SEFRE: Semiexoskeleton Rehabilitation System.

PubMed

Chonnaparamutt, Winai; Supsi, Witsarut

2016-01-01

SEFRE (Shoulder-Elbow-Forearm Robotics Economic) rehabilitation system is presented in this paper. SEFRE Rehab System is composed of a robotic manipulator and an exoskeleton, so-called Forearm Supportive Mechanism (FSM). The controller of the system is developed as the Master PC consisting of five modules, that is, Intelligent Control (IC), Patient Communication (PC), Training with Game (TG), Progress Monitoring (PM), and Patient Supervision (PS). These modules support a patient to exercise with SEFRE in six modes, that is, Passive, Passive Stretching, Passive Guiding, Initiating Active, Active Assisted, and Active Resisted. To validate the advantages of the system, the preclinical trial was carried out at a national rehabilitation center. Here, the implement of the system and the preclinical results are presented as the verifications of SEFRE.

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.

Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit

PubMed Central

Molinuevo, José L.; Cami, Jordi; Carné, Xavier; Carrillo, Maria C.; Georges, Jean; Isaac, Maria B.; Khachaturian, Zaven; Kim, Scott Y. H.; Morris, John C.; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

2016-01-01

Alzheimer’s disease (AD) is among the most significant healthcare burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals’ biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants and disclose or not biomarker status with attention to study type (observational studies versus clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.

PubMed

Okour, Malek; Derimanov, Geo; Barnett, Rodger; Fernandez, Esther; Ferrer, Santiago; Gresham, Stephanie; Hossain, Mohammad; Gamo, Francisco-Javier; Koh, Gavin; Pereira, Adrian; Rolfe, Katie; Wong, Deborah; Young, Graeme; Rami, Harshad; Haselden, John

2018-03-01

GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 μg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607. A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans. The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure. The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound. © 2017 The British Pharmacological Society.

Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer

DTIC Science & Technology

2014-10-01

activity relationship analyses ( QSAR ) to develop rationally designed NPPTA analogs with increased potency and optimized pharmacologic properties...vitro, with the strongest candidates being studied in vivo to provide preclinical safety, efficacy, and toxicology data to support later first-in-human

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.

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.

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 academic institutions, funding agencies, and animal ethics authorities. © 2018 American Heart Association, Inc.

A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

PubMed Central

Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

2011-01-01

Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

Towards a Drug Development Path that Targets Metastatic Progression in Osteosarcoma

PubMed Central

Khanna, Chand; Fan, Timothy M.; Gorlick, Richard; Helman, Lee J; Kleinerman, Eugenie S.; Adamson, Peter C.; Houghton, Peter J.; Tap, William D.; Welch, Danny R.; Steeg, Patricia S.; Merlino, Glenn; Sorensen, Poul HB; Kirsch, David G.; Janeway, Katherine A.; Weigel, Brenda; Randall, R. Lor; Meltzer, Paul; Withrow, Stephen J; Paoloni, Melissa; Kaplan, Rosandra N.; Teicher, Beverly A.; Seibel, Nita L.; Üren, Aykut; Patel, Shreyaskumar R.; Trent, Jeffrey; Savage, Sharon A.; Mirabello, Lisa; Reinke, Denise; Barkauskas, Donald A.; Krailo, Mark; Smith, Malcolm A.; Bernstein, Mark

2014-01-01

Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in osteosarcoma patients. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for osteosarcoma patients in over 30 years. Based on our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda Maryland. The goal of this meeting was to provide a “Perspective” that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: That the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data is needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micro-metastatic disease setting. PMID:24803583

Vitamins in Pancreatic Cancer: A Review of Underlying Mechanisms and Future Applications12

PubMed Central

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-01-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. PMID:26567201

Vitamins in pancreatic cancer: a review of underlying mechanisms and future applications.

PubMed

Davis-Yadley, Ashley H; Malafa, Mokenge P

2015-11-01

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer. © 2015 American Society for Nutrition.

Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies.

PubMed

Jans, Verna; Dondorp, Wybo; Goossens, Ellen; Mertes, Heidi; Pennings, Guido; de Wert, Guido

2018-02-07

In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R's (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research.

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

The role of patent ductus arteriosus and its treatments in the development of bronchopulmonary dysplasia

PubMed Central

Clyman, Ronald I.

2013-01-01

A persistent left-to right shunt through a patent ductus arteriosus (PDA) increases the rate of hydrostatic fluid filtration into the lung’s interstitium, impairs pulmonary mechanics, and prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure leads to improved alveolarization and minimizes the impaired postnatal alveolar development that is the pathologic hallmark of the “new bronchopulmonary dysplasia (BPD)”. Although early pharmacologic closure of the PDA decreases the incidence of pulmonary hemorrhage, intraventricular hemorrhage, and the need for PDA ligation, there is little evidence from controlled, clinical trials to support or refute a causal role for the PDA in the development of BPD. On the other hand, evidence from epidemiologic, preclinical, and randomized controlled clinical trials demonstrate that early ductus ligation is an independent risk factor for the development of BPD and may directly contribute to the neonatal morbidities it is trying to prevent. PMID:23582964

A Preliminary Review of Whether Prior Reproductive Experience Influences Caregiving

ERIC Educational Resources Information Center

Maupin, Angela N.; Roginiel, Aliya C.; Rutherford, Helena J. V.; Mayes, Linda C.

2016-01-01

The transition to parenthood marks a significant developmental period for the mother. Clinical and preclinical studies evidence neural and hormonal changes that support maternal behavior that is critical to infant survival and development. These changes suggest marked plasticity as a result of reproduction in the mother. Furthermore, multiple…

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.

Creating a web-enhanced interactive preclinic technique manual: case report and student response.

PubMed

Boberick, Kenneth G

2004-12-01

This article describes the development, use, and student response to an online manual developed with off-the-shelf software and made available using a web-based course management system (Blackboard) that was used to transform a freshman restorative preclinical technique course from a lecture-only course into an interactive web-enhanced course. The goals of the project were to develop and implement a web-enhanced interactive learning experience in a preclinical restorative technique course and shift preclinical education from a teacher-centered experience to a student-driven experience. The project was evaluated using an anonymous post-course survey (95 percent response rate) of 123 freshman students that assessed enabling (technical support and access to the technology), process (the actual experience and usability), and outcome criteria (acquisition and successful use of the knowledge gained and skills learned) of the online manual. Students responded favorably to sections called "slide galleries" where ideal and non-ideal examples of projects could be viewed. Causes, solutions, and preventive measures were provided for the errors shown. Sections called "slide series" provided cookbook directions allowing for self-paced and student-directed learning. Virtually all of the students, 99 percent, found the quality of the streaming videos adequate to excellent. Regarding Internet connections and video viewing, 65 percent of students successfully viewed the videos from a remote site; cable connections were the most reliable, dial-up connections were inadequate, and DSL connections were variable. Seventy-three percent of the students felt the videos were an effective substitute for in-class demonstrations. Students preferred video with sound over video with subtitles and preferred short video clips embedded in the text over compilation videos. The results showed it is possible to develop and implement web-enhanced and interactive dental education in a preclinical restorative technique course that successfully delivered information beyond the textual format.

Preclinical development of a humanized neutralizing antibody targeting HGF.

PubMed

Kim, Hyori; Hong, Sung Hee; Kim, Jung Yong; Kim, In-Chull; Park, Young-Whan; Lee, Song-Jae; Song, Seong-Won; Kim, Jung Ju; Park, Gunwoo; Kim, Tae Min; Kim, Yun-Hee; Park, Jong Bae; Chung, Junho; Kim, In-Hoo

2017-03-24

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination.

PubMed

Gong, Jun; Le, Thang Q; Massarelli, Erminia; Hendifar, Andrew E; Tuli, Richard

2018-06-04

Several inhibitors of programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved as a form of immunotherapy for multiple cancers. Ionizing radiation therapy (RT) has been shown to enhance the priming and effector phases of the antitumor T-cell response rendering it an attractive therapy to combine with PD-1/PD-L1 inhibitors. Preclinical data support the rational combination of the 2 modalities and has paved way for the clinical development of the combination across a spectrum of cancers. In this review, we highlight the preclinical and clinical development of combined RT and PD-1/PD-L1 blockade to date. In addition to a comprehensive evaluation of available safety and efficacy data, we discuss important points of consideration in clinical trial design for this promising combination.

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

TNF and cancer: the two sides of the coin.

PubMed

Mocellin, Simone; Nitti, Donato

2008-01-01

Despite its name, discovery history and approval as anticancer agent, tumor necrosis factor (TNF) has been implicated in both cancer development and progression in some preclinical models. In particular, as a central mediator of inflammation, TNF might represent one of the molecular links between chronic inflammation and the subsequent development of malignant disease. Furthermore, deregulated TNF expression within the tumor microenvironment appears to favor malignant cell tissue invasion, migration and ultimately metastasis formation. On the other side, TNF clearly possesses antitumor effects not only in preclinical models but also in the clinical setting. In order to reconcile these conflicting findings, we provide readers with an overview on the most relevant available evidence supporting anticancer as well as cancer-promoting TNF effects; on the basis of these data, we propose a model to explain the coexistence of these apparently paradoxical TNF activities.

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

PubMed

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

2015-06-01

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

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

PubMed Central

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

2015-01-01

Opinion Statement Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940’s, and during the last 10–15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence. PMID:26009706

Operation of the Preclinical Head Scanner for Proton CT.

PubMed

Sadrozinski, H F-W; Geoghegan, T; Harvey, E; Johnson, R P; Plautz, T E; Zatserklyaniy, A; Bashkirov, V; Hurley, R F; Piersimoni, P; Schulte, R W; Karbasi, P; Schubert, K E; Schultze, B; Giacometti, V

2016-09-21

We report on the operation and performance tests of a preclinical head scanner developed for proton computed tomography (pCT). After extensive preclinical testing, pCT is intended to be employed in support of proton therapy treatment planning and pre-treatment verification in patients undergoing particle-beam therapy. In order to assess the performance of the scanner, we have performed CT scans with 200 MeV protons from both the synchrotron of the Loma Linda University Medical Center (LLUMC) and the cyclotron of the Northwestern Medicine Chicago Proton Center (NMCPC). The very high sustained rate of data acquisition, exceeding one million protons per second, allowed a full 360° scan to be completed in less than 7 minutes. The reconstruction of various phantoms verified accurate reconstruction of the proton relative stopping power (RSP) and the spatial resolution in a variety of materials. The dose for an image with better than 1% uncertainty in the RSP is found to be close to 1 mGy.

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.

Institute for Molecular Medicine Research Program

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

Phelps, Michael E

2012-12-14

The objectives of the project are the development of new Positron Emission Tomography (PET) imaging instrumentation, chemistry technology platforms and new molecular imaging probes to examine the transformations from normal cellular and biological processes to those of disease in pre-clinical animal models. These technology platforms and imaging probes provide the means to: 1. Study the biology of disease using pre-clinical mouse models and cells. 2. Develop molecular imaging probes for imaging assays of proteins in pre-clinical models. 3. Develop imaging assays in pre-clinical models to provide to other scientists the means to guide and improve the processes for discovering newmore » drugs. 4. Develop imaging assays in pre-clinical models for others to use in judging the impact of drugs on the biology of disease.« less

Challenges and opportunities in bioanalytical support for gene therapy medicinal product development.

PubMed

Ma, Mark; Balasubramanian, Nanda; Dodge, Robert; Zhang, Yan

2017-09-01

Gene and nucleic acid therapies have demonstrated patient benefits to address unmet medical needs. Beside considerations regarding the biological nature of the gene therapy, the quality of bioanalytical methods plays an important role in ensuring the success of these novel therapies. Inconsistent approaches among bioanalytical labs during preclinical and clinical phases have been observed. There are many underlying reasons for this inconsistency. Various platforms and reagents used in quantitative methods, lacking of detailed regulatory guidance on method validation and uncertainty of immunogenicity strategy in supporting gene therapy may all be influential. This review summarizes recent practices and considerations in bioanalytical support of pharmacokinetics/pharmacodynamics and immunogenicity evaluations in gene therapy development with insight into method design, development and validations.

Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests.

USDA-ARS?s Scientific Manuscript database

The current review is part of a special issue entitled “Role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment”; it deals with the description of a pharmacological strategy aiming to actually determine the potential contribution of food-related com...

In Progress: Reports of New Approaches in Medical Education. Annual, Peer-Reviewed Collection of Reports on Innovative Approaches to Medical Education.

ERIC Educational Resources Information Center

Anderson, M. Brownell, Ed.

1997-01-01

Provides summary reports of 81 innovative approaches to medical education in the areas of program management and assessment, admission and student-support programs, computer applications, preclinical and clinical course integration, development of professional skills and values, introduction to clinical medicine, community-based experiences,…

Antitumor Efficacy Testing in Rodents

PubMed Central

2008-01-01

The preclinical research and human clinical trials necessary for developing anticancer therapeutics are costly. One contributor to these costs is preclinical rodent efficacy studies, which, in addition to the costs associated with conducting them, often guide the selection of agents for clinical development. If inappropriate or inaccurate recommendations are made on the basis of these preclinical studies, then additional costs are incurred. In this commentary, I discuss the issues associated with preclinical rodent efficacy studies. These include the identification of proper preclinical efficacy models, the selection of appropriate experimental endpoints, and the correct statistical evaluation of the resulting data. I also describe important experimental design considerations, such as selecting the drug vehicle, optimizing the therapeutic treatment plan, properly powering the experiment by defining appropriate numbers of replicates in each treatment arm, and proper randomization. Improved preclinical selection criteria can aid in reducing unnecessary human studies, thus reducing the overall costs of anticancer drug development. PMID:18957675

Effective visualization of integrated knowledge and data to enable informed decisions in drug development and translational medicine

PubMed Central

2013-01-01

Integrative understanding of preclinical and clinical data is imperative to enable informed decisions and reduce the attrition rate during drug development. The volume and variety of data generated during drug development have increased tremendously. A new information model and visualization tool was developed to effectively utilize all available data and current knowledge. The Knowledge Plot integrates preclinical, clinical, efficacy and safety data by adding two concepts: knowledge from the different disciplines and protein binding. Internal and public available data were gathered and processed to allow flexible and interactive visualizations. The exposure was expressed as the unbound concentration of the compound and the treatment effect was normalized and scaled by including expert opinion on what a biologically meaningful treatment effect would be. The Knowledge Plot has been applied both retrospectively and prospectively in project teams in a number of different therapeutic areas, resulting in closer collaboration between multiple disciplines discussing both preclinical and clinical data. The Plot allows head to head comparisons of compounds and was used to support Candidate Drug selections and differentiation from comparators and competitors, back translation of clinical data, understanding the predictability of preclinical models and assays, reviewing drift in primary endpoints over the years, and evaluate or benchmark compounds in due diligence comparing multiple attributes. The Knowledge Plot concept allows flexible integration and visualization of relevant data for interpretation in order to enable scientific and informed decision-making in various stages of drug development. The concept can be used for communication, decision-making, knowledge management, and as a forward and back translational tool, that will result in an improved understanding of the competitive edge for a particular project or disease area portfolio. In addition, it also builds up a knowledge and translational continuum, which in turn will reduce the attrition rate and costs of clinical development by identifying poor candidates early. PMID:24098919

Ibogaine in the treatment of substance dependence.

