, Marcelo

2018-03-08

Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis METHODS: Curcumin was incorporated in a vaginal cream in three concentrations (0.01, 0.1 and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC RESULTS: The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After six days of pre-clinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction of the inflammatory infiltrate was observed in the group treated with 1.0% cream CONCLUSION: Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The utility of micro-CT and MRI in the assessment of longitudinal growth of liver metastases in a preclinical model of colon carcinoma.

PubMed

Pandit, Prachi; Johnston, Samuel M; Qi, Yi; Story, Jennifer; Nelson, Rendon; Johnson, G Allan

2013-04-01

Liver is a common site for distal metastases in colon and rectal cancer. Numerous clinical studies have analyzed the relative merits of different imaging modalities for detection of liver metastases. Several exciting new therapies are being investigated in preclinical models. But, technical challenges in preclinical imaging make it difficult to translate conclusions from clinical studies to the preclinical environment. This study addresses the technical challenges of preclinical magnetic resonance imaging (MRI) and micro-computed tomography (CT) to enable comparison of state-of-the-art methods for following metastatic liver disease. We optimized two promising preclinical protocols to enable a parallel longitudinal study tracking metastatic human colon carcinoma growth in a mouse model: T2-weighted MRI using two-shot PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) and contrast-enhanced micro-CT using a liposomal contrast agent. Both methods were tailored for high throughput with attention to animal support and anesthesia to limit biological stress. Each modality has its strengths. Micro-CT permitted more rapid acquisition (<10 minutes) with the highest spatial resolution (88-micron isotropic resolution). But detection of metastatic lesions requires the use of a blood pool contrast agent, which could introduce a confound in the evaluation of new therapies. MRI was slower (30 minutes) and had lower anisotropic spatial resolution. But MRI eliminates the need for a contrast agent and the contrast-to-noise between tumor and normal parenchyma was higher, making earlier detection of small lesions possible. Both methods supported a relatively high-throughput, longitudinal study of the development of metastatic lesions. Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.

Affective preclinical modeling of psychiatric disorders: taking imbalanced primal emotional feelings of animals seriously in our search for novel antidepressants

PubMed Central

Panksepp, Jaak

2015-01-01

Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong—to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states. During the past decade, the use of such affective neuroscience-based animal modeling has yielded three novel antidepressants (i) via the alleviation of psychic pain with low doses of buprenorphine; (ii) via the amplification of enthusiasm by direct stimulation of the medial forebrain bundle); and (iii) via the facilitation of the capacity for social joy with play facilitators such as rapastinel (GLYX13). All have progressed to successful human testing. For optimal progress, it may be useful for preclinical investigators to focus on the evolved affective foundations of psychiatrically relevant brain emotional disorders for optimal animal modeling. PMID:26869838

Vaginal wall weakness in parous ewes: a potential preclinical model of pelvic organ prolapse.

PubMed

Young, Natharnia; Rosamilia, Anna; Arkwright, John; Lee, Joseph; Davies-Tuck, Miranda; Melendez, Joan; Werkmeister, Jerome; Gargett, Caroline E

2017-07-01

Ewes develop pelvic organ prolapse (POP) and may be a suitable model for preclinical studies evaluating cell-based therapies for POP. The aim of this study was to establish a clinical score of vaginal weakness and to compare POP Quantification System (POP-Q) values in conscious nulliparous and parous ewes and determine whether ewes are a suitable POP model. Ewes (n = 114) were examined while conscious, without sedation, and standing in a V conveyer by adapting the human POP-Q measurement. Ovine POP was defined as descent to the introitus from POP-Q points Aa 3 cm above the introitus on the anterior wall, Ap 3 cm above the introitus on the posterior wall, or increased Ba anterior wall descent above the urethra (≥0). A test-retest showed good inter- and intrarater reliability. There was no evidence of tissue mobility at Aa, Ap, Ba (all -3 cm) in nulliparous ewes (n = 14). In contrast, multiparous ewes had a median of -1 and interquartile range (IQR) (-2 to 0) for Aa, [0 (-1 to 0)] for Ap and [0 (-2.75 to 0)] for Ba (n = 33; P < 0.0001 in comparison with nulliparous) ewes. Ovine vaginal displacement was seen in 50.9 % of parous ewes and was strongly associated with parity (P = 0.003). A modified POP-Q in conscious ewes was established showing that the vaginal wall of parous animals has similar regions of weakness as do women and may be similarly related to parity. Ewes appear to be a representative preclinical model of human vaginal prolapse.

DNA vaccination for prostate cancer, from preclinical to clinical trials - where we stand?

PubMed Central

2012-01-01

Development of various vaccines for prostate cancer (PCa) is becoming an active research area. PCa vaccines are perceived to have less toxicity compared with the available cytotoxic agents. While various immune-based strategies can elicit anti-tumour responses, DNA vaccines present increased efficacy, inducing both humoural and cellular immunity. This immune activation has been proven effective in animal models and initial clinical trials are encouraging. However, to validate the role of DNA vaccination in currently available PCa management paradigms, strong clinical evidence is still lacking. This article provides an overview of the basic principles of DNA vaccines and aims to provide a summary of preclinical and clinical trials outlining the benefits of this immunotherapy in the management of PCa. PMID:23046944

The basics of preclinical drug development for neurodegenerative disease indications.

PubMed

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

The basics of preclinical drug development for neurodegenerative disease indications

PubMed Central

Steinmetz, Karen L; Spack, Edward G

2009-01-01

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 Program provide funding and

Cardiac AAV9-S100A1 gene therapy rescues postischemic heart failure in a preclinical large animal model

PubMed Central

Pleger, Sven T.; Shan, Changguang; Ksienzyk, Jan; Bekeredjian, Raffi; Boekstegers, Peter; Hinkel, Rabea; Schinkel, Stefanie; Leuchs, Barbara; Ludwig, Jochen; Qiu, Gang; Weber, Christophe; Kleinschmidt, Jürgen A.; Raake, Philip; Koch, Walter J.; Katus, Hugo A.; Müller, Oliver J.; Most, Patrick

2014-01-01

As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the pre-clinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure. PMID:21775667

Ficus deltoidea Prevented Bone Loss in Preclinical Osteoporosis/Osteoarthritis Model by Suppressing Inflammation.

PubMed

Che Ahmad Tantowi, Nur Adeelah; Lau, Seng Fong; Mohamed, Suhaila

2018-05-28

Osteoporosis (OP) and osteoarthritis (OA) are debilitating musculoskeletal diseases of the elderly. Ficus deltoidea (FD) or mistletoe fig, a medicinal plant, was pre-clinically evaluated against OP- and OA-related bone alterations, in postmenopausal OA rat model. Thirty twelfth-week-old female rats were divided into groups (n = 6). Four groups were bilateral ovariectomized (OVX) and OA-induced by intra-articular monosodium iodoacetate (MIA) injection into the right knee joints. The Sham control and OVX-OA non-treated groups were given deionized water. The three other OVX-OA groups were orally administered daily with FD extract (200, 400 mg/kg) or diclofenac (5 mg/kg) for 4 weeks. The rats' bones and blood were evaluated for protein and mRNA expressions of osteoporosis and inflammatory indicators, and micro-CT computed tomography for bone microstructure. The non-treated OVX-OA rats developed severe OP bone loss and bone microstructural damage in the subchondral and metaphyseal regions, supported by reduced serum bone formation markers (osteocalcin, osteoprotegerin) and increased bone resorption markers (RANKL and CTX-I). The FD extract significantly (p < 0.05) mitigated these bone microstructural and biomarker changes by dose-dependently down-regulating pro-inflammatory NF-κβ, TNF-α, and IL-6 mRNA expressions. The FD extract demonstrated good anti-osteoporotic properties in this OP/OA preclinical model by stimulating bone formation and suppressing bone resorption via anti-inflammatory pathways. This is among the few reports relating the subchondral bone plate and trabecular thickening with the metaphyseal trabecular osteopenic bone loss under osteoporotic-osteoarthritis conditions, providing some insights on the debated inverse relationship between osteoporosis and osteoarthritis.

From lead optimization to NDA approval for a new antimicrobial: Use of pre-clinical effect models and pharmacokinetic/pharmacodynamic mathematical modeling.

PubMed

Drusano, G L

2016-12-15

Because of our current crisis of resistance, particularly in nosocomial pathogens, the discovery and development of new antimicrobial agents has become a societal imperative. Changes in regulatory pathways by the Food and Drug Administration and the European Medicines Agency place great emphasis on the use of preclinical models coupled with pharmacokinetic/pharmacodynamic analysis to rapidly and safely move new molecular entities with activity against multi-resistant pathogens through the approval process and into the treatment of patients. In this manuscript, the use of the murine pneumonia system and the Hollow Fiber Infection Model is displayed and the way in which the mathematical analysis of the data arising from these models contributes to the robust choice of dose and schedule for Phase 3 clinical trials is shown. These data and their proper analysis act to de-risk the conduct of Phase 3 trials for anti-infective agents. These trials are the most expensive part of drug development. Further, given the seriousness of the infections treated, they represent the riskiest element for patients. Consequently, these preclinical model systems and their proper analysis have become a central part of accelerated anti-infective development. A final contention of this manuscript is that it is possible to embed these models and in particular, the Hollow Fiber Infection Model earlier in the drug discovery/development process. Examples of 'dynamic driver switching' and the impact of this phenomenon on clinical trial outcome are provided. Identifying dynamic drivers early in drug discovery may lead to improved decision making in the lead optimization process, resulting in the best molecules transitioning to clinical development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models

PubMed Central

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-01-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. PMID:24151975

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

PubMed Central

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

Using Simulation to Model and Validate Invasive Breast Cancer Progression in Women in the Study and Control Groups of the Canadian National Breast Screening Studies I and II.

PubMed

Taghipour, Sharareh; Caudrelier, Laurent N; Miller, Anthony B; Harvey, Bart

2017-02-01

Modeling breast cancer progression and the effect of various risk is helpful in deciding when a woman should start and end screening, and how often the screening should be undertaken. We modeled the natural progression of breast cancer using a hidden Markov process, and incorporated the effects of covariates. Patients are women aged 50-59 (older) and 40-49 (younger) years from the Canadian National Breast Screening Studies. We included prevalent cancers, estimated the screening sensitivities and rates of over-diagnosis, and validated the models using simulation. We found that older women have a higher rate of transition from a healthy to preclinical state and other causes of death but a lower rate of transition from preclinical to clinical state. Reciprocally, younger women have a lower rate of transition from a healthy to preclinical state and other causes of death but a higher rate of transition from a preclinical to clinical state. Different risk factors were significant for the age groups. The mean sojourn times for older and younger women were 2.53 and 2.96 years, respectively. In the study group, the sensitivities of the initial physical examination and mammography for older and younger women were 0.87 and 0.81, respectively, and the sensitivity of the subsequent screens were 0.78 and 0.53, respectively. In the control groups, the sensitivities of the initial physical examination for older and younger women were 0.769 and 0.671, respectively, and the sensitivity of the subsequent physical examinations for the control group aged 50-59 years was 0.37. The upper-bounds for over-diagnosis in older and younger women were 25% and 27%, respectively. The present work offers a basis for the better modeling of cancer incidence for a population with the inclusion of prevalent cancers.

Pre-clinical toxicology considerations for vaccine development.

PubMed

Al-Humadi, Nabil

2017-10-13

Vaccine development requires pre-clinical toxicology studies, following good laboratory practice (GLP), before first in human (phase I) use. Many factors are critical in the final outcome of any pre-clinical toxicology study. The study design is one of these critical factors and should be carefully planned to avoid any false negative and/or false positive results. Preparation is another most critical factor in a successful study. Major changes in any procedure during the course of study should be avoided by all means. For example, if the protocol specified the tail as the site of blood collection and this procedure was used for the control group at the day of necropsy, this collection site should never be replaced by another site (e.g. foot, eye, or heart) in all other treatment groups. Food restrictions and acute restraint stress affect clinical pathology data and should be avoided in rodents. Institutional Animal Care and Use Committee (IACUC) guidelines for frequent blood collections (weekly, monthly, or at necropsy) in any animal species should be strictly followed. Clinical pathology data will be profoundly affected by any diversion from the recommended volumes. If CO 2 is specified in the protocol for anesthesia and/or euthanasia, ensuring enough quantity to use for all groups at necropsy is a very important factor. Using two different anesthetics in any study (e.g. CO 2 vs. pentobarbital) may result in false positive or false negative results in clinical chemistry parameters. Quality assurance elements (SOPs, instrument validation, lab certification etc.) affect the data interpretation and the final outcome of any toxicology study. SOPs should be up to date and written clearly. All lab instruments should be validated and all laboratories should be certified. Published by Elsevier Ltd.

Mitigating risk in academic preclinical drug discovery.

PubMed

Dahlin, Jayme L; Inglese, James; Walters, Michael A

2015-04-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

Preclinical Alzheimer's Disease: Implications for Refinement of the Concept.

PubMed

Vos, Stephanie J B; Visser, Pieter Jelle

2018-05-23

Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

Preclinical Biokinetic Modelling of Tc-99m Radiophamaceuticals Obtained from Semi-Automatic Image Processing.

PubMed

Cornejo-Aragón, Luz G; Santos-Cuevas, Clara L; Ocampo-García, Blanca E; Chairez-Oria, Isaac; Diaz-Nieto, Lorenza; García-Quiroz, Janice

2017-01-01

The aim of this study was to develop a semi automatic image processing algorithm (AIPA) based on the simultaneous information provided by X-ray and radioisotopic images to determine the biokinetic models of Tc-99m radiopharmaceuticals from quantification of image radiation activity in murine models. These radioisotopic images were obtained by a CCD (charge couple device) camera coupled to an ultrathin phosphorous screen in a preclinical multimodal imaging system (Xtreme, Bruker). The AIPA consisted of different image processing methods for background, scattering and attenuation correction on the activity quantification. A set of parametric identification algorithms was used to obtain the biokinetic models that characterize the interaction between different tissues and the radiopharmaceuticals considered in the study. The set of biokinetic models corresponded to the Tc-99m biodistribution observed in different ex vivo studies. This fact confirmed the contribution of the semi-automatic image processing technique developed in this study.

Micro-ultrasound for preclinical imaging

PubMed Central

Foster, F. Stuart; Hossack, John; Adamson, S. Lee

2011-01-01

Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency ‘micro-ultrasound’ has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described. PMID:22866232

Base Flow Model Validation

NASA Technical Reports Server (NTRS)

Sinha, Neeraj; Brinckman, Kevin; Jansen, Bernard; Seiner, John

2011-01-01

A method was developed of obtaining propulsive base flow data in both hot and cold jet environments, at Mach numbers and altitude of relevance to NASA launcher designs. The base flow data was used to perform computational fluid dynamics (CFD) turbulence model assessments of base flow predictive capabilities in order to provide increased confidence in base thermal and pressure load predictions obtained from computational modeling efforts. Predictive CFD analyses were used in the design of the experiments, available propulsive models were used to reduce program costs and increase success, and a wind tunnel facility was used. The data obtained allowed assessment of CFD/turbulence models in a complex flow environment, working within a building-block procedure to validation, where cold, non-reacting test data was first used for validation, followed by more complex reacting base flow validation.

HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

PubMed Central

Larochelle, Andre; Dunbar, Cynthia E.

2013-01-01

The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

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

PubMed Central

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

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis

PubMed Central

Sharma, Raman; Al Jayoussi, Ghaith; Tyrer, Hayley E.; Gamble, Joanne; Hayward, Laura; Priestley, Richard S.; Murphy, Emma A.; Davies, Jill; Waterhouse, David; Cook, Darren A. N.; Clare, Rachel H.; Cassidy, Andrew; Steven, Andrew; Johnston, Kelly L.; McCall, John; Ford, Louise; Hemingway, Janet; Ward, Stephen A.

2017-01-01

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles. PMID:29078351

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

PubMed Central

Burd, Christin E.; Gill, Matthew S.; Niedernhofer, Laura J.; Robbins, Paul D.; Austad, Steven N.; Barzilai, Nir

2016-01-01

Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. PMID:27535964

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms.

PubMed

Burd, Christin E; Gill, Matthew S; Niedernhofer, Laura J; Robbins, Paul D; Austad, Steven N; Barzilai, Nir; Kirkland, James L

2016-11-01

Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

Synchrotron radiation microimaging in rabbit models of cancer for preclinical testing

NASA Astrophysics Data System (ADS)

Umetani, Keiji; Uesugi, Kentaro; Kobatake, Makito; Yamamoto, Akira; Yamashita, Takenori; Imai, Shigeki

2009-10-01

Preclinical laboratory animal imaging modalities such as microangiography and micro-computed tomography (micro-CT) have been developed at the SPring-8 BL20B2 bending magnet beamline. The objective of this paper is to demonstrate the usefulness of microangiography systems for physiological examinations of live animals and micro-CT systems for postmortem morphological examinations. Synchrotron radiation microangiography and micro-CT with contrast agents present the main advantageous capability of depicting the anatomy of small blood vessels with tens of micrometers' diameter. This paper reports two imaging instrument types and their respective applications to preclinical imaging of tumor angiogenic blood vessels in tumor-bearing rabbits, where tumor angiogenesis is characterized morphologically by an increased number of blood vessels. A microangiography system with spatial resolution around 10 μm has been used for therapeutically evaluating angiogenic vessels in a rabbit model of cancer for evaluating embolization materials in transcatheter arterial embolization and for radiation therapy. After an iodine contrast agent was injected into an artery, in vivo imaging was carried out using a high-resolution real-time detector incorporating an X-ray direct-conversion-type SATICON pickup tube. On the other hand, a micro-CT system capably performed three-dimensional visualization of tumor angiogenic blood vessels using tumor-transplanted rabbit specimens with a barium sulfate contrast agent injected into the blood vessels. For specimen imaging, a large-field high-resolution micro-CT system based on a 10-megapixel CCD camera was developed to study tumor-associated alterations in angioarchitecture. Evidence of increased vascularity by tumor angiogenesis and decreased vascularity by tumor treatments was achieved by physiological evaluation of angiogenic small blood vessels in microangiographic imaging and by morphological assessment in micro-CT imaging. These results

Mitigating risk in academic preclinical drug discovery

PubMed Central

Dahlin, Jayme L.; Inglese, James; Walters, Michael A.

2018-01-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research.

PubMed

Galuschka, Claudia; Proynova, Rumyana; Roth, Benjamin; Augustin, Hellmut G; Müller-Decker, Karin

2017-05-15

The devastating diseases of human cancer are mimicked in basic and translational cancer research by a steadily increasing number of tumor models, a situation requiring a platform with standardized reports to share model data. Models in Translational Oncology (MiTO) database was developed as a unique Web platform aiming for a comprehensive overview of preclinical models covering genetically engineered organisms, models of transplantation, chemical/physical induction, or spontaneous development, reviewed here. MiTO serves data entry for metastasis profiles and interventions. Moreover, cell lines and animal lines including tool strains can be recorded. Hyperlinks for connection with other databases and file uploads as supplementary information are supported. Several communication tools are offered to facilitate exchange of information. Notably, intellectual property can be protected prior to publication by inventor-defined accessibility of any given model. Data recall is via a highly configurable keyword search. Genome editing is expected to result in changes of the spectrum of model organisms, a reason to open MiTO for species-independent data. Registered users may deposit own model fact sheets (FS). MiTO experts check them for plausibility. Independently, manually curated FS are provided to principle investigators for revision and publication. Importantly, noneditable versions of reviewed FS can be cited in peer-reviewed journals. Cancer Res; 77(10); 2557-63. ©2017 AACR . ©2017 American Association for Cancer Research.

Validation of Groundwater Models: Meaningful or Meaningless?

NASA Astrophysics Data System (ADS)

Konikow, L. F.

2003-12-01

Although numerical simulation models are valuable tools for analyzing groundwater systems, their predictive accuracy is limited. People who apply groundwater flow or solute-transport models, as well as those who make decisions based on model results, naturally want assurance that a model is "valid." To many people, model validation implies some authentication of the truth or accuracy of the model. History matching is often presented as the basis for model validation. Although such model calibration is a necessary modeling step, it is simply insufficient for model validation. Because of parameter uncertainty and solution non-uniqueness, declarations of validation (or verification) of a model are not meaningful. Post-audits represent a useful means to assess the predictive accuracy of a site-specific model, but they require the existence of long-term monitoring data. Model testing may yield invalidation, but that is an opportunity to learn and to improve the conceptual and numerical models. Examples of post-audits and of the application of a solute-transport model to a radioactive waste disposal site illustrate deficiencies in model calibration, prediction, and validation.

Contrast-Enhanced Sonography Depicts Spontaneous Ovarian Cancer at Early Stages in a Preclinical Animal Model

PubMed Central

Barua, Animesh; Bitterman, Pincas; Bahr, Janice M.; Basu, Sanjib; Sheiner, Eyal; Bradaric, Michael J.; Hales, Dale B.; Luborsky, Judith L.; Abramowicz, Jacques S.

2011-01-01

Objective Our goal was to examine the feasibility of using laying hens, a preclinical model of human spontaneous ovarian cancer, in determining the kinetics of an ultrasound contrast agent indicative of ovarian tumor-associated neoangiogenesis in early-stage ovarian cancer. Methods Three-year-old White Leghorn laying hens with decreased ovarian function were scanned before and after intravenous injection of a human serum albumin–perflutren contrast agent at a dose of 5 µL/kg body weight. Gray scale morphologic characteristics, Doppler indices, the arrival time, peak intensity, and wash-out of the contrast agent were recorded and archived on still images and video clips. Hens were euthanized thereafter; sonographic predictions were compared at gross examination; and ovarian tissues were collected. Archived clips were analyzed to determine contrast parameters and Doppler intensities of vessels. A time-intensity curve per hen was drawn, and the area under the curve was derived. Tumor types and the density of ovarian microvessels were determined by histologic examination and immunohistochemistry and compared to sonographic predictions. Results The contrast agent significantly (P < .05) enhanced the visualization of microvessels, which was confirmed by immunohistochemistry. Contrast parameters, including the time of wash-out and area under the curve, were significantly different (P < .05) between ovaries of normal hens and hens with ovarian cancer and correctly detected cancer at earlier stages than the time of peak intensity. Conclusions The laying hen may be a useful animal model for determining ovarian tumor-associated vascular kinetics diagnostic of early-stage ovarian cancer using a contrast agent. This model may also be useful for testing the efficacy of different contrast agents in a preclinical setting. PMID:21357555

Preclinical drug development.

PubMed

Brodniewicz, Teresa; Grynkiewicz, Grzegorz

2010-01-01

Life sciences provide reasonably sound prognosis for a number and nature of therapeutic targets on which drug design could be based, and search for new chemical entities--future new drugs, is now more than ever based on scientific principles. Nevertheless, current very long and incredibly costly drug discovery and development process is very inefficient, with attrition rate spanning from many thousands of new chemical structures, through a handful of validated drug leads, to single successful new drug launches, achieved in average after 13 years, with compounded cost estimates from hundreds of thousands to over one billion US dollars. Since radical pharmaceutical innovation is critically needed, number of new research projects concerning this area is steeply rising outside of big pharma industry--both in academic environment and in small private companies. Their prospective success will critically depend on project management, which requires combined knowledge of scientific, technical and legal matters, comprising regulations concerning admission of new drug candidates to be subjects of clinical studies. This paper attempts to explain basic rules and requirements of drug development within preclinical study period, in case of new chemical entities of natural or synthetic origin, which belong to low molecular weight category.

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models.

PubMed

Finch, Paul W; Mark Cross, Lawrence J; McAuley, Daniel F; Farrell, Catherine L

2013-09-01

Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

PubMed

Barajaz, Ashley M; Kliethermes, Christopher L

2017-12-01

Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

A crowdsourcing model for creating preclinical medical education study tools.

PubMed

Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

2013-06-01

During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning.

Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model.

PubMed

Curl, Claire L; Danes, Vennetia R; Bell, James R; Raaijmakers, Antonia J A; Ip, Wendy T K; Chandramouli, Chanchal; Harding, Tristan W; Porrello, Enzo R; Erickson, Jeffrey R; Charchar, Fadi J; Kompa, Andrew R; Edgley, Amanda J; Crossman, David J; Soeller, Christian; Mellor, Kimberley M; Kalman, Jonathan M; Harrap, Stephen B; Delbridge, Lea M D

2018-06-01

Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca 2+ operational levels and markedly increased L-type Ca 2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed. Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca 2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α.

PubMed

Lowery, Caitlin D; Blosser, Wayne; Dowless, Michele; Knoche, Shelby; Stephens, Jennifer; Li, Huiling; Surguladze, David; Loizos, Nick; Luffer-Atlas, Debra; Oakley, Gerard J; Guo, Qianxu; Iyer, Seema; Rubin, Brian P; Stancato, Louis

2018-02-15

Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors. Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor. Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin. Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847-57. ©2017 AACR . ©2017 American Association for Cancer Research.

Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review.

PubMed

Maze, Mervyn

2016-02-01

The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury. Databases of the published literature (MEDLINE® and EMBASE™) were appraised for peer-reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators' declarations in the National Institutes of Health clinical trials website were considered. While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon's neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon's efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care. According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility.

Testing and validating environmental models

USGS Publications Warehouse

Kirchner, J.W.; Hooper, R.P.; Kendall, C.; Neal, C.; Leavesley, G.

1996-01-01

Generally accepted standards for testing and validating ecosystem models would benefit both modellers and model users. Universally applicable test procedures are difficult to prescribe, given the diversity of modelling approaches and the many uses for models. However, the generally accepted scientific principles of documentation and disclosure provide a useful framework for devising general standards for model evaluation. Adequately documenting model tests requires explicit performance criteria, and explicit benchmarks against which model performance is compared. A model's validity, reliability, and accuracy can be most meaningfully judged by explicit comparison against the available alternatives. In contrast, current practice is often characterized by vague, subjective claims that model predictions show 'acceptable' agreement with data; such claims provide little basis for choosing among alternative models. Strict model tests (those that invalid models are unlikely to pass) are the only ones capable of convincing rational skeptics that a model is probably valid. However, 'false positive' rates as low as 10% can substantially erode the power of validation tests, making them insufficiently strict to convince rational skeptics. Validation tests are often undermined by excessive parameter calibration and overuse of ad hoc model features. Tests are often also divorced from the conditions under which a model will be used, particularly when it is designed to forecast beyond the range of historical experience. In such situations, data from laboratory and field manipulation experiments can provide particularly effective tests, because one can create experimental conditions quite different from historical data, and because experimental data can provide a more precisely defined 'target' for the model to hit. We present a simple demonstration showing that the two most common methods for comparing model predictions to environmental time series (plotting model time series

Foodstuffs for Preventing Cancer: The Preclinical and Clinical Development of Berries

PubMed Central

Stoner, Gary D.

2009-01-01

Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents, such as anthocyanins and ellagitannins, that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems; for determining these compounds’ mechanisms of action; and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts or individual constituents (anthocyanins) for cancer prevention are also discussed. PMID:19258544

Foodstuffs for preventing cancer: the preclinical and clinical development of berries.

PubMed

Stoner, Gary D

2009-03-01

Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.

The Use of Minipigs for Preclinical Safety Assessment by the Pharmaceutical Industry: Results of an IQ DruSafe Minipig Survey.

PubMed

Colleton, Curtis; Brewster, David; Chester, Anne; Clarke, David O; Heining, Peter; Olaharski, Andrew; Graziano, Michael

2016-04-01

The use of minipigs in preclinical safety testing of pharmaceuticals is considered an alternative to the more traditional dog and nonhuman primate (NHP) nonrodent species. Substantial evidence exists to suggest that the anatomy, physiology, and biochemistry of minipigs are similar enough to humans to consider them as valid nonrodent models for pharmaceutical safety testing. Since the utilization of minipigs was last assessed over 5 years ago, the Preclinical Safety Leadership Group (DruSafe) of the International Consortium for Innovation and Quality in Pharmaceutical Development conducted this survey to provide an updated assessment of the utility, perceived value, and impediments to the use of minipigs in preclinical safety testing. Of the 32 participating members of DruSafe, 15 responded to the survey representing both large and small companies. Respondents indicated that the minipig has been utilized mostly for short-term safety assessment studies with dermal, oral, and parenteral routes of administration. Minipigs are widely accepted as appropriate models for cardiovascular assessments and have been used to a limited extent for reproductive toxicology testing. Overall responses indicated that safety testing for large molecules using this species is relatively low due to a lack of background data, reagents or biomarkers, concerns regarding immune system characterization and poor suitability for developmental toxicity assessments. Most companies utilized contract research organizations for definitive safety toxicity assessment studies. Conclusions of this survey indicate that minipig is an acceptable nonrodent species largely limited to studies using small molecules, primarily dermal products, and results are comparable to those reported 5 years ago. © The Author(s) 2016.

Histological Characterization of the Irritative Zones in Focal Cortical Dysplasia Using a Preclinical Rat Model.

PubMed

Deshmukh, Abhay; Leichner, Jared; Bae, Jihye; Song, Yinchen; Valdés-Hernández, Pedro A; Lin, Wei-Chiang; Riera, Jorge J

2018-01-01

Current clinical practice in focal epilepsy involves brain source imaging (BSI) to localize brain areas where from interictal epileptiform discharges (IEDs) emerge. These areas, named irritative zones , have been useful to define candidate seizures-onset zones during pre-surgical workup. Since human histological data are mostly available from final resected zones, systematic studies characterizing pathophysiological mechanisms and abnormal molecular/cellular substrates in irritative zones-independent of them being epileptogenic-are challenging. Combining BSI and histological analysis from all types of irritative zones is only possible through the use of preclinical animal models. Here, we recorded 32-channel spontaneous electroencephalographic data from rats that have focal cortical dysplasia (FCD) and chronic seizures. BSI for different IED subtypes was performed using the methodology presented in Bae et al. (2015). Post-mortem brain sections containing irritative zones were stained to quantify anatomical, functional, and inflammatory biomarkers specific for epileptogenesis, and the results were compared with those obtained using the contralateral healthy brain tissue. We found abnormal anatomical structures in all irritative zones (i.e., larger neuronal processes, glioreactivity, and vascular cuffing) and larger expressions for neurotransmission (i.e., NR2B) and inflammation (i.e., ILβ1, TNFα and HMGB1). We conclude that irritative zones in this rat preclinical model of FCD comprise abnormal tissues disregarding whether they are actually involved in icto-genesis or not. We hypothesize that seizure perpetuation happens gradually; hence, our results could support the use of IED-based BSI for the early diagnosis and preventive treatment of potential epileptic foci. Further verifications in humans are yet needed.

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma

PubMed Central

Krytska, Kateryna; Ryles, Hannah T.; Sano, Renata; Raman, Pichai; Infarinato, Nicole R.; Hansel, Theodore D.; Makena, Monish R.; Song, Michael M.; Reynolds, C. Patrick; Mossé, Yael P.

2015-01-01

Purpose The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. Experimental Design The sensitivity of human neuroblastoma-derived cell lines, cell line-derived and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. Results In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free-survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). Conclusions Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multi-agent therapy for ALK-aberrant neuroblastoma patients. PMID:26438783

Therapeutic Hypothermia and Hypoxia-Ischemia in the Term-equivalent Neonatal Rat: Characterization of a Translational Pre-clinical Model

PubMed Central

Patel, Shyama D.; Pierce, Leslie; Ciardiello, Amber; Hutton, Alexandra; Paskewitz, Samuel; Aronowitz, Eric; Voss, Henning U.; Moore, Holly; Vannucci, Susan J.

2015-01-01

Background Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity in survivors. Therapeutic hypothermia (TH) is the only available intervention, but the protection is incomplete. Preclinical studies of HIE/TH in the rodent have relied on the postnatal day (P) 7 rat whose brain approximates a 32–36 week gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational. Methods P10–11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 hours recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 hours, 2 and 12 weeks. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition. Results Neuroprotection with TH was apparent at 2 and 12 weeks in both moderately and severely damaged animals. TH improved motor function in moderate, but not severe damage. Impaired object recognition occurred with severe damage with no evidence of protection of TH. Conclusion This adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed longitudinally to provide a useful translational preclinical model. PMID:25996893

Preclinical testing for aortic endovascular grafts: results of a Food and Drug Administration workshop.

PubMed

Abel, Dorothy B; Beebe, Hugh G; Dedashtian, Mark M; Morton, Michael C; Moynahan, Megan; Smith, Loius J; Weinberg, Steven L

2002-05-01

Since their introduction into clinical trials in the United States, endovascular aortic grafts have shown various types of problems. Although details of design and construction vary between different endovascular grafts and failure modes have had a variety of causes and clinical effects, the inability of preclinical testing to predict these failures remains common to all endovascular grafts. The need to improve preclinical testing in an attempt to reduce clinical device failures resulted in a Food and Drug Administration-sponsored workshop on endovascular graft preclinical testing held in Rockville, Md, from July 31 to August 1, 2001. FORMAT: The workshop was not designed as a consensus conference. Instead, it provided a forum for bringing stakeholders together to define problems and identify areas of agreement and disagreement. The workshop had 34 invited participants who represented device manufacturers, the medical community, the Food and Drug Administration, and testing facilities, and international attendance was more than 120 people. Discussion centered on: 1, defining the physiologic, anatomic, and morphologic characteristics of abdominal aortic aneurysms before and after endovascular graft treatment; 2, identifying the types of failures that have been observed clinically; and 3, determining which characteristics should be considered during preclinical modeling to better predict clinical performance. Attendees agreed to the need to better define and address anatomic characteristics and changes in the aneurysm after endograft treatment to optimize preclinical testing. Much discussion and little agreement occurred on the importance of flow-related forces on graft performance or the need or ability to define and model physiologic compliance during durability testing. The discussion and conclusions are summarized in this paper and are provided in detail at: http://www.fda.gov/cdrh/meetings/073101workshop.html. The workshop raised awareness of significant

Preclinical Rheumatoid Arthritis (Autoantibodies): An Updated Review

PubMed Central

Deane, Kevin D.

2014-01-01

Multiple studies demonstrate that there is a period of development of rheumatoid arthritis (RA) during which there are elevations of disease-related biomarkers, including autoantibodies, in the absence of and prior to the development of RA; this period can be termed ‘preclinical RA’. These ‘preclinical’ autoantibodies including rheumatoid factor and antibodies to citrullinated protein antigens, and more recent studies have also identified a wider variety of autoantibodies and a wide range of inflammatory biomarkers. These findings in conjunction with established and emerging data about genetic and environmental risk factors for RA support a model of disease development where certain factors lead to an initial triggering of RA-related autoimmunity that expands over time to the point where symptomatic arthritis classifiable as RA develops. Herein will be reviewed updates in the field, as well as a discussion of current limitations of our understanding of preclinical RA, and potential future directions for study. PMID:24643396

Ground-water models: Validate or invalidate

USGS Publications Warehouse

Bredehoeft, J.D.; Konikow, Leonard F.

1993-01-01

The word validation has a clear meaning to both the scientific community and the general public. Within the scientific community the validation of scientific theory has been the subject of philosophical debate. The philosopher of science, Karl Popper, argued that scientific theory cannot be validated, only invalidated. Popper’s view is not the only opinion in this debate; however, many scientists today agree with Popper (including the authors). To the general public, proclaiming that a ground-water model is validated carries with it an aura of correctness that we do not believe many of us who model would claim. We can place all the caveats we wish, but the public has its own understanding of what the word implies. Using the word valid with respect to models misleads the public; verification carries with it similar connotations as far as the public is concerned. Our point is this: using the terms validation and verification are misleading, at best. These terms should be abandoned by the ground-water community.

Empirical agreement in model validation.

PubMed

Jebeile, Julie; Barberousse, Anouk

2016-04-01

Empirical agreement is often used as an important criterion when assessing the validity of scientific models. However, it is by no means a sufficient criterion as a model can be so adjusted as to fit available data even though it is based on hypotheses whose plausibility is known to be questionable. Our aim in this paper is to investigate into the uses of empirical agreement within the process of model validation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM).

PubMed

Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M

2016-07-01

In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical

Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder.

PubMed

Fuchs, Eberhard

2005-03-01

Animal models are invaluable in preclinical research on human psychopathology. Valid animal models to study the pathophysiology of depression and specific biological and behavioral responses to antidepressant drug treatments are of prime interest. In order to improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation seen in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews. Coexistence of two males in visual and olfactory contact leads to a stable dominant/subordinate relationship, with the subordinates showing obvious changes in behavioral, neuroendocrine, and central nervous activity that are similar to the signs and symptoms observed during episodes of depression in patients. To discover whether this model, besides its "face validity" for depression, also has "predictive validity," we treated subordinate animals with the tricyclic antidepressant clomipramine and found a time-dependent recovery of both endocrine function and normal behavior. In contrast, the anxiolytic diazepam was ineffective. Chronic psychosocial stress in male tree shrews significantly decreased hippocampal volume and the proliferation rate of the granule precursor cells in the dentate gyrus. These stress-induced changes can be prevented by treating the animals with clomipramine, tianeptine, or the selective neurokinin receptor antagonist L-760,735. In addition to its apparent face and predictive validity, the tree shrew model also has a "molecular validity" due to the degradation routes of psychotropic compounds and gene sequences of receptors are very similar to those in humans. Although further research is required to validate this model fully, it provides an adequate and interesting non-rodent experimental paradigm for preclinical research on depression.

QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome

PubMed Central

Chen, Xian; Cass, Jessica D; Bradley, Jenifer A; Dahm, Corinn M; Sun, Zhuoqian; Kadyszewski, Edmund; Engwall, Michael J; Zhou, Jun

2005-01-01

Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration-dependent, and 100 μM (∼18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects. PMID:16158069

Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.

PubMed

Rea, Domenica; Coppola, Carmela; Barbieri, Antonio; Monti, Maria Gaia; Misso, Gabriella; Palma, Giuseppe; Bimonte, Sabrina; Zarone, Mayra Rachele; Luciano, Antonio; Liccardo, Davide; Maiolino, Piera; Cittadini, Antonio; Ciliberto, Gennaro; Arra, Claudio; Maurea, Nicola

2016-01-01

In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography. We generated a mouse model of cardiotoxicity induced by doxorubicin. C57BL 6 mice were divided into two groups, treated for 7 days by intraperitoneal injections of placebo (vehicle) or doxorubicin (2.17 mg/kg), in order to characterize the cardiac phenotype in vivo. We demonstrated that doxorubicin caused ealy remodeling of the left ventricle: after two days of therapy, the radial, circumferential and strain rates were reduced respectively by 35%, 34%, and 39% (p-value ≤0.001). Moreover, histological analysis revealed that doxorubicin treatment increased fibrosis, cardiomyocyte diameter and apoptosis. In a murine model of doxorubicin-induced cardiac injury, we detected left ventricular dysfunction followed by alterations in conventional echocardiographic indices. Our study suggests that a change in strain could be an effective early marker of myocardial dysfunction for new anticancer treatments and, in preclinical studies, it might also be a valuable indicator for the assessment of activity of cardioprotective agents. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Laboratory animals as surrogate models of human obesity

PubMed Central

Nilsson, Cecilia; Raun, Kirsten; Yan, Fei-fei; Larsen, Marianne O; Tang-Christensen, Mads

2012-01-01

Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character. PMID:22301857

Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

PubMed

Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

2015-10-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. ©2015 American Association for Cancer Research.

Pre-clinical validation of a new intra-operative "dual beam Doppler" blood flowmeter in an artificial circuit.

PubMed

Cikirikcioglu, Mustafa; Cikirikcioglu, Y Banu; Khabiri, Ebrahim; Djebaili, M Karim; Kalangos, Afksendiyos; Walpoth, Beat H

2006-01-01

Intra-operative flow measurement during coronary or peripheral bypass operations is helpful for ruling out technical failures and for prediction of complication and patency rates. Preclinical validation of the flowmeters is required in order to rely on the intra-operatively measured results. The aim of this study is to evaluate a new "dual beam Doppler" blood flowmeter before clinical application and to compare it with the established "transit time flow measure-ment" technique in an artificial circuit. Measurements were performed in an experimental flow model using pig blood and pig arteries. Three different flowmeters were used: Quantix OR (dual beam doppler flowmeter), CardioMed (transit time flowmeter), and Transonic (transit time flowmeter). Three validation tests were performed to assess correlation, precision, and repeatability of devices. (1) Correlation and agreement analysis was performed with various flow amounts (10-350 mL/min) (n = 160). (2) Device reproducibility and measurement stability were tested with a constant flow (flow amount = 300 mL/min) (n = 30). (3) A user accuracy test (intra- and inter-observer variability) was performed by 5 different observers with a constant flow (flow amount = 205 mL/min) (n = 75). Time collected true flow was used as a reference method in all steps and all tests were performed in a blind manner. Results are shown as mean values +/- standard deviations. Pear-son's correlation and Bland-Altman plot analyses were used to compare measurements. The mean flow was 167 +/- 98 mL/min for true flow and 162 +/- 94 mL/min, 165 +/- 94 mL/min, and 166 +/- 100 mL/min for Quantix OR, CardioMed, and Transonic, respectively. Correlation coefficients between Quantix OR, Medi-Stim, Transonic, and time collected true flow were over 0.98 (P = .01). Most of the measured results ( > 90%) were between +/- 1.96 SD agreement limits in Bland and Altman plot analysis. All devices showed good results in the reproducibility test. During the user

Towards policy relevant environmental modeling: contextual validity and pragmatic models

USGS Publications Warehouse

Miles, Scott B.

2000-01-01

"What makes for a good model?" In various forms, this question is a question that, undoubtedly, many people, businesses, and institutions ponder with regards to their particular domain of modeling. One particular domain that is wrestling with this question is the multidisciplinary field of environmental modeling. Examples of environmental models range from models of contaminated ground water flow to the economic impact of natural disasters, such as earthquakes. One of the distinguishing claims of the field is the relevancy of environmental modeling to policy and environment-related decision-making in general. A pervasive view by both scientists and decision-makers is that a "good" model is one that is an accurate predictor. Thus, determining whether a model is "accurate" or "correct" is done by comparing model output to empirical observations. The expected outcome of this process, usually referred to as "validation" or "ground truthing," is a stamp on the model in question of "valid" or "not valid" that serves to indicate whether or not the model will be reliable before it is put into service in a decision-making context. In this paper, I begin by elaborating on the prevailing view of model validation and why this view must change. Drawing from concepts coming out of the studies of science and technology, I go on to propose a contextual view of validity that can overcome the problems associated with "ground truthing" models as an indicator of model goodness. The problem of how we talk about and determine model validity has much to do about how we perceive the utility of environmental models. In the remainder of the paper, I argue that we should adopt ideas of pragmatism in judging what makes for a good model and, in turn, developing good models. From such a perspective of model goodness, good environmental models should facilitate communication, convey—not bury or "eliminate"—uncertainties, and, thus, afford the active building of consensus decisions, instead

[Modeling the academic performance of medical students in basic sciences and pre-clinical courses: a longitudinal study].

PubMed

Zúñiga, Denisse; Mena, Beltrán; Oliva, Rose; Pedrals, Nuria; Padilla, Oslando; Bitran, Marcela

2009-10-01

The study of predictors of academic performance is relevant for medical education. Most studies of academic performance use global ratings as outcome measure, and do not evaluate the influence of the assessment methods. To model by multivariate analysis, the academic performance of medical considering, besides academic and demographic variables, the methods used to assess students' learning and their preferred modes of information processing. Two hundred seventy two students admitted to the medical school of the Pontificia Universidad Católica de Chile from 2000 to 2003. Six groups of variables were studied to model the students' performance in five basic science courses (Anatomy, Biology, Calculus, Chemistry and Physics) and two pre-clinical courses (Integrated Medical Clinic I and IT). The assessment methods examined were multiple choice question tests, Objective Structured Clinical Examination and tutor appraisal. The results of the university admission tests (high school grades, mathematics and biology tests), the assessment methods used, the curricular year and previous application to medical school, were predictors of academic performance. The information processing modes influenced academic performance, but only in interaction with other variables. Perception (abstract or concrete) interacted with the assessment methods, and information use (active or reflexive), with sex. The correlation between the real and predicted grades was 0.7. In addition to the academic results obtained prior to university entrance, the methods of assessment used in the university and the information processing modes influence the academic performance of medical students in basic and preclinical courses.

Photobiomodulation (PBM) with 20 W at 640 nm: pre-clinical results and propagation model

NASA Astrophysics Data System (ADS)

Gendron, Denis J.; Ménage, Alexander R.