PubMed

Brown, Thomas Kingsley

2013-03-01

Ibogaine is a psychoactive alkaloid derived from Tabernanthe iboga, a plant used in initiatory rituals in West Central Africa. Largely because of ibogaine's status as a Schedule I substance in the U.S., the development of ibogaine's use in the treatment of drug addiction took place outside conventional clinical and medical settings. This article reviews the history of ibogaine's use in the treatment of drug addiction, and discusses progress made towards, and obstacles blocking, the establishment of controlled clinical trials of ibogaine's efficacy. Preclinical research has generally supported anecdotal claims that ibogaine attenuates withdrawal symptoms and reduces drug cravings. Concerns about ibogaine's safety, as well as a dearth of solid data from human studies, have hampered progress in its development as an approved medication. This article outlines major findings from preclinical studies, discusses concerns about ibogaine's safety, and details previous and ongoing research on ibogaine's use as an anti-addictive treatment for humans.

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

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

Neurological Aspects of Medical Use of Cannabidiol.

PubMed

Mannucci, Carmen; Navarra, Michele; Calapai, Fabrizio; Spagnolo, Elvira V; Busardò, Francesco P; Cas, Roberto D; Ippolito, Francesca M; Calapai, Gioacchino

2017-01-01

Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases. The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field. Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders. Laboratory and clinical studies on the potential role of CBD in Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined. Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Acquisition of dental skills in preclinical technique courses: influence of spatial and manual abilities.

PubMed

Schwibbe, Anja; Kothe, Christian; Hampe, Wolfgang; Konradt, Udo

2016-10-01

Sixty years of research have not added up to a concordant evaluation of the influence of spatial and manual abilities on dental skill acquisition. We used Ackerman's theory of ability determinants of skill acquisition to explain the influence of spatial visualization and manual dexterity on the task performance of dental students in two consecutive preclinical technique courses. We measured spatial and manual abilities of applicants to Hamburg Dental School by means of a multiple choice test on Technical Aptitude and a wire-bending test, respectively. Preclinical dental technique tasks were categorized as consistent-simple and inconsistent-complex based on their contents. For analysis, we used robust regression to circumvent typical limitations in dental studies like small sample size and non-normal residual distributions. We found that manual, but not spatial ability exhibited a moderate influence on the performance in consistent-simple tasks during dental skill acquisition in preclinical dentistry. Both abilities revealed a moderate relation with the performance in inconsistent-complex tasks. These findings support the hypotheses which we had postulated on the basis of Ackerman's work. Therefore, spatial as well as manual ability are required for the acquisition of dental skills in preclinical technique courses. These results support the view that both abilities should be addressed in dental admission procedures in addition to cognitive measures.

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.

Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human.

PubMed

Salphati, Laurent; Pang, Jodie; Plise, Emile G; Chou, Bilin; Halladay, Jason S; Olivero, Alan G; Rudewicz, Patrick J; Tian, Qingping; Wong, Susan; Zhang, Xiaolin

2011-12-01

The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation is associated with the development of many cancers. GDC-0941, a potent and selective inhibitor of PI3K, was characterised preclinically in in vitro and in vivo studies. Plasma protein binding was extensive, with free fraction less than 7%, and blood-to-plasma ratio ranged from 0.6 to 1.2 among the species tested. GDC-0941 human hepatic clearance was predicted to be moderate by liver microsomal incubations. GDC-0941 had high permeability in Madin-Darby canine kidney cells. The clearance of GDC-0941 was high in mouse (63.7 mL/min/kg), rat (49.3 mL/min/kg) and cynomolgus monkey (58.6 mL/min/kg), and moderate in dog (11.9 mL/min/kg). The volume of distribution ranged from 2.52 L/kg in rat to 2.94 L/kg in monkey. Oral bioavailability ranged from 18.6% in monkey to 77.9% in mouse. Predicted human clearance and volume of distribution using allometry were 6 mL/min/kg and 2.9 L/kg, respectively. The human efficacious doses were predicted based on results from preclinical pharmacokinetic studies and xenograft models. GDC-0941 preclinical characterisation and predictions of its properties in human supported its progression towards clinical development. GDC-0941 is currently in phase II clinical trials.

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.

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.

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.

Preclinical tests of an android based dietary logging application.

PubMed

Kósa, István; Vassányi, István; Pintér, Balázs; Nemes, Márta; Kámánné, Krisztina; Kohut, László

2014-01-01

The paper describes the first, preclinical evaluation of a dietary logging application developed at the University of Pannonia, Hungary. The mobile user interface is briefly introduced. The three evaluation phases examined the completeness and contents of the dietary database and the time expenditure of the mobile based diet logging procedure. The results show that although there are substantial individual differences between various dietary databases, the expectable difference with respect to nutrient contents is below 10% on typical institutional menu list. Another important finding is that the time needed to record the meals can be reduced to about 3 minutes daily especially if the user uses set-based search. a well designed user interface on a mobile device is a viable and reliable way for a personalized lifestyle support service.

The Roles of Cigarette Smoking and the Lung in the Transitions between Phases of Preclinical Rheumatoid Arthritis

PubMed Central

Sparks, Jeffrey A.; Karlson, Elizabeth W.

2016-01-01

While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis. PMID:26951253

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.

Remediating lapses in professionalism among undergraduate pre-clinical medical students in an Asian Institution: a multimodal approach.

PubMed

Findyartini, Ardi; Sudarsono, Nani Cahyani

2018-05-02

Fostering personal identity formation and professional development among undergraduate medical students is challenging. Based on situated learning, experiential learning and role-modelling frameworks, a six-week course was developed to remediate lapses in professionalism among undergraduate medical students. This study aims to explore the students' perceptions of their personal identity formation and professional development following completion of the course. This qualitative study, adopting a phenomenological design, uses the participants' reflective diaries as primary data sources. In the pilot course, field work, role-model shadowing and discussions with resource personnel were conducted. A total of 14 students were asked to provide written self-reflections. Consistent, multi-source feedback was provided throughout the course. A thematic analysis was conducted to identify the key processes of personal and professional development among the students during remediation. Three main themes were revealed. First, students highlighted the strength of small group activities in helping them 'internalise the essential concepts'. Second, the role-model shadowing supported their understanding of 'what kind of medical doctors they would become'. Third, the field work allowed them to identify 'what the "noble values" are and how to implement them in daily practice'. By implementing multimodal activities, the course has high potential in supporting personal identity formation and professional development among undergraduate pre-clinical medical students, as well as remediating their lapses in professionalism. However, there are challenges in implementing the model among a larger student population and in documenting the long-term impact of the course.

Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

PubMed Central

Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

2015-01-01

Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

PubMed Central

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

2014-01-01

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

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.

Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs

PubMed Central

Basel, Matthew T.; Balivada, Sivasai; Beck, Amanda P.; Kerrigan, Maureen A.; Pyle, Marla M.; Dekkers, Jack C.M.; Wyatt, Carol R.; Rowland, Robert R.R.; Anderson, David E.; Bossmann, Stefan H.

2012-01-01

Abstract Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans. PMID:23514746

Alteration of Skin Properties with Autologous Dermal Fibroblasts

PubMed Central

Thangapazham, Rajesh L.; Darling, Thomas N.; Meyerle, Jon

2014-01-01

Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue. They are primarily responsible for synthesizing collagen and glycosaminoglycans; components of extracellular matrix supporting the structural integrity of the skin. Dermal fibroblasts play a pivotal role in cutaneous wound healing and skin repair. Preclinical studies suggest wider applications of dermal fibroblasts ranging from skin based indications to non-skin tissue regeneration in tendon repair. One clinical application for autologous dermal fibroblasts has been approved by the Food and Drug Administration (FDA) while others are in preclinical development or various stages of regulatory approval. In this context, we outline the role of fibroblasts in wound healing and discuss recent advances and the current development pipeline for cellular therapies using autologous dermal fibroblasts. The microanatomic and phenotypic differences of fibroblasts occupying particular locations within the skin are reviewed, emphasizing the therapeutic relevance of attributes exhibited by subpopulations of fibroblasts. Special focus is provided to fibroblast characteristics that define regional differences in skin, including the thick and hairless skin of the palms and soles as compared to hair-bearing skin. This regional specificity and functional identity of fibroblasts provides another platform for developing regional skin applications such as the induction of hair follicles in bald scalp or alteration of the phenotype of stump skin in amputees to better support their prosthetic devices. PMID:24828202

Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

PubMed

Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

2016-10-01

[(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gene Therapy for Metachromatic Leukodystrophy

PubMed Central

Rosenberg, Jonathan B.; Kaminsky, Stephen M.; Aubourg, Patrick; Crystal, Ronald G.; Sondhi, Dolan

2016-01-01

Summary Leukodystrophies are rare white matter genetic disorders of the central nervous system (CNS) with progressive neurologic deterioration. One approach to the treatment of leukodystrophies is by gene therapy. Using metachromatic leukodystrophy (MLD), a leukodystrophy resulting from deficiency of a lysosomal catabolic enzyme arylsulfatase A (ARSA) as the example, this review is focused on the current status of preclinical and clinical development of gene therapy as a viable treatment option for leukodystrophies. In MLD, mutations in the ARSA gene result in excess buildup of sulfatides, which triggers apoptosis of glia and neurons. The disease is characterized by severe cerebral demyelination and atrophy, with progressive loss of oligodendrocytes, neurons and Schwann cells. The optimal therapy for MLD would provide persistent and high level expression of ARSA in the CNS. Gene therapy using adeno-associated virus (AAV) is an ideal choice for clinical development as it provides the best balance of potential for efficacy with a reduced safety risk profile. In this review, we have summarized preclinical data that support the use of a gene therapy with the AAVrh.10 serotype for clinical development as a treatment for MLD. PMID:27638601

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

Clinical Trials in a Dish: A Perspective on the Coming Revolution in Drug Development.

PubMed

Fermini, Bernard; Coyne, Shawn T; Coyne, Kevin P

2018-05-01

The pharmaceutical industry is facing unprecedented challenges as the cost of developing new drugs has reached unsustainable levels, fueled in large parts by a high attrition rate in clinical development. Strategies to bridge studies between preclinical testing and clinical trials are needed to reduce the knowledge gap and allow earlier decisions to be made on the continuation or discontinuation of further development of drugs. The discovery and development of human induced pluripotent stem cells (hiPSCs) have opened up new avenues that support the concept of screening for cell-based safety and toxicity at the level of a population. This approach, termed "Clinical Trials in a Dish" (CTiD), allows testing medical therapies for safety or efficacy on cells collected from a representative sample of human patients, before moving into actual clinical trials. It can be applied to the development of drugs for specific populations, and it allows predicting not only the magnitude of effects but also the incidence of patients in a population who will benefit or be harmed by these drugs. This, in turn, can lead to the selection of safer drugs to move into clinical development, resulting in a reduction in attrition. The current article offers a perspective of this new model for "humanized" preclinical drug development.

Beyond bricks and mortar: a rural network approach to preclinical medical education.

PubMed

Myhre, Douglas L; Adamiak, Paul; Turley, Nathan; Spice, Ron; Woloschuk, Wayne

2014-08-09

Countries with expansive rural regions often experience an unequal distribution of physicians between rural and urban communities. A growing body of evidence suggests that the exposure to positive rural learning experiences has an influence on a physician's choice of practice location. Capitalizing on this observation, many medical schools have developed approaches that integrate rural exposure into their curricula during clerkship. It is postulated that a preclinical rural exposure may also be effective. However, to proceed further in development, accreditation requirements must be considered. In this investigation, academic equivalence between a preclinical rural community based teaching method and the established education model was assessed. Two separate preclinical courses from the University of Calgary's three year Undergraduate Medical program were taught at two different rural sites in 2010 (11 students) and 2012 (12 students). The same academic content was delivered in the pilot sites as in the main teaching centre. To ensure consistency of teaching skills, faculty development was provided at each pilot site. Academic equivalence between the rural based learners and a matched cohort at the main University of Calgary site was determined using course examination scores, and the quality of the experience was evaluated through learner feedback. In both pilot courses there was no significant difference between examination scores of the rural distributed learners and the learners at the main University of Calgary site (p > 0.05). Feedback from the participating students demonstrated that the preceptors were very positively rated and, relative to the main site, the small group learning environment appeared to provide strengthened social support. These results suggest that community distributed education in pre-clerkship may offer academically equivalent training to existing traditional medical school curricula while also providing learners with positive rural social learning environments. The approach described may offer the potential to increase exposure to rural practice without the cost of constructing additional physical learning sites.

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

Predicting United States Medical Licensure Examination Step 2 clinical knowledge scores from previous academic indicators.