2017-02-01

A novel treatment modality for photobiomodulation (PBM) is introduced called High Intensity Physio Light (HIPL) Therapy with a light source at 640 nm wavelength, 20 nm bandwidth, and up to 20 W in large 10 cm flat beam. This report exemplifies the efficacy performance of this method with three pre-clinical cases: (i) ankle: sport injury, (ii) foot: bone fractures, and (iii) shoulder: musculoskeletal disorder (MSD). In all cases, the patients systematically experienced a significant pain reduction (by 2 / 10 - 4 / 10) on a visual pain scale. In case (ii) and (iii), a steady improvement and complete recovery of the patient was respectfully obtained. This report describes the experimental treatment condition for each case, and introduces an intensity-dependant propagation model to explain our observation.

Teaching "Instant Experience" with Graphical Model Validation Techniques

ERIC Educational Resources Information Center

Ekstrøm, Claus Thorn

2014-01-01

Graphical model validation techniques for linear normal models are often used to check the assumptions underlying a statistical model. We describe an approach to provide "instant experience" in looking at a graphical model validation plot, so it becomes easier to validate if any of the underlying assumptions are violated.

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

PubMed

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

National Cancer Institute Pediatric Preclinical Testing Program: Model Description for In Vitro Cytotoxicity Testing

PubMed Central

Kang, Min H.; Smith, Malcolm A.; Morton, Christopher L.; Keshelava, Nino; Houghton, Peter J.; Reynolds, C. Patrick

2010-01-01

Background The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. Procedures In vitro cytotoxicity testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC50, absolute IC50, and Ymin values The panel of 23 pediatric cancer cell lines included leukemia (n=6), lymphoma (n=2), rhabdomyosarcoma (n=4), brain tumors (n=3), Ewing family of tumors (EFT, n=4), and neuroblastoma (n=4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. Results We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under preclinical investigation for cancer. To date, the PPTP has completed in vitro testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various “standard” chemotherapy drugs. Conclusions This robust in vitro cytotoxicity testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. PMID:20922763

The Role of Digital 3D Scanned Models in Dental Students' Self-Assessments in Preclinical Operative Dentistry.

PubMed

Lee, Cliff; Kobayashi, Hiro; Lee, Samuel R; Ohyama, Hiroe

2018-04-01

The aim of this study was to determine how dental student self-assessment and faculty assessment of operative preparations compared for conventional visual assessment versus assessment of scanned digital 3D models. In 2016, all third-year students in the Class of 2018 (N=35) at Harvard School of Dental Medicine performed preclinical exams of Class II amalgam preparations (C2AP) and Class III composite preparations (C3CP) and completed self-assessment forms; in 2017, all third-year students in the Class of 2019 (N=34) performed the same exams. Afterwards, the prepared typodont teeth were digitally scanned. Students self-assessed their preparations digitally, and four faculty members graded the preparations conventionally and digitally. The results showed that, overall, the students assessed their preparations higher than the faculty assessments. The mean student-faculty gaps for C2AP and C3CP in the conventional assessments were 11% and 5%, respectively. The mean digital student-faculty gap for C2AP and C3CP were 8% and 2%, respectively. In the conventional assessments, preclinical performance was negatively correlated with the student-faculty gap (r=-0.47, p<0.001). The correlations were not statistically significant with the digital assessments (p=0.39, p=0.26). Students in the bottom quartile significantly improved their self-assessment accuracy using digital self-assessments over conventional assessments (C2AP 10% vs. 17% and C3CP 3% vs. 10%, respectively). These results suggest that digital assessments offered a significant learning opportunity for students to critically self-assess themselves in operative preclinical dentistry. The lower performing students benefitted the most, improving their assessment ability to the level of the rest of the class.

Animal models for bone tissue engineering and modelling disease

PubMed Central

Griffin, Michelle

2018-01-01

ABSTRACT Tissue engineering and its clinical application, regenerative medicine, are instructing multiple approaches to aid in replacing bone loss after defects caused by trauma or cancer. In such cases, bone formation can be guided by engineered biodegradable and nonbiodegradable scaffolds with clearly defined architectural and mechanical properties informed by evidence-based research. With the ever-increasing expansion of bone tissue engineering and the pioneering research conducted to date, preclinical models are becoming a necessity to allow the engineered products to be translated to the clinic. In addition to creating smart bone scaffolds to mitigate bone loss, the field of tissue engineering and regenerative medicine is exploring methods to treat primary and secondary bone malignancies by creating models that mimic the clinical disease manifestation. This Review gives an overview of the preclinical testing in animal models used to evaluate bone regeneration concepts. Immunosuppressed rodent models have shown to be successful in mimicking bone malignancy via the implantation of human-derived cancer cells, whereas large animal models, including pigs, sheep and goats, are being used to provide an insight into bone formation and the effectiveness of scaffolds in induced tibial or femoral defects, providing clinically relevant similarity to human cases. Despite the recent progress, the successful translation of bone regeneration concepts from the bench to the bedside is rooted in the efforts of different research groups to standardise and validate the preclinical models for bone tissue engineering approaches. PMID:29685995

Statistical validation of normal tissue complication probability models.

PubMed

Xu, Cheng-Jian; van der Schaaf, Arjen; Van't Veld, Aart A; Langendijk, Johannes A; Schilstra, Cornelis

2012-09-01

To investigate the applicability and value of double cross-validation and permutation tests as established statistical approaches in the validation of normal tissue complication probability (NTCP) models. A penalized regression method, LASSO (least absolute shrinkage and selection operator), was used to build NTCP models for xerostomia after radiation therapy treatment of head-and-neck cancer. Model assessment was based on the likelihood function and the area under the receiver operating characteristic curve. Repeated double cross-validation showed the uncertainty and instability of the NTCP models and indicated that the statistical significance of model performance can be obtained by permutation testing. Repeated double cross-validation and permutation tests are recommended to validate NTCP models before clinical use. Copyright © 2012 Elsevier Inc. All rights reserved.

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

PubMed

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

A whole-body dual-modality radionuclide optical strategy for preclinical imaging of metastasis and heterogeneous treatment response in different microenvironments.

PubMed

Fruhwirth, Gilbert O; Diocou, Seckou; Blower, Philip J; Ng, Tony; Mullen, Greg E D

2014-04-01

Imaging spontaneous cancer cell metastasis or heterogeneous tumor responses to drug treatment in vivo is difficult to achieve. The goal was to develop a new highly sensitive and reliable preclinical longitudinal in vivo imaging model for this purpose, thereby facilitating discovery and validation of anticancer therapies or molecular imaging agents. The strategy is based on breast cancer cells stably expressing the human sodium iodide symporter (NIS) fused to a red fluorescent protein, thereby permitting radionuclide and fluorescence imaging. Using whole-body nano-SPECT/CT with (99m)TcO4(-), we followed primary tumor growth and spontaneous metastasis in the presence or absence of etoposide treatment. NIS imaging was used to classify organs as small as individual lymph nodes (LNs) to be positive or negative for metastasis, and results were confirmed by confocal fluorescence microscopy. Etoposide treatment efficacy was proven by ex vivo anticaspase 3 staining and fluorescence microscopy. In this preclinical model, we found that the NIS imaging strategy outperformed state-of-the-art (18)F-FDG imaging in its ability to detect small tumors (18.5-fold-better tumor-to-blood ratio) and metastases (LN, 3.6-fold) because of improved contrast in organs close to metastatic sites (12- and 8.5-fold-lower standardized uptake value in the heart and kidney, respectively). We applied the model to assess the treatment response to the neoadjuvant etoposide and found a consistent and reliable improvement in spontaneous metastasis detection. Importantly, we also found that tumor cells in different microenvironments responded in a heterogeneous manner to etoposide treatment, which could be determined only by the NIS-based strategy and not by (18)F-FDG imaging. We developed a new strategy for preclinical longitudinal in vivo cancer cell tracking with greater sensitivity and reliability than (18)F-FDG PET and applied it to track spontaneous and distant metastasis in the presence or absence

Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1.

PubMed

Schiroli, Giulia; Ferrari, Samuele; Conway, Anthony; Jacob, Aurelien; Capo, Valentina; Albano, Luisa; Plati, Tiziana; Castiello, Maria C; Sanvito, Francesca; Gennery, Andrew R; Bovolenta, Chiara; Palchaudhuri, Rahul; Scadden, David T; Holmes, Michael C; Villa, Anna; Sitia, Giovanni; Lombardo, Angelo; Genovese, Pietro; Naldini, Luigi

2017-10-11

Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-all IL2RG (interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of the IL2RG -edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold of IL2RG editing in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Preclinical Alzheimer's disease and longitudinal driving decline.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Head, Denise M; Stout, Sarah H; Vernon, Elizabeth K; Ghoshal, Nupur; Garland, Brad; Barco, Peggy P; Williams, Monique M; Johnson, Ann; Fierberg, Rebecca; Fague, M Scot; Xiong, Chengjie; Mormino, Elizabeth; Grant, Elizabeth A; Holtzman, David M; Benzinger, Tammie L S; Fagan, Anne M; Ott, Brian R; Carr, David B; Morris, John C

2017-01-01

Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 . Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

Turbine Engine Mathematical Model Validation

DTIC Science & Technology

1976-12-01

AEDC-TR-76-90 ~Ec i ? Z985 TURBINE ENGINE MATHEMATICAL MODEL VALIDATION ENGINE TEST FACILITY ARNOLD ENGINEERING DEVELOPMENT CENTER AIR FORCE...i f n e c e s e a ~ ~ d i den t i f y by b l ock number) YJI01-GE-100 engine turbine engines mathematical models computations mathematical...report presents and discusses the results of an investigation to develop a rationale and technique for the validation of turbine engine steady-state

Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression

PubMed Central

Candolfi, Marianela; Curtin, James F.; Stephen Nichols, W.; Muhammad, AKM. G.; King, Gwendalyn D.; Elizabeth Pluhar, G.; McNiel, Elizabeth A.; Ohlfest, John R.; Freese, Andrew B.; Moore, Peter F.; Lerner, Jonathan; Lowenstein, Pedro R.

2008-01-01

Although rodent glioblastoma (GBM) models have been used for over 30 years, the extent to which they recapitulate the characteristics encountered in human GBMs remains controversial. We studied the histopathological features of dog GBM and human xenograft GBM models in immune-deficient mice (U251 and U87 GBM in nude Balb/c), and syngeneic GBMs in immune-competent rodents (GL26 cells in C57BL/6 mice, CNS-1 cells in Lewis rats). All GBMs studied exhibited neovascularization, pleomorphism, vimentin immunoreactivity, and infiltration of T-cells and macrophages. All the tumors showed necrosis and hemorrhages, except the U87 human xenograft, in which the most salient feature was its profuse neovascularization. The tumors differed in the expression of astrocytic intermediate filaments: human and dog GBMs, as well as U251 xenografts expressed glial fibrillary acidic protein (GFAP) and vimentin, while the U87 xenograft and the syngeneic rodent GBMs were GFAP− and vimentin+. Also, only dog GBMs exhibited endothelial proliferation, a key feature that was absent in the murine models. In all spontaneous and implanted GBMs we found histopathological features compatible with tumor invasion into the non-neoplastic brain parenchyma. Our data indicate that murine models of GBM appear to recapitulate several of the human GBM histopathological features and, considering their reproducibility and availability, they constitute a valuable in vivo system for preclinical studies. Importantly, our results indicate that dog GBM emerges as an attractive animal model for testing novel therapies in a spontaneous tumor in the context of a larger brain. PMID:17874037

An Advanced Preclinical Mouse Model for Acute Myeloid Leukemia Using Patients' Cells of Various Genetic Subgroups and In Vivo Bioluminescence Imaging

PubMed Central

Vick, Binje; Rothenberg, Maja; Sandhöfer, Nadine; Carlet, Michela; Finkenzeller, Cornelia; Krupka, Christina; Grunert, Michaela; Trumpp, Andreas; Corbacioglu, Selim; Ebinger, Martin; André, Maya C.; Hiddemann, Wolfgang; Schneider, Stephanie; Subklewe, Marion; Metzeler, Klaus H.; Spiekermann, Karsten; Jeremias, Irmela

2015-01-01

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups. PMID:25793878

Validation of the Filovirus Plaque Assay for Use in Preclinical Studies

PubMed Central

Shurtleff, Amy C.; Bloomfield, Holly A.; Mort, Shannon; Orr, Steven A.; Audet, Brian; Whitaker, Thomas; Richards, Michelle J.; Bavari, Sina

2016-01-01

A plaque assay for quantitating filoviruses in virus stocks, prepared viral challenge inocula and samples from research animals has recently been fully characterized and standardized for use across multiple institutions performing Biosafety Level 4 (BSL-4) studies. After standardization studies were completed, Good Laboratory Practices (GLP)-compliant plaque assay method validation studies to demonstrate suitability for reliable and reproducible measurement of the Marburg Virus Angola (MARV) variant and Ebola Virus Kikwit (EBOV) variant commenced at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). The validation parameters tested included accuracy, precision, linearity, robustness, stability of the virus stocks and system suitability. The MARV and EBOV assays were confirmed to be accurate to ±0.5 log10 PFU/mL. Repeatability precision, intermediate precision and reproducibility precision were sufficient to return viral titers with a coefficient of variation (%CV) of ≤30%, deemed acceptable variation for a cell-based bioassay. Intraclass correlation statistical techniques for the evaluation of the assay’s precision when the same plaques were quantitated by two analysts returned values passing the acceptance criteria, indicating high agreement between analysts. The assay was shown to be accurate and specific when run on Nonhuman Primates (NHP) serum and plasma samples diluted in plaque assay medium, with negligible matrix effects. Virus stocks demonstrated stability for freeze-thaw cycles typical of normal usage during assay retests. The results demonstrated that the EBOV and MARV plaque assays are accurate, precise and robust for filovirus titration in samples associated with the performance of GLP animal model studies. PMID:27110807

Successful reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of type 1 diabetes.

PubMed

Thomas, J M; Contreras, J L; Smyth, C A; Lobashevsky, A; Jenkins, S; Hubbard, W J; Eckhoff, D E; Stavrou, S; Neville, D M; Thomas, F T

2001-06-01

The recent focus on islet transplantation as primary therapy for type 1 diabetes has heightened interest in the reversal of type 1 diabetes in preclinical models using minimal immunosuppression. Here, we demonstrated in a preclinical rhesus model a consistent reversal of all measured glycemic patterns of streptozotocin-induced type 1 diabetes. The model used single-donor islet transplantation with induction of operational tolerance. The term "operational tolerance" is used to indicate durable survival of single-donor major histocompatibility complex (MHC)-mismatched islet allografts without maintenance immunosuppressive therapy and without rejection or loss of functional islet mass or insulin secretory reserve. In this operational tolerance model, all immunosuppression was discontinued after day 14 posttransplant, and recipients recovered with excellent health. The operational tolerance induction protocol combined peritransplant anti-CD3 immunotoxin to deplete T-cells and 15-deoxyspergualin to arrest proinflammatory cytokine production and maturation of dendritic cells. T-cell deficiency was specific but temporary, in that T-cell-dependent responses in long-term survivors recovered to normal, and there was no evidence of increased susceptibility to infection. Anti-donor mixed lymphocyte reaction responses were positive in the long-term survivors, but all showed clear evidence of systemic T-helper 2 deviation, suggesting that an immunoregulatory rather than a deletional process underlies this operational tolerance model. This study provides the first evidence that operational tolerance can protect MHC nonhuman primate islets from rejection as well as loss of functional islet mass. Such an approach has potential to optimize individual recipient recovery from diabetes as well as permitting more widespread islet transplantation with the limited supply of donor islets.

CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

PubMed

Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N; Lopera, Francisco; Bateman, Randall J; Morris, John C; Sperling, Reisa A; Aisen, Paul S; Roses, Allen D; Welsh-Bohmer, Kathleen A; Carrillo, Maria C; Weninger, Stacie

2016-01-01

If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

PubMed Central

Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

2015-01-01

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097.

PubMed

He, Wei; Luistro, Leopoldo; Carvajal, Daisy; Smith, Melissa; Nevins, Tom; Yin, Xuefeng; Cai, James; Higgins, Brian; Kolinsky, Kenneth; Rizzo, Christine; Packman, Kathryn; Heimbrook, David; Boylan, John F

2011-06-01

Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models

PubMed Central

Kenessey, István; Kói, Krisztina; Horváth, Orsolya; Cserepes, Mihály; Molnár, Dávid; Izsák, Vera; Dobos, Judit; Hegedűs, Balázs

2016-01-01

Background In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines. Results We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras. In case of in vitro proliferation, the KRAS-mutant human NSCLC cell lines showed resistance to zoledronic acid wild-type KRAS-cells proved to be sensitive. Combinatory application of zoledronic acid enhanced the cytostatic effect of cisplatin. Zoledronic acid did not induce significant apoptosis. In xenograft model, zoledronic acid significantly reduced the weight of wild type KRAS-EGFR-expressing xenograft tumor by decreasing the proliferative capacity. Futhermore, zoledronic acid induced VEGF expression and improved in vivo tumor vascularization. Materials and methods Membrane association of K-Ras was examined by Western-blot. In vitro cell viability, apoptotic cell death and migration were measured in NSCLC lines with different molecular background. The in vivo effect of zoledronic acid was investigated in a SCID mouse subcutaneous xenograft model. Conclusions The in vitro and in vivo inhibitory effect of zoledronic acid was based on the blockade of cell cycle in wild type KRAS-expressing human NSCLC cells. The zoledronic acid induced vascularization supported in vivo cytostatic effect. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy. PMID:27780929

Global precipitation measurements for validating climate models

NASA Astrophysics Data System (ADS)

Tapiador, F. J.; Navarro, A.; Levizzani, V.; García-Ortega, E.; Huffman, G. J.; Kidd, C.; Kucera, P. A.; Kummerow, C. D.; Masunaga, H.; Petersen, W. A.; Roca, R.; Sánchez, J.-L.; Tao, W.-K.; Turk, F. J.

2017-11-01

The advent of global precipitation data sets with increasing temporal span has made it possible to use them for validating climate models. In order to fulfill the requirement of global coverage, existing products integrate satellite-derived retrievals from many sensors with direct ground observations (gauges, disdrometers, radars), which are used as reference for the satellites. While the resulting product can be deemed as the best-available source of quality validation data, awareness of the limitations of such data sets is important to avoid extracting wrong or unsubstantiated conclusions when assessing climate model abilities. This paper provides guidance on the use of precipitation data sets for climate research, including model validation and verification for improving physical parameterizations. The strengths and limitations of the data sets for climate modeling applications are presented, and a protocol for quality assurance of both observational databases and models is discussed. The paper helps elaborating the recent IPCC AR5 acknowledgment of large observational uncertainties in precipitation observations for climate model validation.

Beware of external validation! - A Comparative Study of Several Validation Techniques used in QSAR Modelling.

PubMed

Majumdar, Subhabrata; Basak, Subhash C

2018-04-26

Proper validation is an important aspect of QSAR modelling. External validation is one of the widely used validation methods in QSAR where the model is built on a subset of the data and validated on the rest of the samples. However, its effectiveness for datasets with a small number of samples but large number of predictors remains suspect. Calculating hundreds or thousands of molecular descriptors using currently available software has become the norm in QSAR research, owing to computational advances in the past few decades. Thus, for n chemical compounds and p descriptors calculated for each molecule, the typical chemometric dataset today has high value of p but small n (i.e. n < p). Motivated by the evidence of inadequacies of external validation in estimating the true predictive capability of a statistical model in recent literature, this paper performs an extensive and comparative study of this method with several other validation techniques. We compared four validation methods: leave-one-out, K-fold, external and multi-split validation, using statistical models built using the LASSO regression, which simultaneously performs variable selection and modelling. We used 300 simulated datasets and one real dataset of 95 congeneric amine mutagens for this evaluation. External validation metrics have high variation among different random splits of the data, hence are not recommended for predictive QSAR models. LOO has the overall best performance among all validation methods applied in our scenario. Results from external validation are too unstable for the datasets we analyzed. Based on our findings, we recommend using the LOO procedure for validating QSAR predictive models built on high-dimensional small-sample data. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

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

Zhang, Bin; Wang, Ken Kang-Hsin, E-mail: kwang27@jhmi.edu; Yu, Jingjing

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 stationarymore » 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

Establishment of a large panel of patient-derived preclinical models of human renal cell carcinoma.

PubMed

Lang, Hervé; Béraud, Claire; Bethry, Audrey; Danilin, Sabrina; Lindner, Véronique; Coquard, Catherine; Rothhut, Sylvie; Massfelder, Thierry

2016-09-13

The objective of the present work was to establish a large panel of preclinical models of human renal cell carcinoma (RCC) directly from patients, faithfully reproducing the biological features of the original tumor. RCC tissues (all stages/subtypes) were collected for 8 years from 336 patients undergoing surgery, xenografted subcutaneously in nude mice, and serially passaged into new mice up to 13 passages. Tissue samples from the primary tumor and tumors grown in mice through passages were analyzed for biological tissue stability by histopathology, mRNA profiling, von Hippel-Lindau gene sequencing, STR fingerprinting, growth characteristics and response to current therapies. Metastatic models were also established by orthotopic implantation and analyzed by imagery. We established a large panel of 30 RCC models (passage > 3, 8.9% success rate). High tumor take rate was associated with high stage and grade. Histopathologic, molecular and genetic characteristics were preserved between original tumors and case-matched xenografts. The models reproduced the sensitivity to targeted therapies observed in the clinic. Overall, these models constitute an invaluable tool for the clinical design of efficient therapies, the identification of predictive biomarkers and translational research.

Tactics for preclinical validation of receptor-binding radiotracers

PubMed Central

Lever, Susan Z.; Fan, Kuo-Hsien; Lever, John R.

2016-01-01

Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was

A Canine Arthroscopic Anterior Cruciate Ligament Reconstruction Model for Study of Synthetic Augmentation of Tendon Allografts.

PubMed

Cook, James L; Smith, Pat; Stannard, James P; Pfeiffer, Ferris; Kuroki, Keiichi; Bozynski, Chantelle C; Cook, Cristi

2017-09-01

Novel graft types, fixation methods, and means for augmenting anterior cruciate ligament (ACL) reconstructions require preclinical validation prior to safe and effective clinical application. The objective of this study was to describe and validate a translational canine model for all-inside arthroscopic complete ACL reconstruction using a quadriceps tendon allograft with internal brace (QTIB). With institutional approval, adult research hounds underwent complete transection of the native ACL followed by all-inside ACL reconstruction using the novel QTIB construct with suspensory fixation ( n  = 10). Contralateral knees were used as nonoperated controls ( n  = 10). Dogs were assessed over a 6-month period using functional, diagnostic imaging, gross, biomechanical, and histologic outcome measures required for preclinical animal models. Study results suggest that the novel QTIB construct used for complete ACL reconstruction can provide sustained knee stability and function without the development of premature osteoarthritis in a rigorous and valid preclinical model. The unique configuration of the QTIB construct-the combination of a tendon allograft with a synthetic suture tape internal brace-allowed for an effective biologic-synthetic load-sharing ACL construct. It prevented early failure, allowed for direct, four-zone graft-to-bone healing, and functional graft remodeling while avoiding problems noted with use of all-synthetic grafts. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options.

PubMed

Gallmeier, Eike; Calhoun, Eric S; Rago, Carlo; Brody, Jonathan R; Cunningham, Steven C; Hucl, Tomas; Gorospe, Myriam; Kohli, Manu; Lengauer, Christoph; Kern, Scott E

2006-06-01

How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models. We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance. FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer. Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.

Preclinical electrogastrography in experimental pigs

PubMed Central

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

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

PubMed

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

CAP—advancing the evaluation of preclinical Alzheimer disease treatments

PubMed Central

Reiman, Eric M.; Langbaum, Jessica B.; Tariot, Pierre N.; Lopera, Francisco; Bateman, Randall J.; Morris, John C.; Sperling, Reisa A.; Aisen, Paul S.; Roses, Allen D.; Welsh-Bohmer, Kathleen A.; Carrillo, Maria C.; Weninger, Stacie

2016-01-01

If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer’s Prevention (CAP)—a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact—and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. PMID:26416539

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

PubMed

Holzgrefe, Henry; Ferber, Georg; Champeroux, Pascal; Gill, Michael; Honda, Masaki; Greiter-Wilke, Andrea; Baird, Theodore; Meyer, Olivier; Saulnier, Muriel

2014-01-01

In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the

The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

PubMed Central

Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

2015-01-01

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. PMID:25845860

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

PubMed

Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

2015-07-01

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles.

PubMed

Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B; Østergaard, Michael E; Gu, Xiaofeng; Kordasiewicz, Holly B; Kay, Chris; Cheung, Daphne; Xie, Yuanyun; Waltl, Sabine; Dal Cengio, Louisa; Findlay-Black, Hailey; Doty, Crystal N; Petoukhov, Eugenia; Iworima, Diepiriye; Slama, Ramy; Ooi, Jolene; Pouladi, Mahmoud A; Yang, X William; Swayze, Eric E; Seth, Punit P; Hayden, Michael R

2017-03-15

Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Preclinical profile of cabazitaxel

PubMed Central

Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil

2014-01-01

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated

Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

PubMed

Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

2014-03-01

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

Robotic Cholecystectomy Using the Newly Developed Korean Robotic Surgical System, Revo-i: A Preclinical Experiment in a Porcine Model.

PubMed

Kang, Chang Moo; Chong, Jae Uk; Lim, Jin Hong; Park, Dong Won; Park, Sung Jun; Gim, Suhyeon; Ye, Hye Jin; Kim, Se Hoon; Lee, Woo Jung

2017-09-01

One Korean company recently successfully produced a robotic surgical system prototype called Revo-i (MSR-5000). We, therefore, conducted a preclinical study for robotic cholecystectomy using Revo-i, and this is a report of the first case of robotic cholecystectomy performed using the Revo-i system in a preclinical porcine model. Revo-i consists of a surgeon console (MSRC-5000), operation cart (MSRO-5000) and vision cart (MSRV-5000), and a 40 kg-healthy female porcine was prepared for robotic cholecystectomy with general anesthesia. The primary end point was the safe completion of these procedures using Revo-i: The total operation time was 88 minutes. The dissection time was defined as the time from the initial dissection of the Calot area to the time to complete gallbladder detachment from the liver bed: The dissection time required 14 minutes. The surgical console time was 45 minutes. There was no gallbladder perforation or significant bleeding noted during the procedure. The porcine survived for two weeks postoperatively without any complications. Like the da Vinci surgical system, the Revo-i provides a three-dimensional operative view and allows for angulated instrument motion (forceps, needle-holders, clip-appliers, scissors, bipolar energy, and hook monopolar energy), facilitating an effective laparoscopic procedure. Our experience suggests that robotic cholecystectomy can be safely completed in a porcine model using Revo-i. © Copyright: Yonsei University College of Medicine 2017.

SDG and qualitative trend based model multiple scale validation

NASA Astrophysics Data System (ADS)

Gao, Dong; Xu, Xin; Yin, Jianjin; Zhang, Hongyu; Zhang, Beike

2017-09-01

Verification, Validation and Accreditation (VV&A) is key technology of simulation and modelling. For the traditional model validation methods, the completeness is weak; it is carried out in one scale; it depends on human experience. The SDG (Signed Directed Graph) and qualitative trend based multiple scale validation is proposed. First the SDG model is built and qualitative trends are added to the model. And then complete testing scenarios are produced by positive inference. The multiple scale validation is carried out by comparing the testing scenarios with outputs of simulation model in different scales. Finally, the effectiveness is proved by carrying out validation for a reactor model.

Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

PubMed Central

Schütte, Moritz; Risch, Thomas; Abdavi-Azar, Nilofar; Boehnke, Karsten; Schumacher, Dirk; Keil, Marlen; Yildiriman, Reha; Jandrasits, Christine; Borodina, Tatiana; Amstislavskiy, Vyacheslav; Worth, Catherine L.; Schweiger, Caroline; Liebs, Sandra; Lange, Martin; Warnatz, Hans- Jörg; Butcher, Lee M.; Barrett, James E.; Sultan, Marc; Wierling, Christoph; Golob-Schwarzl, Nicole; Lax, Sigurd; Uranitsch, Stefan; Becker, Michael; Welte, Yvonne; Regan, Joseph Lewis; Silvestrov, Maxine; Kehler, Inge; Fusi, Alberto; Kessler, Thomas; Herwig, Ralf; Landegren, Ulf; Wienke, Dirk; Nilsson, Mats; Velasco, Juan A.; Garin-Chesa, Pilar; Reinhard, Christoph; Beck, Stephan; Schäfer, Reinhold; Regenbrecht, Christian R. A.; Henderson, David; Lange, Bodo; Haybaeck, Johannes; Keilholz, Ulrich; Hoffmann, Jens; Lehrach, Hans; Yaspo, Marie-Laure

2017-01-01

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab. PMID:28186126

Impact of Comorbidities on Acute Injury and Recovery in Preclinical Stroke Research: Focus on Hypertension and Diabetes

PubMed Central

Ergul, Adviye; Hafez, Sherif; Fouda, Abdelrahman; Fagan, Susan C.

2016-01-01

Human ischemic stroke is very complex and no single preclinical model can comprise all the variables known to contribute to stroke injury and recovery. Hypertension, diabetes and hyperlipidemia are leading comorbidities in stroke patients. The use of predominantly young adult and healthy animals in experimental stroke research has created a barrier for translation of findings to patients. As such, more and more disease models are being incorporated into the research design. This review highlights the major strengths and weaknesses of the most commonly used animal models of these conditions in preclinical stroke research. The goal is to provide guidance in choosing, reporting and executing appropriate disease models that will be subjected to different models of stroke injury. PMID:27026092

Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy

PubMed Central

Wert, Katherine J; Mahajan, Vinit B; Zhang, Lijuan; Yan, Yuanqing; Li, Yao; Tosi, Joaquin; Wei Hsu, Chun; Nagasaki, Takayuki; Janisch, Kerstin M; Grant, Maria B; Mahajan, MaryAnn; Bassuk, Alexander G; Tsang, Stephen H

2016-01-01

Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders. PMID:27195131

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

PubMed

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.

Validation of 2D flood models with insurance claims

NASA Astrophysics Data System (ADS)

Zischg, Andreas Paul; Mosimann, Markus; Bernet, Daniel Benjamin; Röthlisberger, Veronika

2018-02-01

Flood impact modelling requires reliable models for the simulation of flood processes. In recent years, flood inundation models have been remarkably improved and widely used for flood hazard simulation, flood exposure and loss analyses. In this study, we validate a 2D inundation model for the purpose of flood exposure analysis at the river reach scale. We validate the BASEMENT simulation model with insurance claims using conventional validation metrics. The flood model is established on the basis of available topographic data in a high spatial resolution for four test cases. The validation metrics were calculated with two different datasets; a dataset of event documentations reporting flooded areas and a dataset of insurance claims. The model fit relating to insurance claims is in three out of four test cases slightly lower than the model fit computed on the basis of the observed inundation areas. This comparison between two independent validation data sets suggests that validation metrics using insurance claims can be compared to conventional validation data, such as the flooded area. However, a validation on the basis of insurance claims might be more conservative in cases where model errors are more pronounced in areas with a high density of values at risk.

Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration.

PubMed

Trachtenberg, Jordan E; Vo, Tiffany N; Mikos, Antonios G

2015-03-01

Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth.

Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration

PubMed Central

Trachtenberg, Jordan E.; Vo, Tiffany N.; Mikos, Antonios G.

2014-01-01

Pre-clinical animal models play a crucial role in the translation of biomedical technologies from the bench top to the bedside. However, there is a need for improved techniques to evaluate implanted biomaterials within the host, including consideration of the care and ethics associated with animal studies, as well as the evaluation of host tissue repair in a clinically relevant manner. This review discusses non-invasive, quantitative, and real-time techniques for evaluating host-materials interactions, quality and rate of neotissue formation, and functional outcomes of implanted biomaterials for bone and cartilage tissue engineering. Specifically, a comparison will be presented for pre-clinical animal models, histological scoring systems, and non-invasive imaging modalities. Additionally, novel technologies to track delivered cells and growth factors will be discussed, including methods to directly correlate their release with tissue growth. PMID:25319726

Prevention or treatment of ARDS with aspirin: a review of preclinical models and meta- analysis of clinical studies

PubMed Central

Panka, Bernardo Amisa; de Grooth, Harm-Jan; Spoelstra–de Man, Angeliquè; Looney, Mark; Tuinman, Pieter-Roel

2016-01-01

Background The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself, have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. Methods We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. MEDLINE, EMBASE AND COCHRANE databases were searched. Results The literature search yielded 1314 unique articles. Fifteen pre-clinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g. ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps and prostaglandins. High dose ASA may be the drug of choice. A meta-analysis of 3 clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36–0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. Conclusion This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models is being evaluated to guide optimal timing and dose

Validating EHR clinical models using ontology patterns.

PubMed

Martínez-Costa, Catalina; Schulz, Stefan

2017-12-01

Clinical models are artefacts that specify how information is structured in electronic health records (EHRs). However, the makeup of clinical models is not guided by any formal constraint beyond a semantically vague information model. We address this gap by advocating ontology design patterns as a mechanism that makes the semantics of clinical models explicit. This paper demonstrates how ontology design patterns can validate existing clinical models using SHACL. Based on the Clinical Information Modelling Initiative (CIMI), we show how ontology patterns detect both modeling and terminology binding errors in CIMI models. SHACL, a W3C constraint language for the validation of RDF graphs, builds on the concept of "Shape", a description of data in terms of expected cardinalities, datatypes and other restrictions. SHACL, as opposed to OWL, subscribes to the Closed World Assumption (CWA) and is therefore more suitable for the validation of clinical models. We have demonstrated the feasibility of the approach by manually describing the correspondences between six CIMI clinical models represented in RDF and two SHACL ontology design patterns. Using a Java-based SHACL implementation, we found at least eleven modeling and binding errors within these CIMI models. This demonstrates the usefulness of ontology design patterns not only as a modeling tool but also as a tool for validation. Copyright © 2017 Elsevier Inc. All rights reserved.

Classification of brain tumors using texture based analysis of T1-post contrast MR scans in a preclinical model

NASA Astrophysics Data System (ADS)

Tang, Tien T.; Zawaski, Janice A.; Francis, Kathleen N.; Qutub, Amina A.; Gaber, M. Waleed

2018-02-01

Accurate diagnosis of tumor type is vital for effective treatment planning. Diagnosis relies heavily on tumor biopsies and other clinical factors. However, biopsies do not fully capture the tumor's heterogeneity due to sampling bias and are only performed if the tumor is accessible. An alternative approach is to use features derived from routine diagnostic imaging such as magnetic resonance (MR) imaging. In this study we aim to establish the use of quantitative image features to classify brain tumors and extend the use of MR images beyond tumor detection and localization. To control for interscanner, acquisition and reconstruction protocol variations, the established workflow was performed in a preclinical model. Using glioma (U87 and GL261) and medulloblastoma (Daoy) models, T1-weighted post contrast scans were acquired at different time points post-implant. The tumor regions at the center, middle, and peripheral were analyzed using in-house software to extract 32 different image features consisting of first and second order features. The extracted features were used to construct a decision tree, which could predict tumor type with 10-fold cross-validation. Results from the final classification model demonstrated that middle tumor region had the highest overall accuracy at 79%, while the AUC accuracy was over 90% for GL261 and U87 tumors. Our analysis further identified image features that were unique to certain tumor region, although GL261 tumors were more homogenous with no significant differences between the central and peripheral tumor regions. In conclusion our study shows that texture features derived from MR scans can be used to classify tumor type with high success rates. Furthermore, the algorithm we have developed can be implemented with any imaging datasets and may be applicable to multiple tumor types to determine diagnosis.

The nature of outsourced preclinical research--the example of chemical synthesis.

PubMed

Festel, Gunter W

2013-09-01

The possibility to buy standardized external services or even new and innovative methods within drug discovery has increased dramatically during the last decades. Service providers are able to provide timely and efficient solutions to any given problem within preclinical research. The outsourcing behavior depends on the specific company type. Generally, the outsourcing level of emerging pharmaceutical and biotechnology companies is much higher than established companies due to low or missing internal resources. Whereas the "make-or-buy" decisions of large and fully integrated pharmaceutical companies are mainly competency driven, those of mid-size and small pharmaceutical, as well as biotech companies show a specific combination of cost/capacity and competency. The three different cooperation models "price competition", "project selection," and "strategic partnership" were identified. For all types of companies, the cooperation model of "strategic partnership" offers access to high-level expertise while reducing fixed costs and complexity. This was shown using chemical synthesis as an example but is also true for other areas of preclinical research.

Preclinical magnetic resonance imaging and systems biology in cancer research: current applications and challenges.

PubMed

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.

Validation of urban freeway models.

DOT National Transportation Integrated Search

2015-01-01

This report describes the methodology, data, conclusions, and enhanced models regarding the validation of two sets of models developed in the Strategic Highway Research Program 2 (SHRP 2) Reliability Project L03, Analytical Procedures for Determining...

Turbulence Modeling Verification and Validation

NASA Technical Reports Server (NTRS)

Rumsey, Christopher L.

2014-01-01

Computational fluid dynamics (CFD) software that solves the Reynolds-averaged Navier-Stokes (RANS) equations has been in routine use for more than a quarter of a century. It is currently employed not only for basic research in fluid dynamics, but also for the analysis and design processes in many industries worldwide, including aerospace, automotive, power generation, chemical manufacturing, polymer processing, and petroleum exploration. A key feature of RANS CFD is the turbulence model. Because the RANS equations are unclosed, a model is necessary to describe the effects of the turbulence on the mean flow, through the Reynolds stress terms. The turbulence model is one of the largest sources of uncertainty in RANS CFD, and most models are known to be flawed in one way or another. Alternative methods such as direct numerical simulations (DNS) and large eddy simulations (LES) rely less on modeling and hence include more physics than RANS. In DNS all turbulent scales are resolved, and in LES the large scales are resolved and the effects of the smallest turbulence scales are modeled. However, both DNS and LES are too expensive for most routine industrial usage on today's computers. Hybrid RANS-LES, which blends RANS near walls with LES away from walls, helps to moderate the cost while still retaining some of the scale-resolving capability of LES, but for some applications it can still be too expensive. Even considering its associated uncertainties, RANS turbulence modeling has proved to be very useful for a wide variety of applications. For example, in the aerospace field, many RANS models are considered to be reliable for computing attached flows. However, existing turbulence models are known to be inaccurate for many flows involving separation. Research has been ongoing for decades in an attempt to improve turbulence models for separated and other nonequilibrium flows. When developing or improving turbulence models, both verification and validation are important

Preclinical models used for immunogenicity prediction of therapeutic proteins.

PubMed

Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim

2013-07-01

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

Mesenchymal stem cell therapy promotes the improvement and recovery of renal function in a preclinical model

PubMed Central

Urt-Filho, Antônio; Oliveira, Rodrigo Juliano; Hermeto, Larissa Correa; Pesarini, João Renato; de David, Natan; Cantero, Wilson de Barros; Falcão, Gustavo; Marks, Guido; Antoniolli-Silva, Andréia Conceição Milan Brochado

2016-01-01

Abstract Acute renal failure (ARF) is an extremely important public health issue in need of novel therapies. The present study aimed to evaluate the capacity of mesenchymal stem cell (MSC) therapy to promote the improvement and recovery of renal function in a preclinical model. Wistar rats were used as the experimental model, and our results show that cisplatin (5mg/kg) can efficiently induce ARF, as measured by changes in biochemical (urea and creatinine) and histological parameters. MSC therapy performed 24h after the administration of chemotherapy resulted in normalized plasma urea and creatinine levels 30 and 45d after the onset of kidney disease. Furthermore, MSC therapy significantly reduced histological changes (intratubular cast formation in protein overload nephropathy and tubular hydropic degeneration) in this ARF model. Thus, considering that current therapies for ARF are merely palliative and that MSC therapy can promote the improvement and recovery of renal function in this model system, we suggest that innovative/alternative therapies involving MSCs should be considered for clinical studies in humans to treat ARF. PMID:27275667

Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

PubMed

Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

2015-04-06

In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key

Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk.

PubMed

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.

Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

PubMed Central

Sudres, Muriel; Maurer, Marie; Robinet, Marieke; Bismuth, Jacky; Truffault, Frédérique; Girard, Diane; Dragin, Nadine; Attia, Mohamed; Fadel, Elie; Santelmo, Nicola; Sicsic, Camille; Brenner, Talma

2017-01-01

Myasthenia gravis (MG) with anti–acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro–preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell–related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases. PMID:28405609

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia.

PubMed

Caldwell, Matthew; Moroz, Tracy; Hapuarachchi, Tharindi; Bainbridge, Alan; Robertson, Nicola J; Cooper, Chris E; Tachtsidis, Ilias

2015-01-01

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue.

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia

PubMed Central

Bainbridge, Alan; Robertson, Nicola J.; Cooper, Chris E.

2015-01-01

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. PMID:26445281

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

PubMed Central

Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John

2016-01-01

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia. PMID:27725886

SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

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

Shang, M; Sands, M; Bolch, W

2015-06-15

Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adultmore » beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.« less

Cultural Geography Model Validation

DTIC Science & Technology

2010-03-01

the Cultural Geography Model (CGM), a government owned, open source multi - agent system utilizing Bayesian networks, queuing systems, the Theory of...referent determined either from theory or SME opinion. 4. CGM Overview The CGM is a government-owned, open source, data driven multi - agent social...HSCB, validation, social network analysis ABSTRACT: In the current warfighting environment , the military needs robust modeling and simulation (M&S

Assessment of clinical reasoning: A Script Concordance test designed for pre-clinical medical students.

PubMed

Humbert, Aloysius J; Johnson, Mary T; Miech, Edward; Friedberg, Fred; Grackin, Janice A; Seidman, Peggy A

2011-01-01

The Script Concordance test (SCT) measures clinical reasoning in the context of uncertainty by comparing the responses of examinees and expert clinicians. It uses the level of agreement with a panel of experts to assign credit for the examinee's answers. This study describes the development and validation of a SCT for pre-clinical medical students. Faculty from two US medical schools developed SCT items in the domains of anatomy, biochemistry, physiology, and histology. Scoring procedures utilized data from a panel of 30 expert physicians. Validation focused on internal reliability and the ability of the SCT to distinguish between different cohorts. The SCT was administered to an aggregate of 411 second-year and 70 fourth-year students from both schools. Internal consistency for the 75 test items was satisfactory (Cronbach's alpha = 0.73). The SCT successfully differentiated second- from fourth-year students and both student groups from the expert panel in a one-way analysis of variance (F(2,508) = 120.4; p < 0.0001). Mean scores for students from the two schools were not significantly different (p = 0.20). This SCT successfully differentiated pre-clinical medical students from fourth-year medical students and both cohorts of medical students from expert clinicians across different institutions and geographic areas. The SCT shows promise as an easy-to-administer measure of "problem-solving" performance in competency evaluation even in the beginning years of medical education.

Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells*

PubMed Central

Lee, Andrew S.; Xu, Dan; Plews, Jordan R.; Nguyen, Patricia K.; Nag, Divya; Lyons, Jennifer K.; Han, Leng; Hu, Shijun; Lan, Feng; Liu, Junwei; Huang, Mei; Narsinh, Kazim H.; Long, Charles T.; de Almeida, Patricia E.; Levi, Benjamin; Kooreman, Nigel; Bangs, Charles; Pacharinsak, Cholawat; Ikeno, Fumiaki; Yeung, Alan C.; Gambhir, Sanjiv S.; Robbins, Robert C.; Longaker, Michael T.; Wu, Joseph C.

2011-01-01

Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia. PMID:21719696

NCI Pediatric Preclinical Testing Consortium

Cancer.gov

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.

Sponge-supported cultures of primary head and neck tumors for an optimized preclinical model.

PubMed

Dohmen, Amy J C; Sanders, Joyce; Canisius, Sander; Jordanova, Ekaterina S; Aalbersberg, Else A; van den Brekel, Michiel W M; Neefjes, Jacques; Zuur, Charlotte L

2018-05-18

Treatment of advanced head and neck cancer is associated with low survival, high toxicity and a widely divergent individual response. The sponge-gel-supported histoculture model was previously developed to serve as a preclinical model for predicting individual treatment responses. We aimed to optimize the sponge-gel-supported histoculture model and provide more insight in cell specific behaviour by evaluating the tumor and its microenvironment using immunohistochemistry. We collected fresh tumor biopsies from 72 untreated patients and cultured them for 7 days. Biopsies from 57 patients (79%) were successfully cultured and 1451 tumor fragments (95.4%) were evaluated. Fragments were scored for percentage of tumor, tumor viability and proliferation, EGF-receptor expression and presence of T-cells and macrophages. Median tumor percentage increased from 53% at day 0 to 80% at day 7. Viability and proliferation decreased after 7 days, from 90% to 30% and from 30% to 10%, respectively. Addition of EGF, folic acid and hydrocortisone can lead to improved viability and proliferation, however this was not systematically observed. No patient subgroup could be identified with higher culture success rates. Immune cells were still present at day 7, illustrating that the tumor microenvironment is sustained. EGF supplementation did not increase viability and proliferation in patients overexpressing EGF-Receptor.