PubMed

Monteiro, Kristina A; George, Paul; Dollase, Richard; Dumenco, Luba

2017-01-01

The use of multiple academic indicators to identify students at risk of experiencing difficulty completing licensure requirements provides an opportunity to increase support services prior to high-stakes licensure examinations, including the United States Medical Licensure Examination (USMLE) Step 2 clinical knowledge (CK). Step 2 CK is becoming increasingly important in decision-making by residency directors because of increasing undergraduate medical enrollment and limited available residency vacancies. We created and validated a regression equation to predict students' Step 2 CK scores from previous academic indicators to identify students at risk, with sufficient time to intervene with additional support services as necessary. Data from three cohorts of students (N=218) with preclinical mean course exam score, National Board of Medical Examination subject examinations, and USMLE Step 1 and Step 2 CK between 2011 and 2013 were used in analyses. The authors created models capable of predicting Step 2 CK scores from academic indicators to identify at-risk students. In model 1, preclinical mean course exam score and Step 1 score accounted for 56% of the variance in Step 2 CK score. The second series of models included mean preclinical course exam score, Step 1 score, and scores on three NBME subject exams, and accounted for 67%-69% of the variance in Step 2 CK score. The authors validated the findings on the most recent cohort of graduating students (N=89) and predicted Step 2 CK score within a mean of four points (SD=8). The authors suggest using the first model as a needs assessment to gauge the level of future support required after completion of preclinical course requirements, and rescreening after three of six clerkships to identify students who might benefit from additional support before taking USMLE Step 2 CK.

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.

gPKPDSim: a SimBiology®-based GUI application for PKPD modeling in drug development.

PubMed

Hosseini, Iraj; Gajjala, Anita; Bumbaca Yadav, Daniela; Sukumaran, Siddharth; Ramanujan, Saroja; Paxson, Ricardo; Gadkar, Kapil

2018-04-01

Modeling and simulation (M&S) is increasingly used in drug development to characterize pharmacokinetic-pharmacodynamic (PKPD) relationships and support various efforts such as target feasibility assessment, molecule selection, human PK projection, and preclinical and clinical dose and schedule determination. While model development typically require mathematical modeling expertise, model exploration and simulations could in many cases be performed by scientists in various disciplines to support the design, analysis and interpretation of experimental studies. To this end, we have developed a versatile graphical user interface (GUI) application to enable easy use of any model constructed in SimBiology ® to execute various common PKPD analyses. The MATLAB ® -based GUI application, called gPKPDSim, has a single screen interface and provides functionalities including simulation, data fitting (parameter estimation), population simulation (exploring the impact of parameter variability on the outputs of interest), and non-compartmental PK analysis. Further, gPKPDSim is a user-friendly tool with capabilities including interactive visualization, exporting of results and generation of presentation-ready figures. gPKPDSim was designed primarily for use in preclinical and translational drug development, although broader applications exist. gPKPDSim is a MATLAB ® -based open-source application and is publicly available to download from MATLAB ® Central™. We illustrate the use and features of gPKPDSim using multiple PKPD models to demonstrate the wide applications of this tool in pharmaceutical sciences. Overall, gPKPDSim provides an integrated, multi-purpose user-friendly GUI application to enable efficient use of PKPD models by scientists from various disciplines, regardless of their modeling expertise.

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

Issues related to development of antiepileptogenic therapies.

PubMed

Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R; Dudek, F Edward; Friedman, Daniel; Galanopoulou, Aristea S; Jensen, Frances E; Kaminski, Rafal M; Kapur, Jaideep; Klitgaard, Henrik; Löscher, Wolfgang; Mody, Istvan; Schmidt, Dieter

2013-08-01

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura.

PubMed

Kopić, A; Benamara, K; Piskernik, C; Plaimauer, B; Horling, F; Höbarth, G; Ruthsatz, T; Dietrich, B; Muchitsch, E-M; Scheiflinger, F; Turecek, M; Höllriegl, W

2016-07-01

Essentials ADAMTS-13-deficiency is a cause of thrombotic thrombocytopenic purpura (TTP). Preclinical safety of recombinant human ADAMTS-13 (BAX930) was shown in animal models. Preclinical efficacy of BAX930 was shown in a mouse model of TTP. BAX930 showed advantageous efficacy over fresh frozen plasma, the current standard of care. Click to hear Dr Cataland and Prof. Lämmle present a seminar on Thrombotic Thrombocytopenic Purpura (TTP): new Insights in Pathogenesis and Treatment Modalities. Background Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by microthrombosis in small blood vessels of the body, resulting in a low platelet count. Baxalta has developed a new recombinant ADAMTS-13 (rADAMTS-13) product (BAX930) for on-demand and prophylactic treatment of patients with hereditary TTP (hTTP). Objectives To evaluate the pharmacokinetics, efficacy and safety of BAX930 in different species, by use of an extensive preclinical program. Methods The prophylactic and therapeutic efficacies of BAX930 were tested in a previously established TTP mouse model. Pharmacokinetics were evaluated after single intravenous bolus injection in mice and rats, and after repeated dosing in cynomolgus monkeys. Toxicity was assessed in rats and monkeys, safety pharmacology in monkeys, and local tolerance in rabbits. Results BAX930 was shown to be efficacious, as demonstrated by a stabilized platelet count in ADAMTS-13 knockout mice that were thrombocytopenic when treated. Prophylactic efficacy was dose-dependent and comparable with that achieved by treatment with fresh frozen plasma, the mainstay of hTTP treatment. Therapeutic efficacy was treatment interval-dependent. Safety pharmacology evaluation did not show any deleterious effects of BAX930 on cardiovascular and respiratory functions in monkeys. The compound's pharmacokinetics were similar and dose-proportional in mice, rats, and monkeys. BAX930 was well tolerated in rats, monkeys, and rabbits, even at the highest doses tested. Conclusions These results demonstrate that BAX930 has a favorable preclinical profile, and support the clinical development of rADAMTS-13 for the treatment of hTTP. © 2016 International Society on Thrombosis and Haemostasis.

Medications Development for the Treatment of Alcohol Use Disorder: Insights into the Predictive Value of Animal and Human Laboratory Models

PubMed Central

Yardley, Megan M.; Ray, Lara A.

2016-01-01

Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research. PMID:26833803

How modeling and simulation have enhanced decision making in new drug development.

PubMed

Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

2005-04-01

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

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.

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.

Is prostate cancer different in black men? Answers from three natural history models

PubMed Central

Tsodikov, Alex; Gulati, Roman; de Carvalho, Tiago M.; Heijnsdijk, Eveline A. M.; Hunter-Merrill, Rachel A.; Mariotto, Angela B.; de Koning, Harry J.; Etzioni, Ruth

2017-01-01

Background Black men in the US have substantially higher prostate cancer incidence rates than the general population. The extent to which the incidence disparity is due to prostate cancer being more prevalent, more aggressive, and/or more frequently diagnosed in black men is unknown. Methods We estimated three independently developed models of prostate cancer natural history in black men and in the general population using an updated reconstruction of PSA screening, based on the National Health Interview Survey in 2005, and prostate cancer incidence from the Surveillance, Epidemiology, and End Results program in 1975–2000. Using the estimated models, we compared prostate cancer natural history in black men and in the general population. Results The models projected that 30–43% (range across models) of black men develop preclinical prostate cancer by age 85 years, a risk that is (relatively) 28–56% higher than in the general population. Among men who have had preclinical disease onset, black men have a similar risk of diagnosis (35–49%) compared with the general population (32–44%), but their risk of progression to metastatic disease by the time of diagnosis is 44–75% higher than in the general population. Conclusions Prostate cancer incidence patterns implicate higher incidence of preclinical disease and higher risk of metastatic progression among black men. The findings suggest screening black men earlier than white men and support further research into the benefit-harm tradeoffs of more aggressive screening policies for black men. PMID:28436011

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

Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review.

PubMed

Roffi, Alice; Di Matteo, Berardo; Krishnakumar, Gopal Shankar; Kon, Elizaveta; Filardo, Giuseppe

2017-02-01

The treatment of large bone defects represents a significant challenge for orthopaedic surgeons. In recent years, biologic agents have also been used to further improve bone healing. Among these, platelet-rich plasma (PRP) is the most exploited strategy. The aim of the present study was to systematically review the available literature to identify: 1) preclinical in-vivo results supporting the rational of PRP use for bone healing; 2) evidence from the clinical practice on the actual clinical benefit of PRP for the treatment of fractures and complications such as delayed unions and non-unions. A systematic review of the literature was performed on the application of PRP in bone healing, using the following inclusion criteria: pre-clinical and clinical reports of any level of evidence, written in English language, published in the last 20 years (1996-2016), on the use of PRP to stimulate long-bone defect treatment, with focus on fracture and delayed/non-unions healing. The search in the Pubmed database identified 64 articles eligible for inclusion: 45 were preclinical in-vivo studies and 19 were clinical studies. Despite the fact that the overall pre-clinical results seem to support the benefit of PRP in 91.1 % of the studies, a more in depth analysis underlined a lower success rate, with a positive outcome of 84.4 % in terms of histological analysis, and even lower values considering radiological and biomechanical results (75.0 % and 72.7 % positive outcome respectively). This was also mirrored in the clinical literature, where the real benefit of PRP use to treat fractures and non-unions is still under debate. Overall, the available literature presents major limitations in terms of low quality and extreme heterogeneity, which hamper the possibility to optimize PRP treatment and translate it into a real clinical benefit despite positive preclinical findings on its biological potential to favour bone healing.

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

PubMed

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

2010-07-01

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

What Does Sex Have to Do with It? The Role of Sex as a Biological Variable in the Development of Posttraumatic Stress Disorder.

PubMed

Kornfield, Sara L; Hantsoo, Liisa; Epperson, C Neill

2018-05-18

This review highlights the neurobiological aspects of sex differences in posttraumatic stress disorder (PTSD), specifically focusing on the physiological responses to trauma and presents evidence supporting hormone and neurosteroid/peptide differences from both preclinical and clinical research. While others have suggested that trauma type or acute emotional reaction are responsible for women's disproportionate risk to PTSD, neither of these explanations fully accounts for the sex differences in PTSD. Sex differences in brain neurocircuitry, anatomy, and neurobiological processes, such as those involved in learning and memory, are discussed as they have been implicated in risk and resilience for the development of PTSD. Gonadal and stress hormones have been found to modulate sex differences in the neurocircuitry and neurochemistry underlying fear learning and extinction. Preclinical research has not consistently controlled for hormonal and reproductive status of rodents nor have clinical studies consistently examined these factors as potential moderators of risk for PTSD. Sex as a biological variable (SABV) should be considered, in addition to the endocrine and reproductive status of participants, in all stress physiology and PTSD research.

An interlaboratory transfer of a multi-analyte assay between continents.

PubMed

Georgiou, Alexandra; Dong, Kelly; Hughes, Stephen; Barfield, Matthew

2015-01-01

Alex has worked at GlaxoSmithKline for the past 15 years and currently works within the bioanalytical and toxicokinetic group in the United Kingdom. Alex's role in previous years has been the in-house support of preclinical and clinical bioanalysis, from method development through to sample analysis activities as well as acting as PI for GLP bioanalysis and toxicokinetics. For the past two years, Alex has applied this analytical and regulatory experience to focus on the outsourcing of preclinical bioanalysis, toxicokinetics and clinical bioanalysis, working closely with multiple bioanalytical and in-life CRO partners worldwide. Alex works to support DMPK and Safety Assessment outsourcing activities for GSK across multiple therapeutic areas, from the first GLP study through to late stage clinical PK studies. Transfer and cross-validation of an existing analytical assay between a laboratory providing current analytical support, and a laboratory needed for new or additional support, can present the bioanalyst with numerous challenges. These challenges can be technical or logistical in nature and may prove to be significant when transferring an assay between laboratories in different continents. Part of GlaxoSmithKline's strategy to improve confidence in providing quality data, is to cross-validate between laboratories. If the cross-validation fails predefined acceptance criteria, then a subsequent investigation would follow. This may also prove to be challenging. The importance of thorough planning and good communication throughout assay transfer, cross-validation and any subsequent investigations is illustrated in this case study.

Strategies for bringing drug delivery tools into discovery.

PubMed

Kwong, Elizabeth; Higgins, John; Templeton, Allen C

2011-06-30

The past decade has yielded a significant body of literature discussing approaches for development and discovery collaboration in the pharmaceutical industry. As a result, collaborations between discovery groups and development scientists have increased considerably. The productivity of pharma companies to deliver new drugs to the market, however, has not increased and development costs continue to rise. Inability to predict clinical and toxicological response underlies the high attrition rate of leads at every step of drug development. A partial solution to this high attrition rate could be provided by better preclinical pharmacokinetics measurements that inform PD response based on key pathways that drive disease progression and therapeutic response. A critical link between these key pharmacology, pharmacokinetics and toxicology studies is the formulation. The challenges in pre-clinical formulation development include limited availability of compounds, rapid turn-around requirements and the frequent un-optimized physical properties of the lead compounds. Despite these challenges, this paper illustrates some successes resulting from close collaboration between formulation scientists and discovery teams. This close collaboration has resulted in development of formulations that meet biopharmaceutical needs from early stage preclinical in vivo model development through toxicity testing and development risk assessment of pre-clinical drug candidates. Published by Elsevier B.V.

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.

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

A De Novo Tool to Measure the Preclinical Learning Climate of Medical Faculties in Turkey

ERIC Educational Resources Information Center

Yilmaz, Nilufer Demiral; Velipasaoglu, Serpil; Sahin, Hatice; Basusta, Bilge Uzun; Midik, Ozlem; Coskun, Ozlem; Budakoglu, Isil Irem; Mamakli, Sumer; Tengiz, Funda Ifakat; Durak, Halil Ibrahim; Ozan, Sema

2015-01-01

Although several scales are used to measure general and clinical learning climates, there are no scales that assess the preclinical learning climate. Therefore, the purpose of this study was to develop an effective measurement tool in order to assess the preclinical learning climate. In this cross-sectional study, data were collected from 3,540…

Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD

PubMed Central

Wolk, David A.; Mancuso, Lauren; Kliot, Daria; Arnold, Steven E.; Dickerson, Bradford C.