Evaluating the Impact of Naltrexone on the Rat Gambling Task to Test Its Predictive Validity for Gambling Disorder.

PubMed

Di Ciano, Patricia; Le Foll, Bernard

2016-01-01

Gambling Disorder has serious consequences and no medications are currently approved for the treatment of this disorder. One factor that may make medication development difficult is the lack of animal models of gambling that would allow for the pre-clinical screening of efficacy. Despite this, there is evidence from clinical trials that opiate antagonists, in particular naltrexone, may be useful in treating gambling disorder. To-date, the effects of naltrexone on pre-clinical models of gambling have not been evaluated. The purpose of the present study was to evaluate the effects of naltrexone in an animal model of gambling, the rat gambling task (rGT), to determine whether this model has some predictive validity. The rGT is a model in which rats are given a choice of making either a response that produces a large reward or a small reward. The larger the reward, the greater the punishment, and thus this task requires that the animal inhibit the 'tempting' choice, as the smaller reward option produces overall the most number of rewards per session. People with gambling disorder chose the tempting option more, thus the rGT may provide a model of problem gambling. It was found that naltrexone improved performance on this task in a subset of animals that chose the 'tempting', disadvantageous choice, more at baseline. Thus, the results of this study suggest that the rGT should be further investigated as a pre-clinical model of gambling disorder and that further investigation into whether opioid antagonists are effective in treating Gambling Disorder may be warranted.

Saccharin Aza Bioisosteres-Synthesis and Preclinical Property Comparisons.

PubMed

Chen, Yantao; Aurell, Carl-Johan; Pettersen, Anna; Lewis, Richard J; Hayes, Martin A; Lepistö, Matti; Jonson, Anna C; Leek, Hanna; Thunberg, Linda

2017-06-08

Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B ), and two new types of aza-saccharins (clusters C and D ). We demonstrate a convenient protocol to selectively synthesize products in cluster C or D when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters C and D offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.

A modified collagen gel enhances healing outcome in a preclinical swine model of excisional wounds.

PubMed

Elgharably, Haytham; Roy, Sashwati; Khanna, Savita; Abas, Motaz; Dasghatak, Piya; Das, Amitava; Mohammed, Kareem; Sen, Chandan K

2013-01-01

Collagen-based dressings are of great interest in wound care. However, evidence supporting their mechanism of action is scanty. This work provides first results from a preclinical swine model of excisional wounds, elucidating the mechanism of action of a modified collagen gel (MCG) dressing. Following wounding, wound-edge tissue was collected at specific time intervals (3, 7, 14, and 21 days postwounding). On day 7, histological analysis showed significant increase in the length of rete ridges, suggesting improved biomechanical properties of the healing wound tissue. Rapid and transient mounting of inflammation is necessary for efficient healing. MCG significantly accelerated neutrophil and macrophage recruitment to the wound site on day 3 and day 7 with successful resolution of inflammation on day 21. MCG induced monocyte chemotactic protein-1 expression in neutrophil-like human promyelocytic leukemia-60 cells in vitro. In vivo, MCG-treated wound tissue displayed elevated vascular endothelial growth factor expression. Consistently, MCG-treated wounds displayed significantly higher abundance of endothelial cells with increased blood flow to the wound area indicating improved vascularization. This observation was explained by the finding that MCG enhanced proliferation of wound-site endothelial cells. In MCG-treated wound tissue, Masson's trichrome and picrosirius red staining showed higher abundance of collagen and increased collagen type I:III ratio. This work presents first evidence from a preclinical setting explaining how a collagen-based dressing may improve wound closure by targeting multiple key mechanisms. The current findings warrant additional studies to determine whether the responses to the MCG are different from other collagen-based products used in clinical setting. © 2013 by the Wound Healing Society.

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

PubMed

Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

2016-10-01

Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under

Modelling human skull growth: a validated computational model

PubMed Central

Marghoub, Arsalan; Johnson, David; Khonsari, Roman H.; Fagan, Michael J.; Moazen, Mehran

2017-01-01

During the first year of life, the brain grows rapidly and the neurocranium increases to about 65% of its adult size. Our understanding of the relationship between the biomechanical forces, especially from the growing brain, the craniofacial soft tissue structures and the individual bone plates of the skull vault is still limited. This basic knowledge could help in the future planning of craniofacial surgical operations. The aim of this study was to develop a validated computational model of skull growth, based on the finite-element (FE) method, to help understand the biomechanics of skull growth. To do this, a two-step validation study was carried out. First, an in vitro physical three-dimensional printed model and an in silico FE model were created from the same micro-CT scan of an infant skull and loaded with forces from the growing brain from zero to two months of age. The results from the in vitro model validated the FE model before it was further developed to expand from 0 to 12 months of age. This second FE model was compared directly with in vivo clinical CT scans of infants without craniofacial conditions (n = 56). The various models were compared in terms of predicted skull width, length and circumference, while the overall shape was quantified using three-dimensional distance plots. Statistical analysis yielded no significant differences between the male skull models. All size measurements from the FE model versus the in vitro physical model were within 5%, with one exception showing a 7.6% difference. The FE model and in vivo data also correlated well, with the largest percentage difference in size being 8.3%. Overall, the FE model results matched well with both the in vitro and in vivo data. With further development and model refinement, this modelling method could be used to assist in preoperative planning of craniofacial surgery procedures and could help to reduce reoperation rates. PMID:28566514

Modelling human skull growth: a validated computational model.

PubMed

Libby, Joseph; Marghoub, Arsalan; Johnson, David; Khonsari, Roman H; Fagan, Michael J; Moazen, Mehran

2017-05-01

During the first year of life, the brain grows rapidly and the neurocranium increases to about 65% of its adult size. Our understanding of the relationship between the biomechanical forces, especially from the growing brain, the craniofacial soft tissue structures and the individual bone plates of the skull vault is still limited. This basic knowledge could help in the future planning of craniofacial surgical operations. The aim of this study was to develop a validated computational model of skull growth, based on the finite-element (FE) method, to help understand the biomechanics of skull growth. To do this, a two-step validation study was carried out. First, an in vitro physical three-dimensional printed model and an in silico FE model were created from the same micro-CT scan of an infant skull and loaded with forces from the growing brain from zero to two months of age. The results from the in vitro model validated the FE model before it was further developed to expand from 0 to 12 months of age. This second FE model was compared directly with in vivo clinical CT scans of infants without craniofacial conditions ( n = 56). The various models were compared in terms of predicted skull width, length and circumference, while the overall shape was quantified using three-dimensional distance plots. Statistical analysis yielded no significant differences between the male skull models. All size measurements from the FE model versus the in vitro physical model were within 5%, with one exception showing a 7.6% difference. The FE model and in vivo data also correlated well, with the largest percentage difference in size being 8.3%. Overall, the FE model results matched well with both the in vitro and in vivo data. With further development and model refinement, this modelling method could be used to assist in preoperative planning of craniofacial surgery procedures and could help to reduce reoperation rates. © 2017 The Author(s).

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

PubMed

Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph J H; Garbow, Joel R

2017-05-01

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

Can anti-Vascular Endothelial Growth Factor Antibody Reverse Radiation Necrosis? A Preclinical Investigation

PubMed Central

Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph JH; Garbow, Joel R

2017-01-01

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife PerfexionTM and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4 to 12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P<0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P<0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation. PMID:28425047

Biological characterization of preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model: A multi-modality approach

PubMed Central

Garimella, Rama; Eskew, Jeff; Bhamidi, Priyanka; Vielhauer, George; Hong, Yan; Anderson, H. Clarke; Tawfik, Ossama; Rowe, Peter

2013-01-01

Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60–70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model. PMID:25688332

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

PubMed

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.

Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

PubMed Central

Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

2015-01-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.

PubMed

Winterhoff, Boris; Freyer, Luisa; Hammond, Edward; Giri, Shailendra; Mondal, Susmita; Roy, Debarshi; Teoman, Attila; Mullany, Sally A; Hoffmann, Robert; von Bismarck, Antonia; Chien, Jeremy; Block, Matthew S; Millward, Michael; Bampton, Darryn; Dredge, Keith; Shridhar, Viji

2015-05-01

Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

PubMed

Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

2018-02-01

The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

External validation of preexisting first trimester preeclampsia prediction models.

PubMed

Allen, Rebecca E; Zamora, Javier; Arroyo-Manzano, David; Velauthar, Luxmilar; Allotey, John; Thangaratinam, Shakila; Aquilina, Joseph

2017-10-01

To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Problem-Solving in the Pre-Clinical Curriculum: The Uses of Computer Simulations.

ERIC Educational Resources Information Center

Michael, Joel A.; Rovick, Allen A.

1986-01-01

Promotes the use of computer-based simulations in the pre-clinical medical curriculum as a means of providing students with opportunities for problem solving. Describes simple simulations of skeletal muscle loads, complex simulations of major organ systems and comprehensive simulation models of the entire human body. (TW)

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

PubMed Central

Walther, Sebastian; Halpern, Michael

2010-01-01

The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. PMID:27713372

Calibration and validation of rockfall models

NASA Astrophysics Data System (ADS)

Frattini, Paolo; Valagussa, Andrea; Zenoni, Stefania; Crosta, Giovanni B.

2013-04-01

Calibrating and validating landslide models is extremely difficult due to the particular characteristic of landslides: limited recurrence in time, relatively low frequency of the events, short durability of post-event traces, poor availability of continuous monitoring data, especially for small landslide and rockfalls. For this reason, most of the rockfall models presented in literature completely lack calibration and validation of the results. In this contribution, we explore different strategies for rockfall model calibration and validation starting from both an historical event and a full-scale field test. The event occurred in 2012 in Courmayeur (Western Alps, Italy), and caused serious damages to quarrying facilities. This event has been studied soon after the occurrence through a field campaign aimed at mapping the blocks arrested along the slope, the shape and location of the detachment area, and the traces of scars associated to impacts of blocks on the slope. The full-scale field test was performed by Geovert Ltd in the Christchurch area (New Zealand) after the 2011 earthquake. During the test, a number of large blocks have been mobilized from the upper part of the slope and filmed with high velocity cameras from different viewpoints. The movies of each released block were analysed to identify the block shape, the propagation path, the location of impacts, the height of the trajectory and the velocity of the block along the path. Both calibration and validation of rockfall models should be based on the optimization of the agreement between the actual trajectories or location of arrested blocks and the simulated ones. A measure that describe this agreement is therefore needed. For calibration purpose, this measure should simple enough to allow trial and error repetitions of the model for parameter optimization. In this contribution we explore different calibration/validation measures: (1) the percentage of simulated blocks arresting within a buffer of the

External validation of a Cox prognostic model: principles and methods

PubMed Central

2013-01-01

Background A prognostic model should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of model performance in a sample independent of that used to develop the model. Unlike for logistic regression models, external validation of Cox models is sparsely treated in the literature. Successful validation of a model means achieving satisfactory discrimination and calibration (prediction accuracy) in the validation sample. Validating Cox models is not straightforward because event probabilities are estimated relative to an unspecified baseline function. Methods We describe statistical approaches to external validation of a published Cox model according to the level of published information, specifically (1) the prognostic index only, (2) the prognostic index together with Kaplan-Meier curves for risk groups, and (3) the first two plus the baseline survival curve (the estimated survival function at the mean prognostic index across the sample). The most challenging task, requiring level 3 information, is assessing calibration, for which we suggest a method of approximating the baseline survival function. Results We apply the methods to two comparable datasets in primary breast cancer, treating one as derivation and the other as validation sample. Results are presented for discrimination and calibration. We demonstrate plots of survival probabilities that can assist model evaluation. Conclusions Our validation methods are applicable to a wide range of prognostic studies and provide researchers with a toolkit for external validation of a published Cox model. PMID:23496923

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

PubMed

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.

Preclinical evaluation of posterior spine stabilization devices: can the current standards represent basic everyday life activities?

PubMed

La Barbera, Luigi; Galbusera, Fabio; Wilke, Hans-Joachim; Villa, Tomaso

2016-09-01

To discuss whether the available standard methods for preclinical evaluation of posterior spine stabilization devices can represent basic everyday life activities and how to compare the results obtained with different procedures. A comparative finite element study compared ASTM F1717 and ISO 12189 standards to validated instrumented L2-L4 segments undergoing standing, upper body flexion and extension. The internal loads on the spinal rod and the maximum stress on the implant are analysed. ISO recommended anterior support stiffness and force allow for reproducing bending moments measured in vivo on an instrumented physiological segment during upper body flexion. Despite the significance of ASTM model from an engineering point of view, the overly conservative vertebrectomy model represents an unrealistic worst case scenario. A method is proposed to determine the load to apply on assemblies with different anterior support stiffnesses to guarantee a comparable bending moment and reproduce specific everyday life activities. The study increases our awareness on the use of the current standards to achieve meaningful results easy to compare and interpret.

Overview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes.

PubMed

Usary, Jerry; Darr, David Brian; Pfefferle, Adam D; Perou, Charles M

2016-03-18

Advances in the screening of new therapeutic options have significantly reduced the breast cancer death rate over the last decade. Despite these advances, breast cancer remains the second leading cause of cancer death among women. This is due in part to the complexity of the disease, which is characterized by multiple subtypes that are driven by different genetic mechanisms and that likely arise from different cell types of origin. Because these differences often drive treatment options and outcomes, it is important to select relevant preclinical model systems to study new therapeutic interventions and tumor biology. Described in this unit are the characteristics and applications of validated genetically engineered mouse models (GEMMs) of basal-like, luminal, and claudin-low human subtypes of breast cancer. These different subtypes have different clinical outcomes and require different treatment strategies. These GEMMs can be considered faithful surrogates of their human disease counterparts. They represent alternative preclinical tumor models to cell line and patient-derived xenografts for preclinical drug discovery and tumor biology studies. Copyright © 2016 John Wiley & Sons, Inc.

The case for introducing pre-registered confirmatory pharmacological pre-clinical studies.

PubMed

Kiwanuka, Olivia; Bellander, Bo-Michael; Hånell, Anders

2018-05-01

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

Nephron segment specific microRNA biomarkers of pre-clinical drug-induced renal toxicity: Opportunities and challenges

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

Nassirpour, Rounak, E-mail: Rounak.nassirpour@pfiz

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 asmore » 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.« less

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE

PubMed Central

and, Kevin D. Deane; El-Gabalawy, Hani

2014-01-01

Established and emerging data demonstrate that a ‘preclinical’ period of disease precedes the onset of clinical rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as other autoimmune rheumatic diseases (ARDs).This preclinical stage of development of disease is characterized by abnormalities in disease-related biomarkers before the onset of the clinically apparent signs and symptoms. Numerous genetic and environmental risk factors for ARDs have also been identified, and many of these factors are likely to act before the clinical appearance of tissue injury to initiate and/or propagate autoimmunity and autoimmune disease. Thus, biomarkers representative of these autoimmune processes could potentially be used in conjunction with other clinical parameters during the preclinical period of ARDs to predict the future development of clinically apparent disease. This Review focuses on the preclinical stages of RA and SLE, as our current understanding of these diseases can be used to present an overall model of the development of ARDs that might ultimately be used to develop screening programmes and preventive strategies. Important considerations for the future development of such approaches, in particular, the issues that require additional research and how they might be addressed, are also discussed. PMID:24514912

Considering sex as a biological variable in preclinical research.

PubMed

Miller, Leah R; Marks, Cheryl; Becker, Jill B; Hurn, Patricia D; Chen, Wei-Jung; Woodruff, Teresa; McCarthy, Margaret M; Sohrabji, Farida; Schiebinger, Londa; Wetherington, Cora Lee; Makris, Susan; Arnold, Arthur P; Einstein, Gillian; Miller, Virginia M; Sandberg, Kathryn; Maier, Susan; Cornelison, Terri L; Clayton, Janine A

2017-01-01

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. © FASEB.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

PubMed Central

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

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

PubMed Central

Spinello, Chiara; Laviola, Giovanni; Macrì, Simone

2016-01-01

Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes

Applicability Analysis of Validation Evidence for Biomedical Computational Models

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

Pathmanathan, Pras; Gray, Richard A.; Romero, Vicente J.

Computational modeling has the potential to revolutionize medicine the way it transformed engineering. However, despite decades of work, there has only been limited progress to successfully translate modeling research to patient care. One major difficulty which often occurs with biomedical computational models is an inability to perform validation in a setting that closely resembles how the model will be used. For example, for a biomedical model that makes in vivo clinically relevant predictions, direct validation of predictions may be impossible for ethical, technological, or financial reasons. Unavoidable limitations inherent to the validation process lead to challenges in evaluating the credibilitymore » of biomedical model predictions. Therefore, when evaluating biomedical models, it is critical to rigorously assess applicability, that is, the relevance of the computational model, and its validation evidence to the proposed context of use (COU). However, there are no well-established methods for assessing applicability. In this paper, we present a novel framework for performing applicability analysis and demonstrate its use with a medical device computational model. The framework provides a systematic, step-by-step method for breaking down the broad question of applicability into a series of focused questions, which may be addressed using supporting evidence and subject matter expertise. The framework can be used for model justification, model assessment, and validation planning. While motivated by biomedical models, it is relevant to a broad range of disciplines and underlying physics. Finally, the proposed applicability framework could help overcome some of the barriers inherent to validation of, and aid clinical implementation of, biomedical models.« less

Applicability Analysis of Validation Evidence for Biomedical Computational Models

DOE PAGES

Pathmanathan, Pras; Gray, Richard A.; Romero, Vicente J.; ...

2017-09-07

Computational modeling has the potential to revolutionize medicine the way it transformed engineering. However, despite decades of work, there has only been limited progress to successfully translate modeling research to patient care. One major difficulty which often occurs with biomedical computational models is an inability to perform validation in a setting that closely resembles how the model will be used. For example, for a biomedical model that makes in vivo clinically relevant predictions, direct validation of predictions may be impossible for ethical, technological, or financial reasons. Unavoidable limitations inherent to the validation process lead to challenges in evaluating the credibilitymore » of biomedical model predictions. Therefore, when evaluating biomedical models, it is critical to rigorously assess applicability, that is, the relevance of the computational model, and its validation evidence to the proposed context of use (COU). However, there are no well-established methods for assessing applicability. In this paper, we present a novel framework for performing applicability analysis and demonstrate its use with a medical device computational model. The framework provides a systematic, step-by-step method for breaking down the broad question of applicability into a series of focused questions, which may be addressed using supporting evidence and subject matter expertise. The framework can be used for model justification, model assessment, and validation planning. While motivated by biomedical models, it is relevant to a broad range of disciplines and underlying physics. Finally, the proposed applicability framework could help overcome some of the barriers inherent to validation of, and aid clinical implementation of, biomedical models.« less

Cross-validation to select Bayesian hierarchical models in phylogenetics.

PubMed

Duchêne, Sebastián; Duchêne, David A; Di Giallonardo, Francesca; Eden, John-Sebastian; Geoghegan, Jemma L; Holt, Kathryn E; Ho, Simon Y W; Holmes, Edward C

2016-05-26

Recent developments in Bayesian phylogenetic models have increased the range of inferences that can be drawn from molecular sequence data. Accordingly, model selection has become an important component of phylogenetic analysis. Methods of model selection generally consider the likelihood of the data under the model in question. In the context of Bayesian phylogenetics, the most common approach involves estimating the marginal likelihood, which is typically done by integrating the likelihood across model parameters, weighted by the prior. Although this method is accurate, it is sensitive to the presence of improper priors. We explored an alternative approach based on cross-validation that is widely used in evolutionary analysis. This involves comparing models according to their predictive performance. We analysed simulated data and a range of viral and bacterial data sets using a cross-validation approach to compare a variety of molecular clock and demographic models. Our results show that cross-validation can be effective in distinguishing between strict- and relaxed-clock models and in identifying demographic models that allow growth in population size over time. In most of our empirical data analyses, the model selected using cross-validation was able to match that selected using marginal-likelihood estimation. The accuracy of cross-validation appears to improve with longer sequence data, particularly when distinguishing between relaxed-clock models. Cross-validation is a useful method for Bayesian phylogenetic model selection. This method can be readily implemented even when considering complex models where selecting an appropriate prior for all parameters may be difficult.

Imaging biomarkers to predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer

PubMed Central

Shah, Chirayu; Miller, Todd W.; Wyatt, Shelby K.; McKinley, Eliot T.; Olivares, Maria Graciela; Sanchez, Violeta; Nolting, Donald D.; Buck, Jason R.; Zhao, Ping; Ansari, M. Sib; Baldwin, Ronald M.; Gore, John C.; Schiff, Rachel; Arteaga, Carlos L.; Manning, H. Charles

2010-01-01

Purpose To evaluate non-invasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and non-responding tumor-bearing cohorts. Experimental Design Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin-V accumulation), glucose metabolism ([18F]FDG-PET), and proliferation ([18F]FLT-PET) were evaluated throughout a bi-weekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical (IHC) analysis of cleaved caspase-3, phosphorylated AKT (p-AKT) and Ki67. Results NIR700-Annexin-V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed, but not in non-responding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and IHC analysis. Conclusions Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2(+) tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not appear to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer. PMID:19584166

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

PubMed

Pop, Andreea S; Gomez-Mancilla, Baltazar; Neri, Giovanni; Willemsen, Rob; Gasparini, Fabrizio

2014-03-01

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

Validation of a preclinical model of diethylnitrosamine-induced hepatic neoplasia in Yucatan miniature pigs

PubMed Central

Mitchell, Jennifer; Tinkey, Peggy T.; Avritscher, Rony; Van Pelt, Carolyn; Eskandari, Ghazaleh; George, Suraj Konnath; Xiao, Lianchun; Cressman, Erik; Morris, Jeffrey S.; Rashid, Asif; Kaseb, Ahmed O.; Amin, Hesham M.; Uthamanthil, Rajesh

2016-01-01

Objective The purpose of this study was to reduce time to tumor onset in a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) swine model via partial liver embolization (PLE) and to characterize the model for use in translational research. Methods Eight Yucatan miniature pigs were injected intraperitoneally with either saline (n=2) or DEN (n=6) solution weekly for 12 weeks. Three of the DEN-treated pigs underwent PLE. Animals underwent periodic radiological evaluation, liver biopsy, and blood sampling, and full necropsy was performed at study termination (~29 months). Results All DEN-treated pigs developed hepatic adenoma and HCC. PLE accelerated the time to adenoma development but not to HCC development. Biomarker analysis results showed that IGF1 levels decreased in all DEN-treated pigs, as functional liver capacity decreased with progression of HCC. VEGF and IL-6 levels were positively correlated with disease progression. Immunohistochemical probing of HCC tissues demonstrated the expression of several important survival-promoting proteins. Conclusion To our knowledge, we are the first to demonstrate accelerated development of hepatic neoplasia in Yucatan miniature pigs. Our HCC swine model closely mimics the human condition (i.e., progressive disease stages and expression of relevant molecular markers) and is a viable translational model. PMID:27305144

The neuropsychology of normal aging and preclinical Alzheimer's disease.