2013-01-01

There is great interest in the development of cognitive markers that differentiate “normal” age-associated cognitive change from that of Alzheimer's disease (AD) in its prodromal (i.e., mild cognitive impairment; MCI) or even preclinical stages. Dual process models posit that recognition memory is supported by the dissociable processes of recollection and familiarity. Familiarity-based memory has generally been considered to be spared during normal aging, but it remains controversial whether this type of memory is impaired in early AD. Here, we describe findings of estimates of recollection and familiarity in young adults (YA), cognitively normal older adults (CN), and patients with amnestic-MCI (a-MCI). These measures in the CN and a-MCI patients were then related to a structural imaging biomarker of AD that has previously been demonstrated to be sensitive to preclinical and prodromal AD, the Cortical Signature of AD (ADsig). Consistent with much work in the literature, recollection, but not familiarity, was impaired in CN versus YA. Replicating our prior findings, a-MCI patients displayed impairment in both familiarity and recollection. Finally, the familiarity measure was correlated with the ADsig biomarker across the CN and a-MCI group, as well as within the CN adults alone. No other standard psychometric measure was as highly associated with the ADsig, suggesting that familiarity may be a sensitive biomarker of AD-specific brain changes in preclinical and prodromal AD and that it may offer a qualitatively distinct measure of early AD memory impairment relative to normal age-associated change. PMID:23474075

Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.

PubMed

Graham, Mark J; Lee, Richard G; Bell, Thomas A; Fu, Wuxia; Mullick, Adam E; Alexander, Veronica J; Singleton, Walter; Viney, Nick; Geary, Richard; Su, John; Baker, Brenda F; Burkey, Jennifer; Crooke, Stanley T; Crooke, Rosanne M

2013-05-24

Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

PubMed Central

Beatty, Gregory L.; Li, Yan; Long, Kristen B.

2017-01-01

INTRODUCTION CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. AREAS COVERED We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. EXPERT COMMENTARY There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance. PMID:27927088

Development of the PANVAC-VF vaccine for pancreatic cancer.

PubMed

Petrulio, Christian A; Kaufman, Howard L

2006-02-01

PANVAC-VF is a vaccine regimen composed of a priming dose of recombinant vaccinia virus and booster doses of recombinant fowlpox virus expressing carcinoembryonic antigen, mucin-1 and a triad of costimulatory molecules (TRICOM), which include B7.1, intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. Vaccination is administered by subcutaneous injection followed by 4 days of local recombinant adjuvant granulocyte-macrophage colony-stimulating factor at the vaccination site. The vaccine has been developed for patients with advanced pancreatic cancer and has now entered a randomized Phase III clinical trial. This review will describe the background of recombinant poxvirus technology for tumor vaccine development, detail the key preclinical studies supporting the regimen, review the clinical trials supporting the current Phase III study, and highlight the key challenges and future obstacles to successful implementation of PANVAC-VF for pancreatic cancer.

A community of practice approach to bioanalysis delivery: the role of the Preclinical Bioanalysis and Toxicokinetics department at AstraZeneca.

PubMed

Wilson, Amanda; Silvester, Stephen; Woods, Karen

2014-05-01

Retaining regulated bioanalysis within AstraZeneca (AZ) is important for the effective delivery of nonclinical and clinical bioanalysis. The focus for the in-house team is the delivery of high-throughput bioanalysis and toxicokinetics support for investigational toxicology; however, by retaining GLP compliance, AZ will have an in-house understanding of every candidate drug that is progressed into development by supporting the first rodent GLP study for each project. The majority of nonclinical bioanalysis and all of the clinical bioanalysis are delivered by two external partnership models. This article describes the key benefits of retaining GLP compliance, the partnership interactions, discusses the management of non-GLP support in a GLP environment and how, having practical experience of regulatory facing method development, validation and study execution adds value to the AZ portfolio delivery.

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 isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes. PMID:27445678

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

High-performance dual-energy imaging with a flat-panel detector: imaging physics from blackboard to benchtop to bedside

NASA Astrophysics Data System (ADS)

Siewerdsen, J. H.; Shkumat, N. A.; Dhanantwari, A. C.; Williams, D. B.; Richard, S.; Daly, M. J.; Paul, N. S.; Moseley, D. J.; Jaffray, D. A.; Yorkston, J.; Van Metter, R.

2006-03-01

The application of high-performance flat-panel detectors (FPDs) to dual-energy (DE) imaging offers the potential for dramatically improved detection and characterization of subtle lesions through reduction of "anatomical noise," with applications ranging from thoracic imaging to image-guided interventions. In this work, we investigate DE imaging performance from first principles of image science to preclinical implementation, including: 1.) generalized task-based formulation of NEQ and detectability as a guide to system optimization; 2.) measurements of imaging performance on a DE imaging benchtop; and 3.) a preclinical system developed in our laboratory for cardiac-gated DE chest imaging in a research cohort of 160 patients. Theoretical and benchtop studies directly guide clinical implementation, including the advantages of double-shot versus single-shot DE imaging, the value of differential added filtration between low- and high-kVp projections, and optimal selection of kVp pairs, filtration, and dose allocation. Evaluation of task-based NEQ indicates that the detectability of subtle lung nodules in double-shot DE imaging can exceed that of single-shot DE imaging by a factor of 4 or greater. Filter materials are investigated that not only harden the high-kVp beam (e.g., Cu or Ag) but also soften the low-kVp beam (e.g., Ce or Gd), leading to significantly increased contrast in DE images. A preclinical imaging system suitable for human studies has been constructed based upon insights gained from these theoretical and experimental studies. An important component of the system is a simple and robust means of cardiac-gated DE image acquisition, implemented here using a fingertip pulse oximeter. Timing schemes that provide cardiac-gated image acquisition on the same or successive heartbeats is described. Preclinical DE images to be acquired under research protocol will afford valuable testing of optimal deployment, facilitate the development of DE CAD, and support comparison of DE diagnostic imaging performance to low-dose CT and radiography.

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.

Peer-mentoring Program during the Preclinical Years of Medical School at Bonn University: a Project Description.

PubMed

Lapp, Hendrik; Makowka, Philipp; Recker, Florian

2018-01-01

Introduction: To better prepare young medical students in a thorough and competent manner for the ever increasing clinical, scientific, as well as psychosocial requirements, universities should enable a close, personal transfer of experience and knowledge. Structured mentoring programs are a promising approach to incorporate clinical subjects earlier into the preclinical training. Such a mentoring program facilitates the prioritization of concepts from a broad, theory-heavy syllabus. Here we report the experiences and results of the preclinical mentoring program of Bonn University, which was introduced in the winter semester of 2012/2013. Project desciption: The program is characterized by the concept of peer-to-peer teaching during the preclinical semesters of medical school. Regular, voluntary course meetings with different clinical case examples provide students the opportunity to apply knowledge acquired from the basic science curricula; furthermore, a personal contact for advice and support is ensured. Thus, an informal exchange of experiences is made possible, which provides to the students motivational and learning aids, in particular for the oral examination at the end of the premedical semesters as well as for other examinations during medical school. Results: Over the course of the preceding three years the number of participants and the interest in the program grew steadily. The analysis of collected evaluations confirms very good communication between mentors and students (>80%), as well as consistently good to very good quality and usefulness in terms of the mentors' subject-specific and other advice. The overall final evaluation of the mentoring program was always good to very good (winter semester: very good 64.8±5.0%, good 35.2±5.0%, summer semester: very good 83.9±7.5%, good 16.1±7.5%) Summary: In summary, it has been shown that the mentoring program had a positive impact on the development, education and satisfaction of students beginning their preclinical semesters at Bonn University.

Update on Standard Operating Procedures in Preclinical Research for DMD and SMA Report of TREAT-NMD Alliance Workshop, Schiphol Airport, 26 April 2015, The Netherlands.

PubMed

van Putten, Maaike; Aartsma-Rus, Annemieke; Grounds, Miranda D; Kornegay, Joe N; Mayhew, Anna; Gillingwater, Thomas H; Takeda, Shin'ichi; Rüegg, Markus A; De Luca, Annamaria; Nagaraju, Kanneboyina; Willmann, Raffaella

A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies.

The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders.

PubMed

Collins, Gregory T; Gerak, Lisa R; France, Charles P

2017-12-12

Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) 2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT 2C receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT 2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. Copyright © 2017 Elsevier Ltd. All rights reserved.

Big data sharing and analysis to advance research in post-traumatic epilepsy.

PubMed

Duncan, Dominique; Vespa, Paul; Pitkanen, Asla; Braimah, Adebayo; Lapinlampi, Nina; Toga, Arthur W

2018-06-01

We describe the infrastructure and functionality for a centralized preclinical and clinical data repository and analytic platform to support importing heterogeneous multi-modal data, automatically and manually linking data across modalities and sites, and searching content. We have developed and applied innovative image and electrophysiology processing methods to identify candidate biomarkers from MRI, EEG, and multi-modal data. Based on heterogeneous biomarkers, we present novel analytic tools designed to study epileptogenesis in animal model and human with the goal of tracking the probability of developing epilepsy over time. Copyright © 2017. Published by Elsevier Inc.

Army Science Conference Proceedings Held in Orlando, Florida on June 22 - 25, 1992. Volume 1, Principal Authors A Through G.

DTIC Science & Technology

1992-06-25

Michael See Bryzik, Walter I 205 Reid, Robert H. Oral, Microencapsulated, CFA/II III 35 Vaccine Against E. coli Diarrheal Disease: Preclinical Evaluation...Cloning, Characterization, and III 179 Expression of Animal Toxin Genes for Vaccine Development Smith, Stan See Juhasz, Arpad II 159 Soicher, Haim...modeling predictions that were supported by test data. FWD AND AFT SHELLS LONGERONS T300 GR/934 EPOXYAND T300 GR/934 EPOXY(BASELINE) CORK HS (BASELINE) GR

Honey and contemporary wound care: an overview.

PubMed

Cutting, Keith F

2007-11-01

A growing body of research and empirical evidence have supported the re-discovery of medicinal grade honey as a wound management agent. Pre-clinical study results suggest that honey has therapeutic benefit; clinical study results have shown that honey effectively addresses exudate, inflammation, devitalized tissue, and infection. Honey-containing dressings and gels have been developed to facilitate the application of medicinal-grade honey to the wound. Clinical studies to compare the safety and effectiveness of these products to other moisture-retentive dressings and treatment modalities are warranted.

An analysis of technology usage for streaming digital video in support of a preclinical curriculum.

PubMed

Dev, P; Rindfleisch, T C; Kush, S J; Stringer, J R

2000-01-01

Usage of streaming digital video of lectures in preclinical courses was measured by analysis of the data in the log file maintained on the web server. We observed that students use the video when it is available. They do not use it to replace classroom attendance but rather for review before examinations or when a class has been missed. Usage of video has not increased significantly for any course within the 18 month duration of this project.

Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats.

PubMed

Tétreault, Pascal; Dansereau, Marc-André; Doré-Savard, Louis; Beaudet, Nicolas; Sarret, Philippe

2011-09-01

Preclinical pain assessment remains a key step for the development of new and potent painkillers. Significant progress in pain evaluation has been achieved with the development of non-reflexive tools. Seeking efficient and clinically relevant devices for pain-related quality of life assessment, we evaluated a new Dynamic Weight Bearing (DWB) device based on pressure captors in three different preclinical chronic pain models. Inflammatory (CFA), neuropathic (CCI) and bone cancer pain (femoral tumor) models were evaluated in Sprague Dawley rats for mechanical allodynia using dynamic von Frey for pain-related behaviors and DWB for discomfort. We observed similar impairment patterns in all of the models for both von Frey (allodynia) and DWB (weight balance) during the complete observation period, starting at day 3 in CCI- and CFA-affected limbs and at day 14 in bone cancer-afflicted rats, indicating that the DWB could be a useful tool for supporting pain assessment. Interestingly, we demonstrated that the main compensation, when animals experienced pain, was seen in the forepaws, ranging from 46% to 69% of increased load compared to normal. Other pain-related coping behaviors were also measured, such as the time spent on each paw and the contact surface. Our results revealed that CFA, CCI and cancerous rats decreased the use of their ipsilateral hind paws by 30% and showed a 50% reduction in paw surface pressed against the floor. In conclusion, this new device improves methods for preclinical evaluation of discomfort and quality of life proxies and could be helpful in screening putative analgesics. Copyright © 2011 Elsevier Inc. All rights reserved.

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

Gut microbiota-bone axis.

PubMed

Villa, Christopher R; Ward, Wendy E; Comelli, Elena M

2017-05-24

The gut microbiota (GM) is an important regulator of body homeostasis, including intestinal and extra-intestinal effects. This review focuses on the GM-bone axis, which we define as the effect of the gut-associated microbial community or the molecules they synthesize, on bone health. While research in this field is limited, findings from preclinical studies support that gut microbes positively impact bone mineral density and strength parameters. Moreover, administration of beneficial bacteria (probiotics) in preclinical models has demonstrated higher bone mineralization and greater bone strength. The preferential bacterial genus that has shown these beneficial effects in bone is Lactobacillus and thus lactobacilli are among the best candidates for future clinical intervention trials. However, their effectiveness is dependent on stage of development, as early life constitutes an important time for impacting bone health, perhaps via modulation of the GM. In addition, sex-specific difference also impacts the efficacy of the probiotics. Although auspicious, many questions regarding the GM-bone axis require consideration of potential mechanisms; sex-specific efficacy; effective dose of probiotics; and timing and duration of treatment.

A low-cost touchscreen operant chamber using a Raspberry Pi™.

PubMed

O'Leary, James D; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

2018-03-08

The development of a touchscreen platform for rodent testing has allowed new methods for cognitive testing that have been back-translated from clinical assessment tools to preclinical animal models. This platform for cognitive assessment in animals is comparable to human neuropsychological tests such as those employed by the Cambridge Neuropsychological Test Automated Battery, and thus has several advantages compared to the standard maze apparatuses typically employed in rodent behavioral testing, such as the Morris water maze. These include improved translation of preclinical models, as well as high throughput and the automation of animal testing. However, these systems are relatively expensive, which can impede progress for researchers with limited resources. Here we describe a low-cost touchscreen operant chamber based on the single-board computer, Raspberry Pi TM , which is capable of performing tasks similar to those supported by current state-of-the-art systems. This system provides an affordable alternative for cognitive testing in a touchscreen operant paradigm for researchers with limited funding.

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease.

PubMed

Schneider, Lon S

2014-03-01

The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Biopsychosocial influence on shoulder pain: rationale and protocol for a pre-clinical trial

PubMed Central

George, Steven Z.; Staud, Roland; Borsa, Paul A.; Wu, Samuel S.; Wallace, Margaret R.; Greenfield, Warren. H.; Mackie, Lauren N.; Fillingim, Roger B.

2017-01-01

Background Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12 month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Methods Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. Conclusion This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. Trial Registration ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015) PMID:28315479

Biopsychosocial influence on shoulder pain: Rationale and protocol for a pre-clinical trial.

PubMed

George, Steven Z; Staud, Roland; Borsa, Paul A; Wu, Samuel S; Wallace, Margaret R; Greenfield, Warren H; Mackie, Lauren N; Fillingim, Roger B

2017-05-01

Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015). Copyright © 2017 Elsevier Inc. All rights reserved.

Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel.

PubMed

Sémiond, D; Sidhu, S S; Bissery, M-C; Vrignaud, P

2013-09-01

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed. Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51. Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence. These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Matrix reloaded: CCN, tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities.

PubMed

Thakur, Ravi; Mishra, Durga Prasad

2016-12-01

Matricellular proteins (MCPs) are the non-structural extracellular matrix (ECM) proteins with various regulatory functions. MCPs are critical regulators of ECM homeostasis and are often found dysregulated in various malignancies. They interact with various proteins like ECM structural proteins, integrins, growth factor receptors and growth factors to modulate their availability and activity. Cancer-supporting MCPs are known to induce proliferation, migration and invasion of cancer cells. MCPs also support cancer stem (like) cell growth and induce a drug-resistant state. Apart from their direct effects on cancer cells, they play key roles in angiogenesis, immunomodulation, stromal cell infiltration, stromal proliferation and matrix remodeling. High expression of various MCPs belonging to the tenascin, CCN and SIBLING families is often associated with aggressive tumors and poor patient prognosis. Due to their differential expression and distinct functional role, these MCPs are perceived as attractive therapeutic targets in cancer. Studies on preclinical models have indicated that targeting tumor-supportive MCPs could be a potent avenue for developing anti-cancer therapies. The MCP receptors, like integrins and some associated growth factor receptors, are already being targeted using pharmacological inhibitors and neutralizing antibodies. Neutralizing antibodies against CCNs, tenascins and SIBLINGs have shown promising results in preclinical cancer models, suggesting an opportunity to develop anti-MCP therapies to target cancer. Peptides derived from anti-cancer MCPs could also serve as therapeutic entities. In the present review, in continuation with the expanding horizon of MCP functions and disease association, we focus on (i) their unique domain arrangement, (ii) their association with cancer hallmarks and (iii) available and possible therapeutic interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.

PubMed

Bisi, John E; Sorrentino, Jessica A; Roberts, Patrick J; Tavares, Francis X; Strum, Jay C

2016-05-01

Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first- and second-line treatment of small-cell lung cancer. Mol Cancer Ther; 15(5); 783-93. ©2016 AACR. ©2016 American Association for Cancer Research.

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.

Human Milk Oligosaccharides and the Preterm Infant: A Journey in Sickness and in Health.

PubMed

Moukarzel, Sara; Bode, Lars

2017-03-01

Human milk oligosaccharides (HMOs) are a group of approximately 200 different unconjugated sugar structures in human milk proposed to support infant growth and development. Data from several preclinical animal studies and human cohort studies suggest HMOs reduce preterm infant mortality and morbidity by shaping the gut microbiome and protecting against necrotizing enterocolitis, candidiasis, and several other immune-related diseases. Current feeding practices and clinical algorithms do not consider infant HMO intake when assessing dietary adequacy or disease risk. Advancements in HMO analytical methodologies and HMO synthesis facilitate cohort and intervention studies to investigate which particular HMOs are most relevant in supporting preterm infants. Copyright © 2016 Elsevier Inc. All rights reserved.

The paradox of natural products as pharmaceuticals. Experimental evidences of a mango stem bark extract.

PubMed

Núñez-Sellés, Alberto J; Delgado-Hernández, René; Garrido-Garrido, Gabino; García-Rivera, Dagmar; Guevara-García, Mariela; Pardo-Andreu, Gilberto L

2007-05-01

Recent findings regarding basic, pre-clinical and clinical studies on a mango stem bark extract (MSBE) developed in Cuba (Vimang) on an industrial scale are summarized. Ethnomedical studies, extract reproducibility, biological effects and clinical evaluations in terms of patient quality of life are described as experimental evidences to support the statement that natural products, even being a mixture of compounds, could be as effective as "monoceuticals" for medical uses. Discussion about the use of "monoceuticals" versus "natureceuticals" in health care and medicine is based on effectiveness and availability, taking Vimang as an example of a natural product with supported scientific evidence to be used as antioxidant, analgesic, anti-inflammatory and immunomodulator.

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.

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.

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

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

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study

PubMed Central

Aschenbrenner, Andrew J.; Balota, David A.; Fagan, Anne M.; Duchek, Janet M.; Benzinger, Tammie L.S.; Morris, John C.

2015-01-01

Objective Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed in order to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. Method All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within two years of the initial assessment to collect cerebrospinal fluid (CSF) and a PET-PIB scan for amyloid imaging. Results Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. Conclusion These results indicate that measures of attentional control and episodic memory can be utilized to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change. PMID:26416094

Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials.

PubMed

Will, Elke; Bailey, Jeff; Schuesler, Todd; Modlich, Ute; Balcik, Brenden; Burzynski, Ben; Witte, David; Layh-Schmitt, Gerlinde; Rudolph, Cornelia; Schlegelberger, Brigitte; von Kalle, Christof; Baum, Christopher; Sorrentino, Brian P; Wagner, Lars M; Kelly, Patrick; Reeves, Lilith; Williams, David A

2007-04-01

Although retroviral vectors are one of the most widely used vehicles for gene transfer, there is no uniformly accepted pre-clinical model defined to assess their safety, in particular their risk related to insertional mutagenesis. In the murine pre-clinical study presented here, 40 test and 10 control mice were transplanted with ex vivo manipulated bone marrow cells to assess the long-term effects of the transduction of hematopoietic cells with the retroviral vector MSCV-MGMT(P140K)wc. Test mice had significant gene marking 8-12 months post-transplantation with an average of 0.93 vector copies per cell and 41.5% of peripheral blood cells expressing the transgene MGMT(P140K), thus confirming persistent vector expression. Unexpectedly, six test mice developed malignant lymphoma. No vector was detected in the tumor cells of five animals with malignancies, indicating that the malignancies were not caused by insertional mutagenesis or MGMT(P140K) expression. Mice from a concurrent study with a different transgene also revealed additional cases of vector-negative lymphomas of host origin. We conclude that the background tumor formation in this mouse model complicates safety determination of retroviral vectors and propose an improved study design that we predict will increase the relevance and accuracy of interpretation of pre-clinical mouse studies.

Alzheimer Disease Cerebrospinal Fluid Biomarkers Moderate Baseline Differences and Predict Longitudinal Change in Attentional Control and Episodic Memory Composites in the Adult Children Study.

PubMed

Aschenbrenner, Andrew J; Balota, David A; Fagan, Anne M; Duchek, Janet M; Benzinger, Tammie L S; Morris, John C

2015-09-01

Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change.

Faculty impressions of dental students' performance with and without virtual reality simulation.

PubMed

Gottlieb, Riki; Lanning, Sharon K; Gunsolley, John C; Buchanan, Judith A

2011-11-01

This study compared faculty perceptions and expectations of dental students' abilities using virtual reality simulation (VRS) to those who did not use virtual reality simulation (non-VRS) in an operative dentistry preclinical course. A sixteen-item survey with a ten-point rating scale and three open-ended questions asked about students' abilities in ergonomics, confidence level, performance, preparation, and self-assessment. The surveys were administered three times to a small group of preclinical faculty members. First, faculty members (n=12, 92 percent response rate) gave their perceptions of non-VRS students' abilities at the end of their traditional course. Secondly, faculty members (n=13, 100 percent response rate) gave their expectations of the next incoming class's abilities (VRS students) prior to the start of the course with traditional and VRS components. Finally, faculty members (n=13, 100 percent response rate) gave their perceptions of VRS students' abilities after completion of the course. A Tukey's test for multiple comparisons measured significance among survey items. Faculty perceptions of VRS students' abilities were higher than for non-VRS students for most abilities examined. However, the faculty members' expectations of VRS training were higher than their perceptions of the students' abilities after VRS training for most abilities examined. Since ergonomic development and technical performance were positively impacted by VRS training, these results support the use of VRS in a preclinical dental curriculum.

Preclinical characterization of therapeutic antibodies targeted at the carboxy-terminus of Sonic hedgehog

PubMed Central

Tolani, Bhairavi; Hoang, Ngoc T.; Acevedo, Luis A.; Leprieur, Etienne Giroux; Li, Hui; He, Biao; Jablons, David M.

2018-01-01

The Sonic Hedgehog (Shh) signaling pathway has been implicated in the development and tumor progression of a number of human cancers. Using synthetic peptide mimics to mount an immune response, we generated a mouse mAb to the carboxy (C)-terminus of the Shh protein and characterized its preclinical antitumor effects. In vitro screening guided selection of the best candidate for mAb scale-up production and therapeutic development. C-term anti-Shh, Ab 1C11-2G4 was selected based on ELISA screens, Western blotting, and flow cytometric analyses. Purified Ab 1C11-2G4 was shown to recognize and bind both Shh peptide mimics and cell surface Shh. Administration of Ab 1C11-2G4 not only reduced cell viability in 7 cancer cell lines but also significantly inhibitted tumor growth in a xenograft model of A549 lung cancer cells. Ex vivo analyses of xenograft tumors revealed a reduction in Shh signal transduction and apoptosis in 2G4-treated mice. Collectively, our results provide early demonstration of the antitumor utility of antibodies specific for the C-terminal region of Shh, and support continued development to evaluate their potential efficacy in cancers in which Shh activity is elevated. PMID:29581846

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, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Animal Models and the Development of Vaccines to Treat Substance Use Disorders.

PubMed

Ohia-Nwoko, O; Kosten, T A; Haile, C N

2016-01-01

The development of pharmacotherapies for substance use disorders (SUDs) is a high priority in addiction research. At present, there are no approved pharmacotherapies for cocaine and methamphetamine use disorders, while treatments for nicotine and opioid use are moderately effective. Indeed, many of these treatments can cause adverse drug side effects and have poor medication compliance, which often results in increased drug relapse rates. An alternative to these traditional pharmacological interventions is immunotherapy or vaccines that can target substances associated with SUDs. In this chapter, we discuss the current knowledge on the efficacy of preclinical vaccines, particularly immunogens that target methamphetamine, cocaine, nicotine, or opioids to attenuate drug-induced behaviors in animal models of SUDs. We also review vaccines (and antibodies) against cocaine, nicotine, and methamphetamine that have been assessed in human clinical trials. While preclinical studies indicate that several vaccines show promise, these findings have not necessarily translated to the clinical population. Thus, continued effort to design more effective vaccine immunogens using SUD animal models is necessary in order to support the use of immunotherapy as a viable option for individuals with SUDs. © 2016 Elsevier Inc. All rights reserved.

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 develop any specialist surgical tooling required. The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator. © 2018 IOP Publishing Ltd.

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

PubMed

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

2016-01-01

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

Amyloid-β, anxiety, and cognitive decline in preclinical Alzheimer disease: a multicenter, prospective cohort study.

PubMed

Pietrzak, Robert H; Lim, Yen Ying; Neumeister, Alexander; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Restrepo, Carolina; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

2015-03-01

Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-β (Aβ) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of Aβ-related cognitive decline, such as anxiety and depressive symptoms. To evaluate the association between Aβ status and cognitive changes, and the role of anxiety and depressive symptoms in moderating Aβ-related cognitive changes in the preclinical phase of AD. In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of Aβ, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. A positive Aβ (Aβ+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the Aβ+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the Aβ+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms; furthermore, depressive symptoms and subjective memory complaints did not moderate the association between Aβ and cognitive decline. These results provide additional support for the deleterious effect of elevated Aβ levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of Aβ on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.

Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice.

PubMed

Apps, John Richard; Martinez-Barbera, Juan Pedro

2016-12-01

Since the first identification of CTNNB1 mutations in adamantinomatous craniopharyngioma (ACP), much has been learned about the molecular pathways and processes that are disrupted in ACP pathogenesis. To date this understanding has not translated into tangible patient benefit. The recent development of novel techniques and a range of preclinical models now provides an opportunity to begin to support treatment decisions and develop new therapeutics based on molecular pathology. In this review the authors summarize many of the key findings and pathways implicated in ACP pathogenesis and discuss the challenges that need to be tackled to translate these basic science findings for the benefit of patients.

Lactoferrin and prematurity: a promising milk protein?

PubMed

Ochoa, Theresa J; Sizonenko, Stéphane V

2017-02-01

Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm infants has been shown to reduce the incidence of sepsis and necrotizing enterocolitis. In preclinical models of antenatal stress and perinatal brain injury, bovine Lf protected the developing brain from neuronal loss, improved connectivity, increased neurotrophic factors, and decreased inflammation. It also supported brain development and cognition. Further, Lf can prevent preterm delivery by reducing proinflammatory factors and inhibiting premature cervix maturation. We review here the latest research on Lf in the field of neonatology.