PubMed

Caselli, Richard J; Locke, Dona E C; Dueck, Amylou C; Knopman, David S; Woodruff, Bryan K; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S; Reiman, Eric M

2014-01-01

A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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

PubMed

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.

Individual differences in the behavioral effects of nicotine: A review of the preclinical animal literature

PubMed Central

Falco, Adriana M.; Bevins, Rick A.

2015-01-01

Not everyone who tries tobacco or other nicotine-containing products becomes a long-term user. Certain traits or factors that are differentially present in these individuals must be able to help health care providers and researchers determine who is more likely to become chronic users of nicotine-containing products. Some of these factors, particularly sensation-seeking/novelty, impulsivity, and anxiety, lend themselves to the creation of animal models of reactivity to nicotine. These models of reactivity to nicotine can improve the translational aspects of preclinical animal research on nicotine-induced behaviors and treatments in order to help reduce negative outcomes in human populations. The goal of this review is to evaluate the current status of animal models of individual differences that serve to predict the later behavioral effects of nicotine. The limited utility and inconsistency of existing novelty models is considered, as well as the promise of impulsivity and anxiety models in preclinical animal populations. Finally, other models that could be employed to extend the benefit of the current research are examined. PMID:26410616

Model Validation Against The Modelers’ Data Archive

DTIC Science & Technology

2014-08-01

completion of the planned Jack Rabbit 2 field trials. The relevant task for the effort addressed here is Task 4 of the current Interagency Agreement, as...readily simulates the Prairie Grass sulfur dioxide plumes. Also, Jack Rabbit II field trials are set to be completed during FY16. Once these data are...available, they will also be used to validate the combined models. This validation may prove to be more useful, as the Jack Rabbit II will release

Non-invasive, Contrast-enhanced Spectral Imaging of Breast Cancer Signatures in Preclinical Animal Models In vivo

PubMed Central

Ramanujan, V Krishnan; Ren, Songyang; Park, Sangyong; Farkas, Daniel L

2011-01-01

We report here a non-invasive multispectral imaging platform for monitoring spectral reflectance and fluorescence images from primary breast carcinoma and metastatic lymph nodes in preclinical rat model in vivo. The system is built around a monochromator light source and an acousto-optic tunable filter (AOTF) for spectral selection. Quantitative analysis of the measured reflectance profiles in the presence of a widely-used lymphazurin dye clearly demonstrates the capability of the proposed imaging platform to detect tumor-associated spectral signatures in the primary tumors as well as metastatic lymphatics. Tumor-associated changes in vascular oxygenation and interstitial fluid pressure are reasoned to be the physiological sources of the measured reflectance profiles. We also discuss the translational potential of our imaging platform in intra-operative clinical setting. PMID:21572915

Modeling complex treatment strategies: construction and validation of a discrete event simulation model for glaucoma.

PubMed

van Gestel, Aukje; Severens, Johan L; Webers, Carroll A B; Beckers, Henny J M; Jansonius, Nomdo M; Schouten, Jan S A G

2010-01-01

Discrete event simulation (DES) modeling has several advantages over simpler modeling techniques in health economics, such as increased flexibility and the ability to model complex systems. Nevertheless, these benefits may come at the cost of reduced transparency, which may compromise the model's face validity and credibility. We aimed to produce a transparent report on the construction and validation of a DES model using a recently developed model of ocular hypertension and glaucoma. Current evidence of associations between prognostic factors and disease progression in ocular hypertension and glaucoma was translated into DES model elements. The model was extended to simulate treatment decisions and effects. Utility and costs were linked to disease status and treatment, and clinical and health economic outcomes were defined. The model was validated at several levels. The soundness of design and the plausibility of input estimates were evaluated in interdisciplinary meetings (face validity). Individual patients were traced throughout the simulation under a multitude of model settings to debug the model, and the model was run with a variety of extreme scenarios to compare the outcomes with prior expectations (internal validity). Finally, several intermediate (clinical) outcomes of the model were compared with those observed in experimental or observational studies (external validity) and the feasibility of evaluating hypothetical treatment strategies was tested. The model performed well in all validity tests. Analyses of hypothetical treatment strategies took about 30 minutes per cohort and lead to plausible health-economic outcomes. There is added value of DES models in complex treatment strategies such as glaucoma. Achieving transparency in model structure and outcomes may require some effort in reporting and validating the model, but it is feasible.

Benefits attained from space flight in pre-clinical evaluation of candidate drugs

NASA Astrophysics Data System (ADS)

Stodieck, Louis S.; Bateman, Ted; Ayers, Reed; Ferguson, Virginia; Simske, Steve

1998-01-01

Modern medicine has made great strides in recent decades. The promises of biotechnology and advances in gene identification and manipulation offer tremendous potential for treatment of disease. However, developing new drug therapies by biotechnology and pharmaceutical companies is still a very costly and time consuming process. One of the important milestones in drug development is the successful completion of preclinical evaluation. During this phase, drug candidates must be shown to be safe, yet effective as a treatment of the target disease or disorder. Critical for preclinical testing is the availability of biomedical test models that adequately mimic the target disease. A good model will 1) allow confident prediction of a drug's effects before expensive clinical trials are begun, 2) provide convincing data for use in an FDA new drug application and 3) minimize the time required for testing. Space flight may offer a completely unique and new set of biomedical models for use in pharmaceutical testing. This paper highlights some examples of recent experiments done in space to test new compounds for Chiron, (Emmeryville, CA) and discusses the importance of the International Space Station to greatly expand such commercial opportunities.

Preclinical studies of alcohol binge drinking

PubMed Central

Crabbe, John C.; Harris, R. Adron; Koob, George F.

2011-01-01

Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID:21272009

[Preclinical evaluation of the safety of biotechnology products: specific aspects].

PubMed

Descotes, Jacques; Ravel, Guillaume; Vial, Thierry

2003-01-01

Biotechnology-derived products represent a class of increasingly numerous drugs. One of their major characteristics is extreme diversity, which requires specific approaches for the preclinical evaluation of their safety. The selection of relevant animal species is not easy, as most of these products are human-specific. Thus, only one species will often be used, i.e. primates. As most of these products are large molecules, they can be directly immunogenic. When they are human-specific, no animal model is available to predict the risk. Many biotechnology-derived products have an expected influence on the immune system. This must be taken into account in the preclinical strategy of immunotoxicity evaluation that is now required for every new drug. As conventional toxicity testing is generally limited, safety pharmacology studies should include more than the core battery of assays required by current guidelines in order to complement missing data as much as possible. Because of these particularities, a comprehensive investigation of metabolism and pharmacokinetics is not usually needed. Some products can cross-react with cellular components not intended as therapeutic targets. It is, therefore, essential to rule out the risk of possible cross-reactions that can result in adverse effects. Finally, viral safety is a crucial component of the preclinical safety evaluation of these products. Overall, biotechnology-derived products raise specific issues because of their innovative and original characteristics, and it is difficult to address all these issues if not by using a case-by-case approach.

Animal models of addiction

PubMed Central

Spanagel, Rainer

2017-01-01

In recent years, animal models in psychiatric research have been criticized for their limited translational value to the clinical situation. Failures in clinical trials have thus often been attributed to the lack of predictive power of preclinical animal models. Here, I argue that animal models of voluntary drug intake—under nonoperant and operant conditions—and addiction models based on the Diagnostic and Statistical Manual of Mental Disorders are crucial and informative tools for the identification of pathological mechanisms, target identification, and drug development. These models provide excellent face validity, and it is assumed that the neurochemical and neuroanatomical substrates involved in drug-intake behavior are similar in laboratory rodents and humans. Consequently, animal models of drug consumption and addiction provide predictive validity. This predictive power is best illustrated in alcohol research, in which three approved medications—acamprosate, naltrexone, and nalmefene—were developed by means of animal models and then successfully translated into the clinical situation. PMID:29302222

The relevance of human stem cell-derived organoid models for epithelial translational medicine

PubMed Central

Hynds, Robert E.; Giangreco, Adam

2014-01-01

Epithelial organ remodeling is a major contributing factor to worldwide death and disease, costing healthcare systems billions of dollars every year. Despite this, most fundamental epithelial organ research fails to produce new therapies and mortality rates for epithelial organ diseases remain unacceptably high. In large part, this failure in translating basic epithelial research into clinical therapy is due to a lack of relevance in existing preclinical models. To correct this, new models are required that improve preclinical target identification, pharmacological lead validation, and compound optimization. In this review, we discuss the relevance of human stem cell-derived, three-dimensional organoid models for addressing each of these challenges. We highlight the advantages of stem cell-derived organoid models over existing culture systems, discuss recent advances in epithelial tissue-specific organoids, and present a paradigm for using organoid models in human translational medicine. PMID:23203919

A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

PubMed

Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

2010-09-01

Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

PubMed Central

Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

2016-01-01

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

A comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements.

PubMed

Abdelgaied, A; Fisher, J; Jennings, L M

2018-02-01

A more robust pre-clinical wear simulation framework is required in order to simulate wider and higher ranges of activities, observed in different patient populations such as younger more active patients. Such a framework will help to understand and address the reported higher failure rates for younger and more active patients (National_Joint_Registry, 2016). The current study has developed and validated a comprehensive combined experimental and computational framework for pre-clinical wear simulation of total knee replacements (TKR). The input mechanical (elastic modulus and Poisson's ratio) and wear parameters of the moderately cross-linked ultra-high molecular weight polyethylene (UHMWPE) bearing material were independently measured from experimental studies under realistic test conditions, similar to the loading conditions found in the total knee replacements. The wear predictions from the computational wear simulation were validated against the direct experimental wear measurements for size 3 Sigma curved total knee replacements (DePuy, UK) in an independent experimental wear simulation study under three different daily activities; walking, deep squat, and stairs ascending kinematic conditions. The measured compressive mechanical properties of the moderately cross-linked UHMWPE material were more than 20% lower than that reported in the literature under tensile test conditions. The pin-on-plate wear coefficient of moderately cross-linked UHMWPE was significantly dependant of the contact stress and the degree of cross-shear at the articulating surfaces. The computational wear predictions for the TKR from the current framework were consistent and in a good agreement with the independent full TKR experimental wear simulation measurements, with 0.94 coefficient of determination of the framework. In addition, the comprehensive combined experimental and computational framework was able to explain the complex experimental wear trends from the three different daily

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

PubMed

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.

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

PubMed Central

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

External model validation of binary clinical risk prediction models in cardiovascular and thoracic surgery.

PubMed

Hickey, Graeme L; Blackstone, Eugene H

2016-08-01

Clinical risk-prediction models serve an important role in healthcare. They are used for clinical decision-making and measuring the performance of healthcare providers. To establish confidence in a model, external model validation is imperative. When designing such an external model validation study, thought must be given to patient selection, risk factor and outcome definitions, missing data, and the transparent reporting of the analysis. In addition, there are a number of statistical methods available for external model validation. Execution of a rigorous external validation study rests in proper study design, application of suitable statistical methods, and transparent reporting. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Development of a Conservative Model Validation Approach for Reliable Analysis

DTIC Science & Technology

2015-01-01

CIE 2015 August 2-5, 2015, Boston, Massachusetts, USA [DRAFT] DETC2015-46982 DEVELOPMENT OF A CONSERVATIVE MODEL VALIDATION APPROACH FOR RELIABLE...obtain a conservative simulation model for reliable design even with limited experimental data. Very little research has taken into account the...3, the proposed conservative model validation is briefly compared to the conventional model validation approach. Section 4 describes how to account

The neuropsychology of normal aging and preclinical Alzheimer’s disease

PubMed Central

Caselli, Richard J.; Locke, Dona E.C.; Dueck, Amylou C.; Knopman, David S.; Woodruff, Bryan K.; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S.; Reiman, Eric M.

2013-01-01

Background An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Methods 71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups. Results There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups. Conclusions While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design. PMID:23541188

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

PubMed Central

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Ushering in the study and treatment of preclinical Alzheimer disease.

PubMed

Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

2013-07-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

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

PubMed

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.

A mentorship-based preclinical elective increases exposure, confidence, and interest in surgery.

PubMed

Drolet, Brian C; Sangisetty, Suma; Mulvaney, Patrick M; Ryder, Beth A; Cioffi, William G

2014-02-01

The predicted shortage of surgeons is of growing concern with declining medical student interest in surgical careers. We hypothesized that earlier exposure to operative experiences and the establishment of resident mentors through a preclinical elective would enhance student confidence and interest in surgery. We developed a preclinical elective in surgery, which served as an organized curriculum for junior medical students to experience surgery through a paired resident-mentorship model. We assessed student exposure and confidence with clinical activities before and after the elective (N = 24, 100% response rate). We compared these students with a cohort of peers not enrolled in the elective (N = 147, 67% response rate). We found significantly improved confidence (2.8 vs 4.4) and clinical exposure (2.4 vs 4.3) before versus after the elective, with precourse scores equal to matched peers. This elective incorporates elements that have been shown to positively influence student decision making in surgical career choice. The mentorship model promotes residents as educators, whereas the elective provides a means for early identification of students interested in surgery. Published by Elsevier Inc.

Development of a QDots 800 based fluorescent solid phantom for validation of NIRF imaging platforms

NASA Astrophysics Data System (ADS)

Zhu, Banghe; Sevick-Muraca, Eva M.

2013-02-01

Over the past decade, we developed near-infrared fluorescence (NIRF) devices for non-invasive lymphatic imaging using microdosages of ICG in humans and for detection of lymph node metastasis in animal models mimicking metastatic human prostate cancer. To validate imaging, a NIST traceable phantom is needed so that developed "first-inhumans" drugs may be used with different luorescent imaging platforms. In this work, we developed a QDots 800 based fluorescent solid phantom for installation and operational qualification of clinical and preclinical, NIRF imaging devices. Due to its optical clearance, polyurethane was chosen as the base material. Titanium dioxide was used as the scattering agent because of its miscibility in polyurethane. QDots 800 was chosen owing to its stability and NIR emission spectra. A first phantom was constructed for evaluation of the noise floor arising from excitation light leakage, a phenomenon that can be minimized during engineering and design of fluorescent imaging systems. A second set of phantoms were constructed to enable quantification of device sensitivity associated with our preclinical and clinical devices. The phantoms have been successfully applied for installation and operational qualification of our preclinical and clinical devices. Assessment of excitation light leakage provides a figure of merit for "noise floor" and imaging sensitivity can be used to benchmark devices for specific imaging agents.

Validation of a Monte Carlo simulation of the Inveon PET scanner using GATE

NASA Astrophysics Data System (ADS)

Lu, Lijun; Zhang, Houjin; Bian, Zhaoying; Ma, Jianhua; Feng, Qiangjin; Chen, Wufan

2016-08-01

The purpose of this study is to validate the application of GATE (Geant4 Application for Tomographic Emission) Monte Carlo simulation toolkit in order to model the performance characteristics of Siemens Inveon small animal PET system. The simulation results were validated against experimental/published data in accordance with the NEMA NU-4 2008 protocol for standardized evaluation of spatial resolution, sensitivity, scatter fraction (SF) and noise equivalent counting rate (NECR) of a preclinical PET system. An agreement of less than 18% was obtained between the radial, tangential and axial spatial resolutions of the simulated and experimental results. The simulated peak NECR of mouse-size phantom agreed with the experimental result, while for the rat-size phantom simulated value was higher than experimental result. The simulated and experimental SFs of mouse- and rat- size phantom both reached an agreement of less than 2%. It has been shown the feasibility of our GATE model to accurately simulate, within certain limits, all major performance characteristics of Inveon PET system.

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

PubMed

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.

Stress, Burnout and Coping Strategies in Preclinical Medical Students.

PubMed

Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-02-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

Stress, Burnout and Coping Strategies in Preclinical Medical Students

PubMed Central

Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-01-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students’ stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted. PMID:27042604

Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells

PubMed Central

Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F; Avril, Marie-Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry

2012-01-01

Xeroderma pigmentosum (XP) is a devastating disease associated with dramatic skin cancer proneness. XP cells are deficient in nucleotide excision repair (NER) of bulky DNA adducts including ultraviolet (UV)-induced mutagenic lesions. Approaches of corrective gene transfer in NER-deficient keratinocyte stem cells hold great hope for the long-term treatment of XP patients. To face this challenge, we developed a retrovirus-based strategy to safely transduce the wild-type XPC gene into clonogenic human primary XP-C keratinocytes. De novo expression of XPC was maintained in both mass population and derived independent candidate stem cells (holoclones) after more than 130 population doublings (PD) in culture upon serial propagation (>1040 cells). Analyses of retrovirus integration sequences in isolated keratinocyte stem cells suggested the absence of adverse effects such as oncogenic activation or clonal expansion. Furthermore, corrected XP-C keratinocytes exhibited full NER capacity as well as normal features of epidermal differentiation in both organotypic skin cultures and in a preclinical murine model of human skin regeneration in vivo. The achievement of a long-term genetic correction of XP-C epidermal stem cells constitutes the first preclinical model of ex vivo gene therapy for XP-C patients. PMID:22068429

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

PubMed

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.

Applicability of Monte Carlo cross validation technique for model development and validation using generalised least squares regression

NASA Astrophysics Data System (ADS)

Haddad, Khaled; Rahman, Ataur; A Zaman, Mohammad; Shrestha, Surendra

2013-03-01

SummaryIn regional hydrologic regression analysis, model selection and validation are regarded as important steps. Here, the model selection is usually based on some measurements of goodness-of-fit between the model prediction and observed data. In Regional Flood Frequency Analysis (RFFA), leave-one-out (LOO) validation or a fixed percentage leave out validation (e.g., 10%) is commonly adopted to assess the predictive ability of regression-based prediction equations. This paper develops a Monte Carlo Cross Validation (MCCV) technique (which has widely been adopted in Chemometrics and Econometrics) in RFFA using Generalised Least Squares Regression (GLSR) and compares it with the most commonly adopted LOO validation approach. The study uses simulated and regional flood data from the state of New South Wales in Australia. It is found that when developing hydrologic regression models, application of the MCCV is likely to result in a more parsimonious model than the LOO. It has also been found that the MCCV can provide a more realistic estimate of a model's predictive ability when compared with the LOO.

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib.

PubMed

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.

Model Validation | Center for Cancer Research

Cancer.gov

Research Investigation and Animal Model Validation This activity is also under development and thus far has included increasing pathology resources, delivering pathology services, as well as using imaging and surgical methods to develop and refine animal models in collaboration with other CCR investigators.

Quantitative model validation of manipulative robot systems

NASA Astrophysics Data System (ADS)

Kartowisastro, Iman Herwidiana

This thesis is concerned with applying the distortion quantitative validation technique to a robot manipulative system with revolute joints. Using the distortion technique to validate a model quantitatively, the model parameter uncertainties are taken into account in assessing the faithfulness of the model and this approach is relatively more objective than the commonly visual comparison method. The industrial robot is represented by the TQ MA2000 robot arm. Details of the mathematical derivation of the distortion technique are given which explains the required distortion of the constant parameters within the model and the assessment of model adequacy. Due to the complexity of a robot model, only the first three degrees of freedom are considered where all links are assumed rigid. The modelling involves the Newton-Euler approach to obtain the dynamics model, and the Denavit-Hartenberg convention is used throughout the work. The conventional feedback control system is used in developing the model. The system behavior to parameter changes is investigated as some parameters are redundant. This work is important so that the most important parameters to be distorted can be selected and this leads to a new term called the fundamental parameters. The transfer function approach has been chosen to validate an industrial robot quantitatively against the measured data due to its practicality. Initially, the assessment of the model fidelity criterion indicated that the model was not capable of explaining the transient record in term of the model parameter uncertainties. Further investigations led to significant improvements of the model and better understanding of the model properties. After several improvements in the model, the fidelity criterion obtained was almost satisfied. Although the fidelity criterion is slightly less than unity, it has been shown that the distortion technique can be applied in a robot manipulative system. Using the validated model, the importance of

Economic analysis of model validation for a challenge problem

DOE PAGES

Paez, Paul J.; Paez, Thomas L.; Hasselman, Timothy K.

2016-02-19

It is now commonplace for engineers to build mathematical models of the systems they are designing, building, or testing. And, it is nearly universally accepted that phenomenological models of physical systems must be validated prior to use for prediction in consequential scenarios. Yet, there are certain situations in which testing only or no testing and no modeling may be economically viable alternatives to modeling and its associated testing. This paper develops an economic framework within which benefit–cost can be evaluated for modeling and model validation relative to other options. The development is presented in terms of a challenge problem. Asmore » a result, we provide a numerical example that quantifies when modeling, calibration, and validation yield higher benefit–cost than a testing only or no modeling and no testing option.« less

Model-Based Verification and Validation of Spacecraft Avionics

NASA Technical Reports Server (NTRS)

Khan, M. Omair; Sievers, Michael; Standley, Shaun

2012-01-01

Verification and Validation (V&V) at JPL is traditionally performed on flight or flight-like hardware running flight software. For some time, the complexity of avionics has increased exponentially while the time allocated for system integration and associated V&V testing has remained fixed. There is an increasing need to perform comprehensive system level V&V using modeling and simulation, and to use scarce hardware testing time to validate models; the norm for thermal and structural V&V for some time. Our approach extends model-based V&V to electronics and software through functional and structural models implemented in SysML. We develop component models of electronics and software that are validated by comparison with test results from actual equipment. The models are then simulated enabling a more complete set of test cases than possible on flight hardware. SysML simulations provide access and control of internal nodes that may not be available in physical systems. This is particularly helpful in testing fault protection behaviors when injecting faults is either not possible or potentially damaging to the hardware. We can also model both hardware and software behaviors in SysML, which allows us to simulate hardware and software interactions. With an integrated model and simulation capability we can evaluate the hardware and software interactions and identify problems sooner. The primary missing piece is validating SysML model correctness against hardware; this experiment demonstrated such an approach is possible.

68Ga-DOTATOC and FDG PET Imaging of Preclinical Neuroblastoma Models.

PubMed

Provost, Claire; Prignon, Aurélie; Cazes, Alex; Combaret, Valérie; Delattre, Olivier; Janoueix-Lerosey, Isabelle; Montravers, Françoise; Talbot, Jean-Noël

2016-09-01

Somatostatine receptors subtype 2 (SSTR2) are regarded as a potential target in neuroblastoma (NB) for imaging and promising therapeutic approaches. The purpose of this study was to evaluate and compare the SSTR2 status by (68)Ga-[tetraxetan-D-Phe1, Tyr3]-octreotide ((68)Ga-DOTATOC) positron-emission tomography (PET) and the tumour metabolic activity by (18)F-fluorodeoxyglucose (FDG) PET in different experimental models of NB. Three cell lines of human NB with different levels of expression of SSTR2 were grafted into nude mice. Animals were imaged with FDG and (68)Ga-DOTATOC and the maximum standardized uptake value (SUVmax) was determined to quantify tracer uptake. Ex vivo biodistribution of (68)Ga-DOTATOC and immunohistochemical analysis of NB xenografts were performed. Compared with FDG, the SUVmax of (68)Ga-DOTATOC uptake by the tumour was lower but the ratio to background was higher; there was a strong positive correlation between SUVmax values observed with the two tracers (r(2)=0.65). Sorting the cell lines according to uptake of FDG or (68)Ga-DOTATOC, injected activity per gram of tissue, Ki67 index or expression of SSTR2 assessed visually led to the same classification. (68)Ga-DOTATOC allows preclinical imaging of NB according to the intensity of the expression of SSTR2. In contrast with what has been reported for neuroendocrine tumours, in this NB model, the (68)Ga-DOTATOC uptake was positively correlated with FDG uptake and with Ki67 index, usual markers of tumour aggressiveness. If confirmed in humans, this result would favour a theranostic application of (68)Ga-DOTATOC in NB, even in advanced stages. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Novel application and serial evaluation of tissue-engineered portal vein grafts in a murine model.

PubMed

Maxfield, Mark W; Stacy, Mitchel R; Kurobe, Hirotsugu; Tara, Shuhei; Yi, Tai; Cleary, Muriel A; Zhuang, Zhen W; Rodriguez-Davalos, Manuel I; Emre, Sukru H; Iwakiri, Yasuko; Shinoka, Toshiharu; Breuer, Christopher K

2017-12-01

Surgical management of pediatric extrahepatic portal vein obstruction requires meso-Rex bypass using autologous or synthetic grafts. Tissue-engineered vascular grafts (TEVGs) provide an alternative, but no validated animal models using portal TEVGs exist. Herein, we preclinically assess TEVGs as portal vein bypass grafts. TEVGs were implanted as portal vein interposition conduits in SCID-beige mice, monitored by ultrasound and micro-computed tomography, and histologically assessed postmortem at 12 months. TEVGs remained patent for 12 months. Histologic analysis demonstrated formation of neovessels that resembled native portal veins, with similar content of smooth muscle cells, collagen type III and elastin. TEVGs are feasible portal vein conduits in a murine model. Further preclinical evaluation of TEVGs may facilitate pediatric clinical translation.

Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

DTIC Science & Technology

2014-11-01

LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 39 19b. TELEPHONE...for this mouse cohort was included in Figure 1. Out of 23 GFAP tv- a; p53 floxed mice infected with RCAS-PDGF-B and RCAS-Cre, 18 developed...being used as part of the DIPG preclinical consortium (together with several laboratories that are using human DIPG xenografts ) to help prioritize

Characterization of novel preclinical dose distributions for micro irradiator

NASA Astrophysics Data System (ADS)

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.

Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.

PubMed

Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; Deweese, Theodore L; Herman, Joseph M

2012-04-01

We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

PubMed Central

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana”) in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance. PMID:28469427

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

PubMed

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

PubMed Central

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-01-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 108, 2 × 109 and 2 × 1010 colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 109 CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 1010 CFU). The challenge dose, 2 × 1010 CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. PMID:24028276

Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.

PubMed

Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie

2016-09-21

We show that variability in general levels of drug sensitivity in pre-clinical cancer models confounds biomarker discovery. However, using a very large panel of cell lines, each treated with many drugs, we could estimate a general level of sensitivity to all drugs in each cell line. By conditioning on this variable, biomarkers were identified that were more likely to be effective in clinical trials than those identified using a conventional uncorrected approach. We find that differences in general levels of drug sensitivity are driven by biologically relevant processes. We developed a gene expression based method that can be used to correct for this confounder in future studies.

Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.

PubMed

Xu, Chunxiao; Zhang, Yanping; Rolfe, P Alexander; Hernández, Vivian M; Guzman, Wilson; Kradjian, Giorgio; Marelli, Bo; Qin, Guozhong; Qi, Jin; Wang, Hong; Yu, Huakui; Tighe, Robert; Lo, Kin-Ming; English, Jessie M; Radvanyi, Laszlo; Lan, Yan

2017-10-01

Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies. Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt - mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8 + T cells was evaluated by ELISpot assay. Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8 + T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8 + T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy. Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR . ©2017 American Association for Cancer Research.

Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks

PubMed Central

Xiong, Jianghui; Liu, Juan; Rayner, Simon; Tian, Ze; Li, Yinghui; Chen, Shanguang

2010-01-01

The high rates of failure in oncology drug clinical trials highlight the problems of using pre-clinical data to predict the clinical effects of drugs. Patient population heterogeneity and unpredictable physiology complicate pre-clinical cancer modeling efforts. We hypothesize that gene networks associated with cancer outcome in heterogeneous patient populations could serve as a reference for identifying drug effects. Here we propose a novel in vivo genetic interaction which we call ‘synergistic outcome determination’ (SOD), a concept similar to ‘Synthetic Lethality’. SOD is defined as the synergy of a gene pair with respect to cancer patients' outcome, whose correlation with outcome is due to cooperative, rather than independent, contributions of genes. The method combines microarray gene expression data with cancer prognostic information to identify synergistic gene-gene interactions that are then used to construct interaction networks based on gene modules (a group of genes which share similar function). In this way, we identified a cluster of important epigenetically regulated gene modules. By projecting drug sensitivity-associated genes on to the cancer-specific inter-module network, we defined a perturbation index for each drug based upon its characteristic perturbation pattern on the inter-module network. Finally, by calculating this index for compounds in the NCI Standard Agent Database, we significantly discriminated successful drugs from a broad set of test compounds, and further revealed the mechanisms of drug combinations. Thus, prognosis-guided synergistic gene-gene interaction networks could serve as an efficient in silico tool for pre-clinical drug prioritization and rational design of combinatorial therapies. PMID:21085674

Real-time remote scientific model validation

NASA Technical Reports Server (NTRS)

Frainier, Richard; Groleau, Nicolas

1994-01-01

This paper describes flight results from the use of a CLIPS-based validation facility to compare analyzed data from a space life sciences (SLS) experiment to an investigator's preflight model. The comparison, performed in real-time, either confirms or refutes the model and its predictions. This result then becomes the basis for continuing or modifying the investigator's experiment protocol. Typically, neither the astronaut crew in Spacelab nor the ground-based investigator team are able to react to their experiment data in real time. This facility, part of a larger science advisor system called Principal Investigator in a Box, was flown on the space shuttle in October, 1993. The software system aided the conduct of a human vestibular physiology experiment and was able to outperform humans in the tasks of data integrity assurance, data analysis, and scientific model validation. Of twelve preflight hypotheses associated with investigator's model, seven were confirmed and five were rejected or compromised.

Validation of Computational Models in Biomechanics

PubMed Central

Henninger, Heath B.; Reese, Shawn P.; Anderson, Andrew E.; Weiss, Jeffrey A.

2010-01-01

The topics of verification and validation (V&V) have increasingly been discussed in the field of computational biomechanics, and many recent articles have applied these concepts in an attempt to build credibility for models of complex biological systems. V&V are evolving techniques that, if used improperly, can lead to false conclusions about a system under study. In basic science these erroneous conclusions may lead to failure of a subsequent hypothesis, but they can have more profound effects if the model is designed to predict patient outcomes. While several authors have reviewed V&V as they pertain to traditional solid and fluid mechanics, it is the intent of this manuscript to present them in the context of computational biomechanics. Specifically, the task of model validation will be discussed with a focus on current techniques. It is hoped that this review will encourage investigators to engage and adopt the V&V process in an effort to increase peer acceptance of computational biomechanics models. PMID:20839648

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

PubMed

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 <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an 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.

Performance Evaluation of a Dedicated Preclinical PET/CT System for the Assessment of Mineralization Process in a Mouse Model of Atherosclerosis.

PubMed

Rucher, Guillaume; Cameliere, Lucie; Fendri, Jihene; Abbas, Ahmed; Dupont, Kevin; Kamel, Said; Delcroix, Nicolas; Dupont, Axel; Berger, Ludovic; Manrique, Alain

2018-04-30

The purpose of this study was to assess the impact of positron emission tomography/X-ray computed tomography (PET/CT) acquisition and reconstruction parameters on the assessment of mineralization process in a mouse model of atherosclerosis. All experiments were performed on a dedicated preclinical PET/CT system. CT was evaluated using five acquisition configurations using both a tungsten wire phantom for in-plane resolution assessment and a bar pattern phantom for cross-plane resolution. Furthermore, the radiation dose of these acquisition configurations was calculated. The PET system was assessed using longitudinal line sources to determine the optimal reconstruction parameters by measuring central resolution and its coefficient of variation. An in vivo PET study was performed using uremic ApoE -/- , non-uremic ApoE -/- , and control mice to evaluate optimal PET reconstruction parameters for the detection of sodium [ 18 F]fluoride (Na[ 18 F]F) aortic uptake and for quantitative measurement of Na[ 18 F]F bone influx (Ki) with a Patlak analysis. For CT, the use of 1 × 1 and 2 × 2 binning detector mode increased both in-plane and cross-plane resolution. However, resolution improvement (163 to 62 μm for in-plane resolution) was associated with an important radiation dose increase (1.67 to 32.78 Gy). With PET, 3D-ordered subset expectation maximization (3D-OSEM) algorithm increased the central resolution compared to filtered back projection (1.42 ± 0.35 mm vs. 1.91 ± 0.08, p < 0.001). The use of 3D-OSEM with eight iterations and a zoom factor 2 yielded optimal PET resolution for preclinical study (FWHM = 0.98 mm). These PET reconstruction parameters allowed the detection of Na[ 18 F]F aortic uptake in 3/14 ApoE -/- mice and demonstrated a decreased Ki in uremic ApoE -/- compared to non-uremic ApoE -/- and control mice (p < 0.006). Optimizing reconstruction parameters significantly impacted on the assessment of mineralization process

A Modified Collagen Gel Enhances Healing Outcome in a Pre-Clinical Swine Model of Excisional Wounds

PubMed Central

Elgharably, Haytham; Roy, Sashwati; Khanna, Savita; Abas, Motaz; DasGhatak, Piya; Das, Amitava; Mohammed, Kareem; Sen, Chandan K.

2013-01-01

Collagen-based dressings are of great interest in wound care. However, evidence supporting their mechanism of action in a wound setting in vivo is scanty. This work providesfirst results from a pre-clinical swine model of excisional wounds elucidating the mechanism of action of a modified collagen gel (MCG) dressing. Following wounding, wound-edge tissue was collected at specific time intervals (3, 7, 14, and 21 days post-wounding). On day 7, histological analysis showed significant increase in the length of rete ridges suggesting improved biomechanical properties of the healing wound tissue. Rapid and transient mounting of inflammation is necessary for efficient healing. MCG significantly accelerated neutrophil and macrophages recruitment to the wound site on day 3 and day 7 with successful resolution of inflammation on day 21. MCG induced MCP-1 expression in neutrophil-like HL-60 cells in vitro. In vivo, MCG treated wound tissue displayed elevated VEGF expression. Consistently, MCG-treated wounds displayed significantly higher abundance of endothelial cells with increased blood flow to the wound area indicating improved vascularization. This observation was explained by the finding that MCG enhanced proliferation of wound-site endothelial cells. In MCG-treated wound tissue, Masson’s Trichrome and Picrosirius red staining showed higher abundance of collagen and increased collagen type I:III ratio. This work presents first evidence from a pre-clinical experimental setting explaining how a collagen-based dressing may improve wound closure by targeting multiple key mechanisms as compared to standard of care i.e., Tegadem treated wounds. The current findings warrant additional studies to determine whether the responses to the MCG are different from other modified or unmodified collagen based products used in clinical setting. PMID:23607796

Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides.

PubMed

Li, Liang-Zhu; Yang, Yu; Yuan, Song-Hua; Wan, Yan-Min; Qiu, Chao; Feng, Yan-Ling; Xu, Jian-Qing; Zhang, Xiao-Yan

2010-12-01

To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction. A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis. All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8

Utility of Survival Motor Neuron ELISA for Spinal Muscular Atrophy Clinical and Preclinical Analyses

PubMed Central

Kobayashi, Dione T.; Olson, Rory J.; Sly, Laurel; Swanson, Chad J.; Chung, Brett; Naryshkin, Nikolai; Narasimhan, Jana; Bhattacharyya, Anuradha; Mullenix, Michael; Chen, Karen S.

2011-01-01

Objectives Genetic defects leading to the reduction of the survival motor neuron protein (SMN) are a causal factor for Spinal Muscular Atrophy (SMA). While there are a number of therapies under evaluation as potential treatments for SMA, there is a critical lack of a biomarker method for assessing efficacy of therapeutic interventions, particularly those targeting upregulation of SMN protein levels. Towards this end we have engaged in developing an immunoassay capable of accurately measuring SMN protein levels in blood, specifically in peripheral blood mononuclear cells (PBMCs), as a tool for validating SMN protein as a biomarker in SMA. Methods A sandwich enzyme-linked immunosorbent assay (ELISA) was developed and validated for measuring SMN protein in human PBMCs and other cell lysates. Protocols for detection and extraction of SMN from transgenic SMA mouse tissues were also developed. Results The assay sensitivity for human SMN is 50 pg/mL. Initial analysis reveals that PBMCs yield enough SMN to analyze from blood volumes of less than 1 mL, and SMA Type I patients' PBMCs show ∼90% reduction of SMN protein compared to normal adults. The ELISA can reliably quantify SMN protein in human and mouse PBMCs and muscle, as well as brain, and spinal cord from a mouse model of severe SMA. Conclusions This SMN ELISA assay enables the reliable, quantitative and rapid measurement of SMN in healthy human and SMA patient PBMCs, muscle and fibroblasts. SMN was also detected in several tissues in a mouse model of SMA, as well as in wildtype mouse tissues. This SMN ELISA has general translational applicability to both preclinical and clinical research efforts. PMID:21904622

Increasing efficiency of preclinical research by group sequential designs

PubMed Central

Piper, Sophie K.; Rex, Andre; Florez-Vargas, Oscar; Karystianis, George; Schneider, Alice; Wellwood, Ian; Siegerink, Bob; Ioannidis, John P. A.; Kimmelman, Jonathan; Dirnagl, Ulrich

2017-01-01

Despite the potential benefits of sequential designs, studies evaluating treatments or experimental manipulations in preclinical experimental biomedicine almost exclusively use classical block designs. Our aim with this article is to bring the existing methodology of group sequential designs to the attention of researchers in the preclinical field and to clearly illustrate its potential utility. Group sequential designs can offer higher efficiency than traditional methods and are increasingly used in clinical trials. Using simulation of data, we demonstrate that group sequential designs have the potential to improve the efficiency of experimental studies, even when sample sizes are very small, as is currently prevalent in preclinical experimental biomedicine. When simulating data with a large effect size of d = 1 and a sample size of n = 18 per group, sequential frequentist analysis consumes in the long run only around 80% of the planned number of experimental units. In larger trials (n = 36 per group), additional stopping rules for futility lead to the saving of resources of up to 30% compared to block designs. We argue that these savings should be invested to increase sample sizes and hence power, since the currently underpowered experiments in preclinical biomedicine are a major threat to the value and predictiveness in this research domain. PMID:28282371

Validation of Model Forecasts of the Ambient Solar Wind

NASA Technical Reports Server (NTRS)

Macneice, P. J.; Hesse, M.; Kuznetsova, M. M.; Rastaetter, L.; Taktakishvili, A.

2009-01-01

Independent and automated validation is a vital step in the progression of models from the research community into operational forecasting use. In this paper we describe a program in development at the CCMC to provide just such a comprehensive validation for models of the ambient solar wind in the inner heliosphere. We have built upon previous efforts published in the community, sharpened their definitions, and completed a baseline study. We also provide first results from this program of the comparative performance of the MHD models available at the CCMC against that of the Wang-Sheeley-Arge (WSA) model. An important goal of this effort is to provide a consistent validation to all available models. Clearly exposing the relative strengths and weaknesses of the different models will enable forecasters to craft more reliable ensemble forecasting strategies. Models of the ambient solar wind are developing rapidly as a result of improvements in data supply, numerical techniques, and computing resources. It is anticipated that in the next five to ten years, the MHD based models will supplant semi-empirical potential based models such as the WSA model, as the best available forecast models. We anticipate that this validation effort will track this evolution and so assist policy makers in gauging the value of past and future investment in modeling support.

Prospective validation of pathologic complete response models in rectal cancer: Transferability and reproducibility.

PubMed

van Soest, Johan; Meldolesi, Elisa; van Stiphout, Ruud; Gatta, Roberto; Damiani, Andrea; Valentini, Vincenzo; Lambin, Philippe; Dekker, Andre

2017-09-01

Multiple models have been developed to predict pathologic complete response (pCR) in locally advanced rectal cancer patients. Unfortunately, validation of these models normally omit the implications of cohort differences on prediction model performance. In this work, we will perform a prospective validation of three pCR models, including information whether this validation will target transferability or reproducibility (cohort differences) of the given models. We applied a novel methodology, the cohort differences model, to predict whether a patient belongs to the training or to the validation cohort. If the cohort differences model performs well, it would suggest a large difference in cohort characteristics meaning we would validate the transferability of the model rather than reproducibility. We tested our method in a prospective validation of three existing models for pCR prediction in 154 patients. Our results showed a large difference between training and validation cohort for one of the three tested models [Area under the Receiver Operating Curve (AUC) cohort differences model: 0.85], signaling the validation leans towards transferability. Two out of three models had a lower AUC for validation (0.66 and 0.58), one model showed a higher AUC in the validation cohort (0.70). We have successfully applied a new methodology in the validation of three prediction models, which allows us to indicate if a validation targeted transferability (large differences between training/validation cohort) or reproducibility (small cohort differences). © 2017 American Association of Physicists in Medicine.

A laboratory silicone for preclinical training in ear prosthesis.

PubMed

Anand, Vijay; Haribabu; Vimala; Gnanasamband, Vimala

2013-07-01

This article describes an industrial elastic silicone as a material for the laboratory fabrication of ear prosthesis. It has been tested for toxicity in lab animals by the SGS India Pvt. Ltd and approved as a material to pass the parameter of abnormal toxicity. This material therefore can be safely recommended for laboratory exercise to fabricate facial prosthesis. The high cost of the maxillo facial silicone materials prohibits their use for facial prosthesis in pre-clinical training of post-graduate students in maxillofacial prosthodontics. For this reason, pre-clinical laboratory exercise in facial prosthesis is inadequate. A few institutions use polymethyl methacrylate resins which are rigid and do not have elastic characteristics of silicone, which is used for facial defects. This cost-effective industrial silicone material which mimics the elastic and color characteristics of the conventional silicones can be recommended for preclinical exercises.

A New Preclinical Paradigm for Testing Anti-Aging Therapeutics.

PubMed

Ladiges, Warren; Snyder, Jessica M; Wilkinson, Erby; Imai, Denise M; Snider, Tim; Ge, Xuan; Ciol, Marcia; Pettan-Brewer, Christina; Pillai, Smitha P S; Morton, John; Quarles, Ellen; Rabinovitch, Peter; Niedernhofer, Laura; Liggitt, Denny

2017-06-01

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia

PubMed Central

Chitta, K; Paulus, A; Caulfield, T R; Akhtar, S; Blake, M-KK; Ailawadhi, S; Knight, J; Heckman, M G; Pinkerton, A; Chanan-Khan, A

2014-01-01

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target–ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2Ser70-Ala) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity. PMID:25382610

Reform in Teaching Preclinical Pathophysiology

ERIC Educational Resources Information Center

Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

2015-01-01

Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

PubMed

Corbett, Dale; Carmichael, S Thomas; Murphy, Timothy H; Jones, Theresa A; Schwab, Martin E; Jolkkonen, Jukka; Clarkson, Andrew N; Dancause, Numa; Weiloch, Tadeusz; Johansen-Berg, Heidi; Nilsson, Michael; McCullough, Louise D; Joy, Mary T

2017-08-01

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

Function of MYO7A in the Human RPE and the Validity of Shaker1 Mice as a Model for Usher Syndrome 1B

PubMed Central

Gibbs, Daniel; Diemer, Tanja; Khanobdee, Kornnika; Hu, Jane; Bok, Dean

2010-01-01

Purpose. To investigate the function of MYO7A in human RPE cells and to test the validity of using shaker1 RPE in preclinical studies on therapies for Usher syndrome 1B by comparing human and mouse cells. Methods. MYO7A was localized by immunofluorescence. Primary cultures of human and mouse RPE cells were used to measure melanosome motility and rod outer segment (ROS) phagocytosis and digestion. MYO7A was knocked down in the human RPE cells by RNAi to test for a mutant phenotype in melanosome motility. Results. The distribution of MYO7A in the RPE of human and mouse was found to be comparable, both in vivo and in primary cultures. Primary cultures of human RPE cells phagocytosed and digested ROSs with kinetics comparable to that of primary cultures of mouse RPE cells. Melanosome motility was also comparable, and, after RNAi knockdown, consisted of longer-range fast movements characteristic of melanosomes in shaker1 RPE. Conclusions. The localization and function of MYO7A in human RPE cells is comparable to that in mouse RPE cells. Although shaker1 retinas do not undergo degeneration, correction of mutant phenotypes in the shaker1 RPE represents a valid preclinical test for potential therapeutic treatments. PMID:19643958

Assessing Discriminative Performance at External Validation of Clinical Prediction Models

PubMed Central

Nieboer, Daan; van der Ploeg, Tjeerd; Steyerberg, Ewout W.