Development of a Hampton University Program for Novel Breast Cancer Imaging and Therapy Research

DTIC Science & Technology

2013-04-01

intracavitary brachytherapy procedures during laboratory pre-clinical imaging and dosimetry equipment testing, calibration and data processing, in collaboration... electronics and detector instrumentation development; 4) breast phantom construction and implantation; 5) laboratory pre-clinical device testing...such as the ionization chamber, diode, radiographic verification 6 films and thermoluminescent dosimeters ( TLD ) but the scintillator fiber detectors

Mechanical Circulatory Support of the Critically Ill Child Awaiting Heart Transplantation

PubMed Central

Gazit, Avihu Z; Gandhi, Sanjiv K; C Canter, Charles

2010-01-01

The majority of children awaiting heart transplantation require inotropic support, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO) support. Unfortunately, due to the limited pool of organs, many of these children do not survive to transplant. Mechanical circulatory support of the failing heart in pediatrics is a new and rapidly developing field world-wide. It is utilized in children with acute congestive heart failure associated with congenital heart disease, cardiomyopathy, and myocarditis, both as a bridge to transplantation and as a bridge to myocardial recovery. The current arsenal of mechanical assist devices available for children is limited to ECMO, intra-aortic balloon counterpulsation, centrifugal pump ventricular assist devices, the DeBakey ventricular assist device Child; the Thoratec ventricular assist device; and the Berlin Heart. In the spring of 2004, five contracts were awarded by the National Heart, Lung and Blood Institute to support preclinical development for a range of pediatric ventricular assist devices and similar circulatory support systems. The support of early development efforts provided by this program is expected to yield several devices that will be ready for clinical trials within the next few years. Our work reviews the current international experience with mechanical circulatory support in children and summarizes our own experience since 2005 with the Berlin Heart, comparing the indications for use, length of support, and outcome between these modalities. PMID:21286278

Thunder and lightning: immunotherapy and oncolytic viruses collide.

PubMed

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-06-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers.

Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies

PubMed Central

Ocana, Alberto; Pandiella, Atanasio

2017-01-01

Triple negative breast cancer (TNBC) is still an incurable disease despite the great scientific effort performed during the last years. The huge heterogeneity of this disease has motivated the evaluation of a great number of therapies against different molecular alterations. In this article, we review the biological bases of this entity and how the known molecular evidence supports the current preclinical and clinical development of new therapies. Special attention will be given to ongoing clinical studies and potential options for future drug combinations. PMID:28108739

Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide

PubMed Central

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-01-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers. PMID:21505424

Using standardized patients versus video cases for representing clinical problems in problem-based learning.

PubMed

Yoon, Bo Young; Choi, Ikseon; Choi, Seokjin; Kim, Tae-Hee; Roh, Hyerin; Rhee, Byoung Doo; Lee, Jong-Tae

2016-06-01

The quality of problem representation is critical for developing students' problem-solving abilities in problem-based learning (PBL). This study investigates preclinical students' experience with standardized patients (SPs) as a problem representation method compared to using video cases in PBL. A cohort of 99 second-year preclinical students from Inje University College of Medicine (IUCM) responded to a Likert scale questionnaire on their learning experiences after they had experienced both video cases and SPs in PBL. The questionnaire consisted of 14 items with eight subcategories: problem identification, hypothesis generation, motivation, collaborative learning, reflective thinking, authenticity, patient-doctor communication, and attitude toward patients. The results reveal that using SPs led to the preclinical students having significantly positive experiences in boosting patient-doctor communication skills; the perceived authenticity of their clinical situations; development of proper attitudes toward patients; and motivation, reflective thinking, and collaborative learning when compared to using video cases. The SPs also provided more challenges than the video cases during problem identification and hypotheses generation. SPs are more effective than video cases in delivering higher levels of authenticity in clinical problems for PBL. The interaction with SPs engages preclinical students in deeper thinking and discussion; growth of communication skills; development of proper attitudes toward patients; and motivation. Considering the higher cost of SPs compared with video cases, SPs could be used most advantageously during the preclinical period in the IUCM curriculum.

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

PubMed

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

2016-02-01

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

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA.

PubMed

Canetta, Sarah E; Brown, Alan S

2012-12-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

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

Stewart, J; Lindsay, P; University of Toronto, Toronto

Purpose: Recent progress in small animal radiotherapy systems has provided the foundation for delivering the heterogeneous, millimeter scale dose distributions demanded by preclinical radiobiology investigations. Despite advances in preclinical dose planning, delivery of highly heterogeneous dose distributions is constrained by the fixed collimation systems and large x-ray focal spot common in small animal radiotherapy systems. This work proposes a dual focal spot dose optimization and delivery method with a large x-ray focal spot used to deliver homogeneous dose regions and a small focal spot to paint spatially heterogeneous dose regions. Methods: Two-dimensional dose kernels were measured for a 1 mmmore » circular collimator with radiochromic film at 10 mm depth in a solid water phantom for the small and large x-ray focal spots on a recently developed small animal microirradiator. These kernels were used in an optimization framework which segmented a desired dose distribution into low- and high-spatial frequency regions for delivery by the large and small focal spot, respectively. For each region, the method determined an optimal set of stage positions and beam-on times. The method was demonstrated by optimizing a bullseye pattern consisting of 0.75 mm radius circular target and 0.5 and 1.0 mm wide rings alternating between 0 and 2 Gy. Results: Compared to a large focal spot technique, the dual focal spot technique improved the optimized dose distribution: 69.2% of the optimized dose was within 0.5 Gy of the intended dose for the large focal spot, compared to 80.6% for the dual focal spot method. The dual focal spot design required 14.0 minutes of optimization, and will require 178.3 minutes for automated delivery. Conclusion: The dual focal spot optimization and delivery framework is a novel option for delivering conformal and heterogeneous dose distributions at the preclinical level and provides a new experimental option for unique radiobiological investigations. Funding Support: this work is supported by funding the National Sciences and Engineering Research Council of Canada, and a Mitacs-accelerate fellowship. Conflict of Interest: Dr. Lindsay and Dr. Jaffray are listed as inventors of the small animal microirradiator described herein. This system has been licensed for commercial development.« less

Beyond the VAD: Human Factors Engineering for Mechanically Assisted Circulation in the 21st Century.

PubMed

Throckmorton, Amy L; Patel-Raman, Sonna M; Fox, Carson S; Bass, Ellen J

2016-06-01

Thousands of ventricular assist devices (VADs) currently provide circulatory support to patients worldwide, and dozens of heart pump designs for adults and pediatric patients are under various stages of development in preparation for translation to clinical use. The successful bench-to-bedside development of a VAD involves a structured evaluation of possible system states, including human interaction with the device and auxiliary component usage in the hospital or home environment. In this study, we review the literature and present the current landscape of preclinical design and assessment, decision support tools and procedures, and patient-centered therapy. Gaps of knowledge are identified. The study findings support the need for more attention to user-centered design approaches for medical devices, such as mechanical circulatory assist systems, that specifically involve detailed qualitative and quantitative assessments of human-device interaction to mitigate risk and failure. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Adjuvant bisphosphonate treatment for breast cancer: Where are we heading and can the pre-clinical literature help us get there?

PubMed

Russell, Kent; Clemons, Mark; Costa, Luis; Addison, Christina L

2012-06-01

Bisphosphonates have demonstrated anti-tumour activity in preclinical studies of bone metastatic disease, thus it was natural to transition these agents into the adjuvant cancer therapy setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest to no benefit or even harm. We sought to explore whether the preclinical results supporting bisphosphonate use provided clues to help explain the current clinical data. Interestingly, the majority of preclinical data suggested that bisphosphonate treatment was more efficacious when administered after the establishment of osseous metastases. This is similar to the findings of one clinical study whereby patients with biopsy evidence of osseous micrometastases derive greater survival benefit from bisphosphonate treatment. Another clinical study found bisphosphonates were associated with increased incidence of visceral metastases, similar to what has been previously published in preclinical models using "preventative" dosing strategies. While the current clinical data suggest bisphosphonates may be more efficacious in post-menopausal or oestrogen depleted patients, or those with hormone receptor positive tumours, to date no appropriately designed preclinical studies have evaluated these effects. Furthermore, putative mechanisms that regulate response to bisphosphonates in other tumour types remain to be evaluated in breast cancer. Despite the initial optimism regarding adjuvant bisphosphonate therapy, the conflicting clinical results from large trials suggest that we should return to the bench to further investigate factors that may influence response to bisphosphonate treatment or identify appropriate characteristics that would indicate the sub-groups of patients most likely to benefit from bisphosphonate treatment.

Is prostate cancer different in black men? Answers from 3 natural history models.

PubMed

Tsodikov, Alex; Gulati, Roman; de Carvalho, Tiago M; Heijnsdijk, Eveline A M; Hunter-Merrill, Rachel A; Mariotto, Angela B; de Koning, Harry J; Etzioni, Ruth

2017-06-15

Black men in the United States have substantially higher prostate cancer incidence rates than the general population. The extent to which this incidence disparity is because prostate cancer is more prevalent, more aggressive, and/or more frequently diagnosed in black men is unknown. The authors estimated 3 independently developed models of prostate cancer natural history in black men and in the general population using an updated reconstruction of prostate-specific antigen screening, based on the National Health Interview Survey in 2005 and on prostate cancer incidence data from the Surveillance, Epidemiology, and End Results program during 1975 through 2000. By using the estimated models, the natural history of prostate cancer was compared between black men and the general population. The models projected that from 30% to 43% (range across models) of black men develop preclinical prostate cancer by age 85 years, a risk that is (relatively) 28% to 56% higher than that in the general population. Among men who had preclinical disease onset, black men had a similar risk of diagnosis (range, 35%-49%) compared with the general population (32%-44%), but their risk of progression to metastatic disease by the time of diagnosis was from 44% to 75% higher than that in the general population. Prostate cancer incidence patterns implicate higher incidence of preclinical disease and higher risk of metastatic progression among black men. The findings suggest screening black men earlier than white men and support further research into the benefit-harm tradeoffs of more aggressive screening policies for black men. Cancer 2017;123:2312-2319. © 2017 American Cancer Society. © 2017 American Cancer Society.

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 Author(s) 2016.

Temporary skin grafts based on hybrid graphene oxide-natural biopolymer nanofibers as effective wound healing substitutes: pre-clinical and pathological studies in animal models.

PubMed

Mahmoudi, N; Eslahi, N; Mehdipour, A; Mohammadi, M; Akbari, M; Samadikuchaksaraei, A; Simchi, A

2017-05-01

In recent years, temporary skin grafts (TSG) based on natural biopolymers modified with carbon nanostructures have received considerable attention for wound healing. Developments are required to improve physico-mechanical properties of these materials to match to natural skins. Additionally, in-deep pre-clinical examinations are necessary to ensure biological performance and toxicity effect in vivo. In the present work, we show superior acute-wound healing effect of graphene oxide nanosheets embedded in ultrafine biopolymer fibers (60 nm) on adult male rats. Nano-fibrous chitosan-based skin grafts crosslinked by Genepin with physico-mechanical properties close to natural skins were prepared by electrospinning of highly concentrated chitosan- polyvinylpyrrolidone solutions containing graphene oxide (GO) nanosheets. No surfactants and organic solvents were utilized to ensure high biocompatibility of the fibrous structure. In vitro evaluations by human skin fibroblast cells including live and dead assay and MTT results show that GO promote cell viability of porous nanofibrous membrane while providing enhanced bactericidal capacity. In vivo studies on rat's skin determine accelerated healing effect, i.e. a large open wound (1.5 × 1.5 cm 2 ) is fully regenerated after 14-day of post operation while healing is observed for sterile gauze sponge (as the control). Pathological studies support thick dermis formation and complete epithelialization in the presence of 1.5 wt% GO nanosheets. Over 99% wound healing occurs after 21 days for the injury covered with TSG containing 1.5 wt% GO while this would takes weeks for the control. Therefore, the developed materials have a high potential to be used as TSG as pre-clinical testing has shown.

Predicting performance: relative importance of students' background and past performance.

PubMed

Stegers-Jager, Karen M; Themmen, Axel P N; Cohen-Schotanus, Janke; Steyerberg, Ewout W

2015-09-01

Despite evidence for the predictive value of both pre-admission characteristics and past performance at medical school, their relative contribution to predicting medical school performance has not been thoroughly investigated. This study was designed to determine the relative importance of pre-admission characteristics and past performance in medical school in predicting student performance in pre-clinical and clinical training. This longitudinal prospective study followed six cohorts of students admitted to a Dutch, 6-year, undergraduate medical course during 2002-2007 (n = 2357). Four prediction models were developed using multivariate logistic regression analysis. Main outcome measures were 'Year 1 course completion within 1 year' (models 1a, 1b), 'Pre-clinical course completion within 4 years' (model 2) and 'Achievement of at least three of five clerkship grades of ≥ 8.0' (model 3). Pre-admission characteristics (models 1a, 1b, 2, 3) and past performance at medical school (models 1b, 2, 3) were included as predictor variables. In model 1a - including pre-admission characteristics only - the strongest predictor for Year 1 course completion was pre-university grade point average (GPA). Success factors were 'selected by admission testing' and 'age > 21 years'; risk factors were 'Surinamese/Antillean background', 'foreign pre-university degree', 'doctor parent' and male gender. In model 1b, number of attempts and GPA at 4 months were the strongest predictors for Year 1 course completion, and male gender remained a risk factor. Year 1 GPA was the strongest predictor for pre-clinical course completion, whereas being male or aged 19-21 years were risk factors. Pre-clinical course GPA positively predicted clinical performance, whereas being non-Dutch or a first-generation university student were important risk factors for lower clinical grades. Nagelkerke's R(2) ranged from 0.16 to 0.62. This study not only confirms the importance of past performance as a predictor of future performance in pre-clinical training, but also reveals the importance of a student's background as a predictor in clinical training. These findings have important practical implications for selection and support during medical school. © 2015 John Wiley & Sons Ltd.

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.

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

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

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

Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.

2012-07-01

Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there hasmore » been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free doxorubicin. ► Mechanistic data identifying differences with free doxorubicin in cardiomyocytes. ► Preclinical safety results support decision to proceed with Phase I clinical trials. ► Suggests platform may be amenable to assay preclinical toxicity of other therapies.« less

Therapeutic Applications of PARP Inhibitors: Anticancer Therapy and Beyond

PubMed Central

Curtin, Nicola; Szabo, Csaba

2013-01-01

The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well. PMID:23370117

Intraoperative intravital microscopy permits the study of human tumour vessels

PubMed Central

Fisher, Daniel T.; Muhitch, Jason B.; Kim, Minhyung; Doyen, Kurt C.; Bogner, Paul N.; Evans, Sharon S.; Skitzki, Joseph J.