2016-01-01

Introduction External validation studies are essential to study the generalizability of prediction models. Recently a permutation test, focusing on discrimination as quantified by the c-statistic, was proposed to judge whether a prediction model is transportable to a new setting. We aimed to evaluate this test and compare it to previously proposed procedures to judge any changes in c-statistic from development to external validation setting. Methods We compared the use of the permutation test to the use of benchmark values of the c-statistic following from a previously proposed framework to judge transportability of a prediction model. In a simulation study we developed a prediction model with logistic regression on a development set and validated them in the validation set. We concentrated on two scenarios: 1) the case-mix was more heterogeneous and predictor effects were weaker in the validation set compared to the development set, and 2) the case-mix was less heterogeneous in the validation set and predictor effects were identical in the validation and development set. Furthermore we illustrated the methods in a case study using 15 datasets of patients suffering from traumatic brain injury. Results The permutation test indicated that the validation and development set were homogenous in scenario 1 (in almost all simulated samples) and heterogeneous in scenario 2 (in 17%-39% of simulated samples). Previously proposed benchmark values of the c-statistic and the standard deviation of the linear predictors correctly pointed at the more heterogeneous case-mix in scenario 1 and the less heterogeneous case-mix in scenario 2. Conclusion The recently proposed permutation test may provide misleading results when externally validating prediction models in the presence of case-mix differences between the development and validation population. To correctly interpret the c-statistic found at external validation it is crucial to disentangle case-mix differences from incorrect

Assessing Discriminative Performance at External Validation of Clinical Prediction Models.

PubMed

Nieboer, Daan; van der Ploeg, Tjeerd; Steyerberg, Ewout W

2016-01-01

External validation studies are essential to study the generalizability of prediction models. Recently a permutation test, focusing on discrimination as quantified by the c-statistic, was proposed to judge whether a prediction model is transportable to a new setting. We aimed to evaluate this test and compare it to previously proposed procedures to judge any changes in c-statistic from development to external validation setting. We compared the use of the permutation test to the use of benchmark values of the c-statistic following from a previously proposed framework to judge transportability of a prediction model. In a simulation study we developed a prediction model with logistic regression on a development set and validated them in the validation set. We concentrated on two scenarios: 1) the case-mix was more heterogeneous and predictor effects were weaker in the validation set compared to the development set, and 2) the case-mix was less heterogeneous in the validation set and predictor effects were identical in the validation and development set. Furthermore we illustrated the methods in a case study using 15 datasets of patients suffering from traumatic brain injury. The permutation test indicated that the validation and development set were homogenous in scenario 1 (in almost all simulated samples) and heterogeneous in scenario 2 (in 17%-39% of simulated samples). Previously proposed benchmark values of the c-statistic and the standard deviation of the linear predictors correctly pointed at the more heterogeneous case-mix in scenario 1 and the less heterogeneous case-mix in scenario 2. The recently proposed permutation test may provide misleading results when externally validating prediction models in the presence of case-mix differences between the development and validation population. To correctly interpret the c-statistic found at external validation it is crucial to disentangle case-mix differences from incorrect regression coefficients.

Preclinical Alzheimer disease and risk of falls.

PubMed

Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

2013-07-30

We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

Preclinical Alzheimer disease and risk of falls

PubMed Central

Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.

2013-01-01

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

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

PubMed

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.

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

PubMed

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 < 0.001), the main effect sizes were small (4.5% and 2.3%, respectively). The time allowed per multiple choice question was not significantly associated with student 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.

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

PubMed Central

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

2015-01-01

Objective: 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. Materials and Methods: 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. Results: 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. Conclusions: Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment. PMID:26430363

Cross-validation pitfalls when selecting and assessing regression and classification models.

PubMed

Krstajic, Damjan; Buturovic, Ljubomir J; Leahy, David E; Thomas, Simon

2014-03-29

We address the problem of selecting and assessing classification and regression models using cross-validation. Current state-of-the-art methods can yield models with high variance, rendering them unsuitable for a number of practical applications including QSAR. In this paper we describe and evaluate best practices which improve reliability and increase confidence in selected models. A key operational component of the proposed methods is cloud computing which enables routine use of previously infeasible approaches. We describe in detail an algorithm for repeated grid-search V-fold cross-validation for parameter tuning in classification and regression, and we define a repeated nested cross-validation algorithm for model assessment. As regards variable selection and parameter tuning we define two algorithms (repeated grid-search cross-validation and double cross-validation), and provide arguments for using the repeated grid-search in the general case. We show results of our algorithms on seven QSAR datasets. The variation of the prediction performance, which is the result of choosing different splits of the dataset in V-fold cross-validation, needs to be taken into account when selecting and assessing classification and regression models. We demonstrate the importance of repeating cross-validation when selecting an optimal model, as well as the importance of repeating nested cross-validation when assessing a prediction error.

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | FNLCR Staging

Cancer.gov

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

Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies.

PubMed

Ette, E I; Howie, C A; Kelman, A W; Whiting, B

1995-05-01

Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive ("quantic") preclinical population pharmacokinetic study with a fixed sample size as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and four time point designs were evaluated in terms of the percent prediction error, design number, individual and joint confidence intervals coverage for parameter estimates approaches, and correlation analysis. The data sets contained random terms for both inter- and residual intra-animal variability. The results showed that the typical population parameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variability (the only random effect parameter that could be estimated) was inefficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fourth time point for the three and four time point designs, respectively, was not critical to the efficiency of overall estimation of all population parameters of the model. However, some individual population pharmacokinetic parameters were sensitive to the location of these times.

Validation of Magnetospheric Magnetohydrodynamic Models

NASA Astrophysics Data System (ADS)

Curtis, Brian

Magnetospheric magnetohydrodynamic (MHD) models are commonly used for both prediction and modeling of Earth's magnetosphere. To date, very little validation has been performed to determine their limits, uncertainties, and differences. In this work, we performed a comprehensive analysis using several commonly used validation techniques in the atmospheric sciences to MHD-based models of Earth's magnetosphere for the first time. The validation techniques of parameter variability/sensitivity analysis and comparison to other models were used on the OpenGGCM, BATS-R-US, and SWMF magnetospheric MHD models to answer several questions about how these models compare. The questions include: (1) the difference between the model's predictions prior to and following to a reversal of Bz in the upstream interplanetary field (IMF) from positive to negative, (2) the influence of the preconditioning duration, and (3) the differences between models under extreme solar wind conditions. A differencing visualization tool was developed and used to address these three questions. We find: (1) For a reversal in IMF Bz from positive to negative, the OpenGGCM magnetopause is closest to Earth as it has the weakest magnetic pressure near-Earth. The differences in magnetopause positions between BATS-R-US and SWMF are explained by the influence of the ring current, which is included in SWMF. Densities are highest for SWMF and lowest for OpenGGCM. The OpenGGCM tail currents differ significantly from BATS-R-US and SWMF; (2) A longer preconditioning time allowed the magnetosphere to relax more, giving different positions for the magnetopause with all three models before the IMF Bz reversal. There were differences greater than 100% for all three models before the IMF Bz reversal. The differences in the current sheet region for the OpenGGCM were small after the IMF Bz reversal. The BATS-R-US and SWMF differences decreased after the IMF Bz reversal to near zero; (3) For extreme conditions in the solar

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging

PubMed Central

Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

2014-01-01

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2−/−/γc−/− mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which

Solar Sail Models and Test Measurements Correspondence for Validation Requirements Definition

NASA Technical Reports Server (NTRS)

Ewing, Anthony; Adams, Charles

2004-01-01

Solar sails are being developed as a mission-enabling technology in support of future NASA science missions. Current efforts have advanced solar sail technology sufficient to justify a flight validation program. A primary objective of this activity is to test and validate solar sail models that are currently under development so that they may be used with confidence in future science mission development (e.g., scalable to larger sails). Both system and model validation requirements must be defined early in the program to guide design cycles and to ensure that relevant and sufficient test data will be obtained to conduct model validation to the level required. A process of model identification, model input/output documentation, model sensitivity analyses, and test measurement correspondence is required so that decisions can be made to satisfy validation requirements within program constraints.

Validity of empirical models of exposure in asphalt paving

PubMed Central

Burstyn, I; Boffetta, P; Burr, G; Cenni, A; Knecht, U; Sciarra, G; Kromhout, H

2002-01-01

Aims: To investigate the validity of empirical models of exposure to bitumen fume and benzo(a)pyrene, developed for a historical cohort study of asphalt paving in Western Europe. Methods: Validity was evaluated using data from the USA, Italy, and Germany not used to develop the original models. Correlation between observed and predicted exposures was examined. Bias and precision were estimated. Results: Models were imprecise. Furthermore, predicted bitumen fume exposures tended to be lower (-70%) than concentrations found during paving in the USA. This apparent bias might be attributed to differences between Western European and USA paving practices. Evaluation of the validity of the benzo(a)pyrene exposure model revealed a similar to expected effect of re-paving and a larger than expected effect of tar use. Overall, benzo(a)pyrene models underestimated exposures by 51%. Conclusions: Possible bias as a result of underestimation of the impact of coal tar on benzo(a)pyrene exposure levels must be explored in sensitivity analysis of the exposure–response relation. Validation of the models, albeit limited, increased our confidence in their applicability to exposure assessment in the historical cohort study of cancer risk among asphalt workers. PMID:12205236

Establishment of a preclinical ovine model for tibial segmental bone defect repair by applying bone tissue engineering strategies.

PubMed

Reichert, Johannes C; Epari, Devakara R; Wullschleger, Martin E; Saifzadeh, Siamak; Steck, Roland; Lienau, Jasmin; Sommerville, Scott; Dickinson, Ian C; Schütz, Michael A; Duda, Georg N; Hutmacher, Dietmar W

2010-02-01

Currently, well-established clinical therapeutic approaches for bone reconstruction are restricted to the transplantation of autografts and allografts, and the implantation of metal devices or ceramic-based implants to assist bone regeneration. Bone grafts possess osteoconductive and osteoinductive properties; however, they are limited in access and availability and associated with donor-site morbidity, hemorrhage, risk of infection, insufficient transplant integration, graft devitalization, and subsequent resorption resulting in decreased mechanical stability. As a result, recent research focuses on the development of alternative therapeutic concepts. The field of tissue engineering has emerged as an important approach to bone regeneration. However, bench-to-bedside translations are still infrequent as the process toward approval by regulatory bodies is protracted and costly, requiring both comprehensive in vitro and in vivo studies. The subsequent gap between research and clinical translation, hence, commercialization, is referred to as the "Valley of Death" and describes a large number of projects and/or ventures that are ceased due to a lack of funding during the transition from product/technology development to regulatory approval and subsequently commercialization. One of the greatest difficulties in bridging the Valley of Death is to develop good manufacturing processes and scalable designs and to apply these in preclinical studies. In this article, we describe part of the rationale and road map of how our multidisciplinary research team has approached the first steps to translate orthopedic bone engineering from bench to bedside by establishing a preclinical ovine critical-sized tibial segmental bone defect model, and we discuss our preliminary data relating to this decisive step.

A comparative analysis of acute-phase proteins as inflammatory biomarkers in preclinical toxicology studies: implications for preclinical to clinical translation.

PubMed

Watterson, Claire; Lanevschi, Anne; Horner, Judith; Louden, Calvert

2009-01-01

Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations.

PubMed

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-06-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10(8) , 2 × 10(9) and 2 × 10(10) colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10(9) CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10(10) CFU). The challenge dose, 2 × 10(10) CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. © 2013 The Authors. APMIS published by John Wiley & Sons Ltd.

Validation techniques of agent based modelling for geospatial simulations

NASA Astrophysics Data System (ADS)

Darvishi, M.; Ahmadi, G.

2014-10-01

One of the most interesting aspects of modelling and simulation study is to describe the real world phenomena that have specific properties; especially those that are in large scales and have dynamic and complex behaviours. Studying these phenomena in the laboratory is costly and in most cases it is impossible. Therefore, Miniaturization of world phenomena in the framework of a model in order to simulate the real phenomena is a reasonable and scientific approach to understand the world. Agent-based modelling and simulation (ABMS) is a new modelling method comprising of multiple interacting agent. They have been used in the different areas; for instance, geographic information system (GIS), biology, economics, social science and computer science. The emergence of ABM toolkits in GIS software libraries (e.g. ESRI's ArcGIS, OpenMap, GeoTools, etc) for geospatial modelling is an indication of the growing interest of users to use of special capabilities of ABMS. Since ABMS is inherently similar to human cognition, therefore it could be built easily and applicable to wide range applications than a traditional simulation. But a key challenge about ABMS is difficulty in their validation and verification. Because of frequent emergence patterns, strong dynamics in the system and the complex nature of ABMS, it is hard to validate and verify ABMS by conventional validation methods. Therefore, attempt to find appropriate validation techniques for ABM seems to be necessary. In this paper, after reviewing on Principles and Concepts of ABM for and its applications, the validation techniques and challenges of ABM validation are discussed.

A Formal Approach to Empirical Dynamic Model Optimization and Validation

NASA Technical Reports Server (NTRS)

Crespo, Luis G; Morelli, Eugene A.; Kenny, Sean P.; Giesy, Daniel P.

2014-01-01

A framework was developed for the optimization and validation of empirical dynamic models subject to an arbitrary set of validation criteria. The validation requirements imposed upon the model, which may involve several sets of input-output data and arbitrary specifications in time and frequency domains, are used to determine if model predictions are within admissible error limits. The parameters of the empirical model are estimated by finding the parameter realization for which the smallest of the margins of requirement compliance is as large as possible. The uncertainty in the value of this estimate is characterized by studying the set of model parameters yielding predictions that comply with all the requirements. Strategies are presented for bounding this set, studying its dependence on admissible prediction error set by the analyst, and evaluating the sensitivity of the model predictions to parameter variations. This information is instrumental in characterizing uncertainty models used for evaluating the dynamic model at operating conditions differing from those used for its identification and validation. A practical example based on the short period dynamics of the F-16 is used for illustration.

An Approach to Comprehensive and Sustainable Solar Wind Model Validation

NASA Astrophysics Data System (ADS)

Rastaetter, L.; MacNeice, P. J.; Mays, M. L.; Boblitt, J. M.; Wiegand, C.

2017-12-01

The number of models of the corona and inner heliosphere and of their updates and upgrades grows steadily, as does the number and character of the model inputs. Maintaining up to date validation of these models, in the face of this constant model evolution, is a necessary but very labor intensive activity. In the last year alone, both NASA's LWS program and the CCMC's ongoing support of model forecasting activities at NOAA SWPC have sought model validation reports on the quality of all aspects of the community's coronal and heliospheric models, including both ambient and CME related wind solutions at L1. In this presentation I will give a brief review of the community's previous model validation results of L1 wind representation. I will discuss the semi-automated web based system we are constructing at the CCMC to present comparative visualizations of all interesting aspects of the solutions from competing models.This system is designed to be easily queried to provide the essential comprehensive inputs to repeat andupdate previous validation studies and support extensions to them. I will illustrate this by demonstrating how the system is being used to support the CCMC/LWS Model Assessment Forum teams focused on the ambient and time dependent corona and solar wind, including CME arrival time and IMF Bz.I will also discuss plans to extend the system to include results from the Forum teams addressing SEP model validation.

Guidelines for pre-clinical assessment of the acetylcholine receptor-specific passive transfer myasthenia gravis model - recommendations for methods and experimental designs

PubMed Central

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

Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases

PubMed Central

Hoenerhoff, Mark; Hixon, Julie A.; Durum, Scott K.; Qiu, Ting-hu; He, Siping; Burkett, Sandra; Liu, Zi-Yao; Swanson, Steven M.; Green, Jeffrey E.

2016-01-01

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in

Parameterization of Model Validating Sets for Uncertainty Bound Optimizations. Revised

NASA Technical Reports Server (NTRS)

Lim, K. B.; Giesy, D. P.

2000-01-01

Given measurement data, a nominal model and a linear fractional transformation uncertainty structure with an allowance on unknown but bounded exogenous disturbances, easily computable tests for the existence of a model validating uncertainty set are given. Under mild conditions, these tests are necessary and sufficient for the case of complex, nonrepeated, block-diagonal structure. For the more general case which includes repeated and/or real scalar uncertainties, the tests are only necessary but become sufficient if a collinearity condition is also satisfied. With the satisfaction of these tests, it is shown that a parameterization of all model validating sets of plant models is possible. The new parameterization is used as a basis for a systematic way to construct or perform uncertainty tradeoff with model validating uncertainty sets which have specific linear fractional transformation structure for use in robust control design and analysis. An illustrative example which includes a comparison of candidate model validating sets is given.

Validation of the Poisson Stochastic Radiative Transfer Model

NASA Technical Reports Server (NTRS)

Zhuravleva, Tatiana; Marshak, Alexander

2004-01-01

A new approach to validation of the Poisson stochastic radiative transfer method is proposed. In contrast to other validations of stochastic models, the main parameter of the Poisson model responsible for cloud geometrical structure - cloud aspect ratio - is determined entirely by matching measurements and calculations of the direct solar radiation. If the measurements of the direct solar radiation is unavailable, it was shown that there is a range of the aspect ratios that allows the stochastic model to accurately approximate the average measurements of surface downward and cloud top upward fluxes. Realizations of the fractionally integrated cascade model are taken as a prototype of real measurements.

AdViSHE: A Validation-Assessment Tool of Health-Economic Models for Decision Makers and Model Users.

PubMed

Vemer, P; Corro Ramos, I; van Voorn, G A K; Al, M J; Feenstra, T L

2016-04-01

A trade-off exists between building confidence in health-economic (HE) decision models and the use of scarce resources. We aimed to create a practical tool providing model users with a structured view into the validation status of HE decision models, to address this trade-off. A Delphi panel was organized, and was completed by a workshop during an international conference. The proposed tool was constructed iteratively based on comments from, and the discussion amongst, panellists. During the Delphi process, comments were solicited on the importance and feasibility of possible validation techniques for modellers, their relevance for decision makers, and the overall structure and formulation in the tool. The panel consisted of 47 experts in HE modelling and HE decision making from various professional and international backgrounds. In addition, 50 discussants actively engaged in the discussion at the conference workshop and returned 19 questionnaires with additional comments. The final version consists of 13 items covering all relevant aspects of HE decision models: the conceptual model, the input data, the implemented software program, and the model outcomes. Assessment of the Validation Status of Health-Economic decision models (AdViSHE) is a validation-assessment tool in which model developers report in a systematic way both on validation efforts performed and on their outcomes. Subsequently, model users can establish whether confidence in the model is justified or whether additional validation efforts should be undertaken. In this way, AdViSHE enhances transparency of the validation status of HE models and supports efficient model validation.

Terminal-decline effects for select cognitive tasks after controlling for preclinical dementia.

PubMed

Laukka, Erika J; MacDonald, Stuart W S; Bäckman, Lars

2008-05-01

In a previous study, the authors found no accelerated decline in close proximity to death for a measure of global cognitive functioning, after excluding persons in a preclinical phase of dementia. However, specific cognitive tasks might be more sensitive to terminal-decline effects. The purpose of this study was to explore possible terminal-decline effects for a range of cognitive tasks after controlling for preclinical dementia. Community-based cohort study. The Kungsholmen district of Stockholm. A total of 585 persons (75+ years) were repeatedly assessed over an 11-year period. Level and change in cognitive performance were compared for three groups: persons in close proximity to death, persons in a preclinical phase of dementia, and persons who remained alive and nondemented throughout the study. Tasks assessing primary and episodic memory, verbal ability, and visuospatial skill. Compared with an analysis where all dead subjects were included in the impending-death group, removing the preclinical dementia cases resulted in markedly attenuated mortality-related effects. However, the impending-death group still declined at a faster rate relative to the comparison group on Digit Span-forward, word recognition, and category fluency. Notably, these were tasks for which the comparison group showed no significant decline. A considerable proportion of the terminal-decline effect is accounted for by the impact of preclinical dementia. However, for tasks that are relatively resistant to age-related change, such effects might be detected independently of preclinical dementia.

The design and pre-clinical evaluation of knee replacements for osteoarthritis.

PubMed

Walker, Peter S

2015-03-18

One of the concepts that Rik Huiskes promoted was that implants such as knee and hip replacements could be analyzed and optimized using numerical models such as finite element analysis, or by experimental testing, an area he called pre-clinical testing. The design itself could be formulated or improved by defining a specific goal or asking a key question. These propositions are examined in the light of almost five decades of experience with knee implants. Achieving the required laxity and stability, was achieved by attempting to reproduce anatomical values by suitable radii of curvature and selective ligament retention. Obtaining durable fixation was based on testing many configurations to obtain the most uniform stress distribution at the implant-bone interface. Achieving the best overall kinematics has yet to be fully solved due to the variations in activities and patients. These and many other factors have usually been addressed individually rather than as a composite, although as time has gone on, successful features have gradually been assimilated into most designs. But even a systematic approach has been flawed because some unrecognized response was not accounted for in the pre-clinical model, a limitation of models in general. In terms of the design process, so far no method has emerged for systematically reaching an optimal solution from all aspects, although this is possible in principle. Overall however, predictive numerical or physical models should be an essential element in the design of new or improved knee replacements, a part of the design process itself. Copyright © 2015. Published by Elsevier Ltd.

Geographic and temporal validity of prediction models: Different approaches were useful to examine model performance

PubMed Central

Austin, Peter C.; van Klaveren, David; Vergouwe, Yvonne; Nieboer, Daan; Lee, Douglas S.; Steyerberg, Ewout W.

2017-01-01

Objective Validation of clinical prediction models traditionally refers to the assessment of model performance in new patients. We studied different approaches to geographic and temporal validation in the setting of multicenter data from two time periods. Study Design and Setting We illustrated different analytic methods for validation using a sample of 14,857 patients hospitalized with heart failure at 90 hospitals in two distinct time periods. Bootstrap resampling was used to assess internal validity. Meta-analytic methods were used to assess geographic transportability. Each hospital was used once as a validation sample, with the remaining hospitals used for model derivation. Hospital-specific estimates of discrimination (c-statistic) and calibration (calibration intercepts and slopes) were pooled using random effects meta-analysis methods. I2 statistics and prediction interval width quantified geographic transportability. Temporal transportability was assessed using patients from the earlier period for model derivation and patients from the later period for model validation. Results Estimates of reproducibility, pooled hospital-specific performance, and temporal transportability were on average very similar, with c-statistics of 0.75. Between-hospital variation was moderate according to I2 statistics and prediction intervals for c-statistics. Conclusion This study illustrates how performance of prediction models can be assessed in settings with multicenter data at different time periods. PMID:27262237