2016-01-01

Tumour vessels have been studied extensively as they are critical sites for drug delivery, anti-angiogenic therapies and immunotherapy. As a preclinical tool, intravital microscopy (IVM) allows for in vivo real-time direct observation of vessels at the cellular level. However, to date there are no reports of intravital high-resolution imaging of human tumours in the clinical setting. Here we report the feasibility of IVM examinations of human malignant disease with an emphasis on tumour vasculature as the major site of tumour-host interactions. Consistent with preclinical observations, we show that patient tumour vessels are disorganized, tortuous and ∼50% do not support blood flow. Human tumour vessel diameters are larger than predicted from immunohistochemistry or preclinical IVM, and thereby have lower wall shear stress, which influences delivery of drugs and cellular immunotherapies. Thus, real-time clinical imaging of living human tumours is feasible and allows for detection of characteristics within the tumour microenvironment. PMID:26883450

Applications of iQID cameras

NASA Astrophysics Data System (ADS)

Han, Ling; Miller, Brian W.; Barrett, Harrison H.; Barber, H. Bradford; Furenlid, Lars R.

2017-09-01

iQID is an intensified quantum imaging detector developed in the Center for Gamma-Ray Imaging (CGRI). Originally called BazookaSPECT, iQID was designed for high-resolution gamma-ray imaging and preclinical gamma-ray single-photon emission computed tomography (SPECT). With the use of a columnar scintillator, an image intensifier and modern CCD/CMOS sensors, iQID cameras features outstanding intrinsic spatial resolution. In recent years, many advances have been achieved that greatly boost the performance of iQID, broadening its applications to cover nuclear and particle imaging for preclinical, clinical and homeland security settings. This paper presents an overview of the recent advances of iQID technology and its applications in preclinical and clinical scintigraphy, preclinical SPECT, particle imaging (alpha, neutron, beta, and fission fragment), and digital autoradiography.

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…

The role of alternative and natural agents, cryotherapy, and/or laser for management of alimentary mucositis.

PubMed

Migliorati, Cesar A; Oberle-Edwards, Loree; Schubert, Mark

2006-06-01

To review the literature and update the current guidelines of alternative/natural agents, cryotherapy, and/or laser therapy in the management of alimentary mucositis (AM). The original guidelines developed by the Multinational Association for Supportive Care in Cancer (MASCC)/International Society for Oral Oncology (ISOO) mucositis study group were the basis for this study. A medical librarian conducted an initial Medline search to identify research articles published between 2002 and 2005 in English language. A search term combination that included stomatitis, mucositis, mucous membrane, neoplasm, lasers, complimentary therapies, amino acids, antioxidants, vitamins, minerals, plant extracts, and cryotherapy was conducted. This initial search identified articles with a strong scientific methodology that included both preclinical and clinical research. Using standardized scoring forms, authors reviewed and scored individual articles. A consensus result of the review was achieved in a meeting of reviewers in June of 2005. The initial search identified a total of 167 new articles. Of these, 14 were selected and reviewed: alternative/natural therapy (one preclinical study); cryotherapy (four clinical studies); lasers (two clinical studies); and alternative/natural agents (seven clinical studies). A new guideline could be established for the use of cryotherapy in the management of AM in hematopoietic stem cell transplant (HSCT) patients receiving melphalan in the conditioning phase. The rapid progress in the understanding of AM created a need for new prevention and management protocols. Frequent literature review is now necessary to identify agents and protocols being developed in this important area of supportive care in cancer.

Newer insights into the role of miRNA a tiny genetic tool in psychiatric disorders: focus on post-traumatic stress disorder.

PubMed

Giridharan, V V; Thandavarayan, R A; Fries, G R; Walss-Bass, C; Barichello, T; Justice, N J; Reddy, M K; Quevedo, J

2016-11-15

Post-traumatic stress disorder (PTSD) is a mental disorder occurring in about 2-9% of individuals after their exposure to life-threatening events, such as severe accidents, sexual abuse, combat or a natural catastrophe. Because PTSD patients are exposed to trauma, it is likely that epigenetic modifications have an important role in disease development and prognosis. For the past two decades, abnormal expression of the epigenetic regulators microRNAs (miRs) and miR-mediated gene regulation have been given importance in a variety of human diseases, such as cancer, heart disease and viral infection. Emerging evidence supports a role for miR dysregulation in psychiatric and neurological disorders, including schizophrenia, bipolar disorder, anxiety, major depressive disorder, autism spectrum disorder and Tourette's syndrome. Recently mounting of evidence supports the role of miR both in preclinical and clinical settings of psychiatric disorders. Abnormalities in miR expression can fine-tune the expression of multiple genes within a biological network, suggesting that miR dysregulation may underlie many of the molecular changes observed in PTSD pathogenesis. This provides strong evidence that miR not only has a critical role in PTSD pathogenesis, but can also open up new avenues for the development of diagnostic tools and therapeutic targets for the PTSD phenotype. In this review, we revisit some of the recent evidence associated with miR and PTSD in preclinical and clinical settings. We also discuss the possible clinical applications and future use of miRs in PTSD therapy.

Newer insights into the role of miRNA a tiny genetic tool in psychiatric disorders: focus on post-traumatic stress disorder

PubMed Central

Giridharan, V V; Thandavarayan, R A; Fries, G R; Walss-Bass, C; Barichello, T; Justice, N J; Reddy, M K; Quevedo, J

2016-01-01

Post-traumatic stress disorder (PTSD) is a mental disorder occurring in about 2–9% of individuals after their exposure to life-threatening events, such as severe accidents, sexual abuse, combat or a natural catastrophe. Because PTSD patients are exposed to trauma, it is likely that epigenetic modifications have an important role in disease development and prognosis. For the past two decades, abnormal expression of the epigenetic regulators microRNAs (miRs) and miR-mediated gene regulation have been given importance in a variety of human diseases, such as cancer, heart disease and viral infection. Emerging evidence supports a role for miR dysregulation in psychiatric and neurological disorders, including schizophrenia, bipolar disorder, anxiety, major depressive disorder, autism spectrum disorder and Tourette's syndrome. Recently mounting of evidence supports the role of miR both in preclinical and clinical settings of psychiatric disorders. Abnormalities in miR expression can fine-tune the expression of multiple genes within a biological network, suggesting that miR dysregulation may underlie many of the molecular changes observed in PTSD pathogenesis. This provides strong evidence that miR not only has a critical role in PTSD pathogenesis, but can also open up new avenues for the development of diagnostic tools and therapeutic targets for the PTSD phenotype. In this review, we revisit some of the recent evidence associated with miR and PTSD in preclinical and clinical settings. We also discuss the possible clinical applications and future use of miRs in PTSD therapy. PMID:27845777

PRENATAL INFECTION, MATERNAL IMMUNE ACTIVATION, AND RISK FOR SCHIZOPHRENIA

PubMed Central

Canetta, Sarah E.; Brown, Alan S.

2013-01-01

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed. PMID:23956839

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials.

PubMed

Brown, Matt A; Bishnoi, Ram J; Dholakia, Sara; Velligan, Dawn I

2016-01-20

Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.

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.

Using standardized patients versus video cases for representing clinical problems in problem-based learning

PubMed Central

2016-01-01

Purpose: The quality of problem representation is critical for developing students’ problem-solving abilities in problem-based learning (PBL). This study investigates preclinical students’ experience with standardized patients (SPs) as a problem representation method compared to using video cases in PBL. Methods: A cohort of 99 second-year preclinical students from Inje University College of Medicine (IUCM) responded to a Likert scale questionnaire on their learning experiences after they had experienced both video cases and SPs in PBL. The questionnaire consisted of 14 items with eight subcategories: problem identification, hypothesis generation, motivation, collaborative learning, reflective thinking, authenticity, patient-doctor communication, and attitude toward patients. Results: The results reveal that using SPs led to the preclinical students having significantly positive experiences in boosting patient-doctor communication skills; the perceived authenticity of their clinical situations; development of proper attitudes toward patients; and motivation, reflective thinking, and collaborative learning when compared to using video cases. The SPs also provided more challenges than the video cases during problem identification and hypotheses generation. Conclusion: SPs are more effective than video cases in delivering higher levels of authenticity in clinical problems for PBL. The interaction with SPs engages preclinical students in deeper thinking and discussion; growth of communication skills; development of proper attitudes toward patients; and motivation. Considering the higher cost of SPs compared with video cases, SPs could be used most advantageously during the preclinical period in the IUCM curriculum. PMID:26923094

A psychological approach to providing self-management education for people with type 2 diabetes: the Diabetes Manual

PubMed Central

Sturt, Jackie; Taylor, Hafrun; Docherty, Andrea; Dale, Jeremy; Louise, Taylor

2006-01-01

Background The objectives of this study were twofold (i) to develop the Diabetes Manual, a self-management educational intervention aimed at improving biomedical and psychosocial outcomes (ii) to produce early phase evidence relating to validity and clinical feasibility to inform future research and systematic reviews. Methods Using the UK Medical Research Council's complex intervention framework, the Diabetes Manual and associated self management interventions were developed through pre-clinical, and phase I evaluation phases guided by adult-learning and self-efficacy theories, clinical feasibility and health policy protocols. A qualitative needs assessment and an RCT contributed data to the pre-clinical phase. Phase I incorporated intervention development informed by the pre-clinical phase and a feasibility survey. Results The pre-clinical and phase I studies resulted in the production in the Diabetes Manual programme for trial evaluation as delivered within routine primary care consultations. Conclusion This complex intervention shows early feasibility and face validity for both diabetes health professionals and people with diabetes. Randomised trial will determine effectiveness against clinical and psychological outcomes. Further study of some component parts, delivered in alternative combinations, is recommended. PMID:17129376

Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder.

PubMed

Postuma, Ronald B; Gagnon, Jean-François; Vendette, Mélanie; Desjardins, Catherine; Montplaisir, Jacques Y

2011-05-01

For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein-mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease. Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free. Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease-free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex-adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM-100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan-Meier 5-year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages. Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Copyright © 2011 American Neurological Association.

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).

Preclinical and clinical properties of trimegestone: a potent and selective progestin.

PubMed

Sitruk-Ware, Regine; Bossemeyer, Ronald; Bouchard, Phillipe

2007-06-01

Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.

(±)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA.

PubMed

Pitts, Elizabeth G; Curry, Daniel W; Hampshire, Karly N; Young, Matthew B; Howell, Leonard L

2018-02-01

The use of (±)-3,4-methylenedioxymethamphetamine ((±)-MDMA) as an adjunct to psychotherapy in the treatment of psychiatric and behavioral disorders dates back over 50 years. Only in recent years have controlled and peer-reviewed preclinical and clinical studies lent support to (±)-MDMA's hypothesized clinical utility. However, the clinical utility of (±)-MDMA is potentially mitigated by a range of demonstrated adverse effects. One potential solution could lie in the individual S(+) and R(-) enantiomers that comprise (±)-MDMA. Individual enantiomers of racemic compounds have been employed in psychiatry to improve a drug's therapeutic index. Although no research has explored the individual effects of either S(+)-MDMA or R(-)-MDMA in humans in a controlled manner, preclinical research has examined similarities and differences between the two molecules and the racemic compound. This review addresses information related to the pharmacodynamics, neurotoxicity, physiological effects, and behavioral effects of S(+)-MDMA and R(-)-MDMA that might guide preclinical and clinical research. The current preclinical evidence suggests that R(-)-MDMA may provide an improved therapeutic index, maintaining the therapeutic effects of (±)-MDMA with a reduced side effect profile, and that future investigations should investigate the therapeutic potential of R(-)-MDMA.

Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT)

PubMed Central

Atkins, A.S.; Stroescu, I.; Spagnola, N.B.; Davis, V.G.; Patterson, T.D.; Narasimhan, M.; Harvey, P.D.; Keefe, R.S.E.

2015-01-01

Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials. PMID:26618145

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

NASA Astrophysics Data System (ADS)

Bass, Christopher Paul

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of 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.

Rationale of mesenchymal stem cell therapy in kidney injury.

PubMed

Cantaluppi, Vincenzo; Biancone, Luigi; Quercia, Alessandro; Deregibus, Maria Chiara; Segoloni, Giuseppe; Camussi, Giovanni

2013-02-01

Numerous preclinical and clinical studies suggest that mesenchymal stem cells, also known as multipotent mesenchymal stromal cells (MSCs), may improve pathologic conditions involving different organs. These beneficial effects initially were ascribed to the differentiation of MSCs into organ parenchymal cells. However, at least in the kidney, this is a very rare event and the kidney-protective effects of MSCs have been attributed mainly to paracrine mechanisms. MSCs release a number of trophic, anti-inflammatory, and immune-modulatory factors that may limit kidney injury and favor recovery. In this article, we provide an overview of the biologic activities of MSCs that may be relevant for the treatment of kidney injury in the context of a case vignette concerning a patient at high immunologic risk who underwent a second kidney transplantation followed by the development of ischemia-reperfusion injury and acute allograft rejection. We discuss the possible beneficial effect of MSC treatment in the light of preclinical and clinical data supporting the regenerative and immunomodulatory potential of MSCs. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Role of Corticotropin Releasing Factor in Anxiety Disorders: A Translational Research Perspective

PubMed Central

Risbrough, Victoria B.; Stein, Murray B.

2007-01-01

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety. PMID:16870185

Gene Therapy for the Treatment of Diabetic Neuropathy

PubMed Central

Mata, Marina; Chattopadhyay, Munmun; Fink, David J

2009-01-01

Neuropathy is a common, untreatable complication of both type 1 and type 2 diabetes. In animal models peptide neurotrophic factors can be used to protect against the development of neuropathy, but the combination of short half-life and off-target effects of these potent pleiotropic peptides has limited translation to human therapy. Gene transfer is a promising strategy that might circumvent these limitations. In this essay we review the basic methods of gene transfer and the preclinical data in rodent models that support the utility of this approach in the treatment of diabetic neuropathy. The path to a clinical applications and potential pitfalls in developing gene therapy for the treatment of diabetic neuropathy are considered. PMID:18990298

CAPR - Theresa Guerin | Center for Cancer Research

Cancer.gov

Theresa Guerin oversees animal colony management and provides support in breeding experimental animal cohort, preparing documentation for CAPR preclinical studies, as well as assistance in designing drug treatment plans. She also maintains multiple database resources. Expertise

Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses.

PubMed

Guy, Bruno; Guirakhoo, Farshad; Barban, Veronique; Higgs, Stephen; Monath, Thomas P; Lang, Jean

2010-01-08

Dengue viruses (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) are major global health and growing medical problems. While a live-attenuated vaccine exists since decades against the prototype flavivirus, yellow fever virus (YFV), there is an urgent need for vaccines against dengue or West Nile diseases, and for improved vaccines against Japanese encephalitis. Live-attenuated chimeric viruses were constructed by replacing the genes coding for Premembrane (prM) and Envelope (E) proteins from YFV 17D vaccine strain with those of heterologous flaviviruses (ChimeriVax technology). This technology has been used to produce vaccine candidates for humans, for construction of a horse vaccine for West Nile fever, and as diagnostic reagents for dengue, Japanese encephalitis, West Nile and St. Louis encephalitis infections. This review focuses on human vaccines and their characterization from the early stages of research through to clinical development. Phenotypic and genetic properties and stability were examined, preclinical evaluation through in vitro or animal models, and clinical testing were carried out. Theoretical environmental concerns linked to the live and genetically modified nature of these vaccines have been carefully addressed. Results of the extensive characterizations are in accordance with the immunogenicity and excellent safety profile of the ChimeriVax-based vaccine candidates, and support their development towards large-scale efficacy trials and registration.

Gender-specific effects of prenatal and adolescent exposure to tobacco smoke on auditory and visual attention.

PubMed

Jacobsen, Leslie K; Slotkin, Theodore A; Mencl, W Einar; Frost, Stephen J; Pugh, Kenneth R

2007-12-01

Prenatal exposure to active maternal tobacco smoking elevates risk of cognitive and auditory processing deficits, and of smoking in offspring. Recent preclinical work has demonstrated a sex-specific pattern of reduction in cortical cholinergic markers following prenatal, adolescent, or combined prenatal and adolescent exposure to nicotine, the primary psychoactive component of tobacco smoke. Given the importance of cortical cholinergic neurotransmission to attentional function, we examined auditory and visual selective and divided attention in 181 male and female adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. Groups did not differ in age, educational attainment, symptoms of inattention, or years of parent education. A subset of 63 subjects also underwent functional magnetic resonance imaging while performing an auditory and visual selective and divided attention task. Among females, exposure to tobacco smoke during prenatal or adolescent development was associated with reductions in auditory and visual attention performance accuracy that were greatest in female smokers with prenatal exposure (combined exposure). Among males, combined exposure was associated with marked deficits in auditory attention, suggesting greater vulnerability of neurocircuitry supporting auditory attention to insult stemming from developmental exposure to tobacco smoke in males. Activation of brain regions that support auditory attention was greater in adolescents with prenatal or adolescent exposure to tobacco smoke relative to adolescents with neither prenatal nor adolescent exposure to tobacco smoke. These findings extend earlier preclinical work and suggest that, in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention, with concomitant alterations in the efficiency of neurocircuitry supporting auditory attention.

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

PubMed

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

2018-02-01

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

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

PubMed Central

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

2018-01-01

Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet, the manufacture of these vectors is challenging, especially at high titers required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation. The goals of this paper are to report the protocol for manufacturing high-titer third-generation lentivirus for preclinical testing and to provide detailed information on considerations for translating preclinical viral vector manufacture toward scaled-up platforms and processes in order to make gene therapies under Good Manufacturing Practice that are suitable for clinical trials. PMID:29212357

Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.

PubMed

Trump, Donald L; Deeb, Kristin K; Johnson, Candace S

2010-01-01

Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor "bioavailability" of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that high doses of calcitriol (>100 mcg weekly, intravenously, and 0.15 microg /kg weekly, orally) can be given safely. The maximum tolerated dose of calcitriol is unclear. While a 250-patient trial in men with castration-resistant prostate cancer comparing docetaxel (36 mg/sqm weekly) +/- calcitriol 0.15 microg/kg indicated that calcitriol was very safe may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol versus q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or maximum-tolerated dose of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.

Using tablet technology and instructional videos to enhance preclinical dental laboratory learning.

PubMed

Gadbury-Amyot, Cynthia C; Purk, John H; Williams, Brian Joseph; Van Ness, Christopher J

2014-02-01

The purpose of this pilot study was to examine if tablet technology with accompanying instructional videos enhanced the teaching and learning outcomes in a preclinical dental laboratory setting. Two procedures deemed most challenging in Operative Dentistry II were chosen for the development of instructional videos. A random sample of thirty students was chosen to participate in the pilot. Comparison of faculty evaluations of the procedures between the experimental (tablet) and control (no tablet) groups resulted in no significant differences; however, there was a trend toward fewer failures in the experimental group. Examination of the ability to accurately self-assess was compared by exploring correlations between faculty and student evaluations. While correlations were stronger in the experimental group, the control group had significant correlations for all three procedures, while the experimental group had significant correlations on only two of the procedures. Students strongly perceived that the tablets and videos helped them perform better and more accurately self-assess their work products. Students did not support requiring that they purchase/obtain a specific brand of technology. As a result of this pilot study, further development of ideal and non-ideal videos are in progress, and the school will be implementing a "Bring Your Own Device" policy with incoming students.

Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.

PubMed

Wallace, Lindsay M; Saad, Nizar Y; Pyne, Nettie K; Fowler, Allison M; Eidahl, Jocelyn O; Domire, Jacqueline S; Griffin, Danielle A; Herman, Adam C; Sahenk, Zarife; Rodino-Klapac, Louise R; Harper, Scott Q

2018-03-16

RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.

Advances in Degradable Embolic Microspheres: A State of the Art Review

PubMed Central

Doucet, Jensen; Kiri, Lauren; O’Connell, Kathleen; Kehoe, Sharon; Lewandowski, Robert J.; Liu, David M.; Abraham, Robert J.; Boyd, Daniel

2018-01-01

Considerable efforts have been placed on the development of degradable microspheres for use in transarterial embolization indications. Using the guidance of the U.S. Food and Drug Administration (FDA) special controls document for the preclinical evaluation of vascular embolization devices, this review consolidates all relevant data pertaining to novel degradable microsphere technologies for bland embolization into a single reference. This review emphasizes intended use, chemical composition, degradative mechanisms, and pre-clinical safety, efficacy, and performance, while summarizing the key advantages and disadvantages for each degradable technology that is currently under development for transarterial embolization. This review is intended to provide an inclusive reference for clinicians that may facilitate an understanding of clinical and technical concepts related to this field of interventional radiology. For materials scientists, this review highlights innovative devices and current evaluation methodologies (i.e., preclinical models), and is designed to be instructive in the development of innovative/new technologies and evaluation methodologies. PMID:29373510

Microbial exposure in infancy and subsequent appearance of type 1 diabetes mellitus-associated autoantibodies: a cohort study.

PubMed

Virtanen, Suvi M; Takkinen, Hanna-Mari; Nwaru, Bright I; Kaila, Minna; Ahonen, Suvi; Nevalainen, Jaakko; Niinistö, Sari; Siljander, Heli; Simell, Olli; Ilonen, Jorma; Hyöty, Heikki; Veijola, Riitta; Knip, Mikael

2014-08-01

The role of microbial exposure during early life in the development of type 1 diabetes mellitus is unclear. To investigate whether animal contact and other microbial exposures during infancy are associated with the development of preclinical and clinical type 1 diabetes. A birth cohort of children with HLA antigen-DQB1-conferred susceptibility to type 1 diabetes was examined. Participants included 3143 consecutively born children at 2 hospitals in Finland between 1996 and 2004. The following exposures during the first year of life were assessed: indoor and outdoor dogs and cats, farm animals, farming, visit to a stable, day care, and exposure to antibiotics during the first week of life. Clinical and preclinical type 1 diabetes were used as outcomes. The latter was defined as repeated positivity for islet-cell antibodies plus for at least 1 of 3 other diabetes-associated autoantibodies analyzed and/or clinical type 1 diabetes. The autoantibodies were analyzed at 3- to 12-month intervals since the birth of the child. Children exposed to an indoor dog, compared with otherwise similar children without an indoor dog exposure, had a reduced odds of developing preclinical type 1 diabetes (adjusted odds ratio [OR], 0.47; 95% CI, 0.28-0.80; P = .005) and clinical type 1 diabetes (adjusted OR, 0.40; 95% CI, 0.14-1.14; P = .08). All of the other microbial exposures studied were not associated with preclinical or clinical diabetes: the odds ratios ranged from 0.74 to 1.58. Among the 9 early microbial exposures studied, only the indoor dog exposure during the first year of life was inversely associated with the development of preclinical type 1 diabetes. This finding needs to be confirmed in other populations.

Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer’s Disease: A 7-Year Follow-Up Study

PubMed Central

Waragai, Masaaki; Moriya, Masaru; Nojo, Takeshi

2017-01-01

Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice. PMID:28968236

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

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.

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

PubMed

Kiyosawa, Naoki; Manabe, Sunao

2016-01-01

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

Immunotherapeutic Strategies in Breast Cancer: Preclinical and Clinical Trials

DTIC Science & Technology

2011-09-01

infection; known to be HIV positive, have hepatitis, or an immunocompromising condition; concurrent anti-cancer standard or investigational therapies...supportive care, including antibiotics , transfusions, and treatment of other newly diagnosed or concurrent medical conditions. Statistical

Harnessing the potential of noninvasive in vivo preclinical imaging of the immune system: challenges and prospects.

PubMed

Diken, Mustafa; Pektor, Stefanie; Miederer, Matthias

2016-10-01

Preclinical imaging has become a powerful method for investigation of in vivo processes such as pharmacokinetics of therapeutic substances and visualization of physiologic and pathophysiological mechanisms. These are important aspects to understand diseases and develop strategies to modify their progression with pharmacologic interventions. One promising intervention is the application of specifically tailored nanoscale particles that modulate the immune system to generate a tumor targeting immune response. In this complex interaction between immunomodulatory therapies, the immune system and malignant disease, imaging methods are expected to play a key role on the way to generate new therapeutic strategies. Here, we summarize examples which demonstrate the current potential of imaging methods and develop a perspective on the future value of preclinical imaging of the immune system.

Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies

PubMed Central

Cai, Shuang; Bagby, Taryn R; Forrest, M Laird

2011-01-01

Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development. PMID:22229080

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

PubMed

Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L; Albert, Marylin; Weintraub, S; Fortin, Norbert J; Cotman, Carl W

2013-07-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap

PubMed Central

Snigdha, Shikha; Milgram, Norton W.; Willis, Sherry L.; Albert, Marylin; Weintraub, S.; Fortin, Norbert J.; Cotman, Carl W.

2013-01-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer’s disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer’s disease. PMID:23434040

Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

PubMed

Van den Bergh, An; Van Hemelryck, Sandy; Bevernage, Jan; Van Peer, Achiel; Brewster, Marcus; Mackie, Claire; Mannaert, Erik

2018-06-11

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( F abs,sol ) and relative ( F rel, susp/sol ) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having F rel,susp/sol and F abs,sol in both rat and dog at doses around 10 and 5 mg/kg, respectively. The bioavailability outcomes in the dog aligned well with a BCS-like classification based upon the solubility of the active pharmaceutical ingredient (API) in biorelevant media, while the alignment was less clear for the bioavailability data in the rat. A retrospective analysis on the clinically tested formulations for a set of 12 Janssen compounds confirmed that the previously proposed animal bioavailability-based decision tree facilitated decisions on the oral formulation type, with the dog as the most discriminative species. Furthermore, the analysis showed that based on a Do for a standard human dose of 100 mg in aqueous and/or biorelevant media, a similar formulation type would have been selected compared to the one suggested by the animal data. However, the concept of a Do did not distinguish between solubility enhancing or enabling formulations and does not consider the API permeability, and hence, it produces the risk of slow and potentially incomplete oral absorption of an API with poor intestinal permeability. In cases where clinical dose estimations are available early in development, the preclinical bioavailability studies and dose number calculations, used to guide formulation selection, may be performed at more relevant doses instead of the proposed standard human dose. It should be noted, however, that unlike in late development, there is uncertainty on the clinical dose estimated in the early clinical phases because that dose is usually only based on in vitro and/or in vivo animal pharmacology models, or early clinical biomarker information. Therefore, formulation strategies may be adjusted based on emerging data supporting clinical doses. In summary, combined early information on in vitro-assessed API solubility and permeability, preclinical suspension/solution bioavailability data in relation to the intravenous clearance, and metabolic pathways of the API can strengthen formulation decisions. However, these data may not always fully distinguish between conventional (e.g., to be taken with food), enhancing, and enabling formulations. Therefore, to avoid overinvestment in complex and expensive enabling technologies, it is useful to evaluate a conventional and solubility (and/or permeability) enhancing formulation under fasted and fed conditions, as part of a first-in-human study or in a subsequent early human bioavailability study, for compounds with high Do, a low animal F rel,susp/sol , or low F abs,sol caused by precipitation of the solubilized API.

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 ethical and resource matter.

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

Thirty years on: examination performance and career success of the 1950-1 intake of Cambridge medical students.

PubMed

Wakeford, R; Roberts, S

1983-06-04

The relation between preclinical tripos and clinical examination results and subsequent career success of 188 medical graduates of Cambridge University was measured using five indicators of success. A generally positive relation was found, but this was not specific enough to make accurate individual predictions. Present levels of appointment were more closely related to clinical than preclinical results. No support was found for the local assertion that "2.1s" do better than "firsts" in clinical medicine. Since undergraduate examination results seem to be inaccurate predictors of later performance they should not be used as the principal evidence in making selection decisions.

eTRIKS platform: Conception and operation of a highly scalable cloud-based platform for translational research and applications development.

PubMed

Bussery, Justin; Denis, Leslie-Alexandre; Guillon, Benjamin; Liu, Pengfeï; Marchetti, Gino; Rahal, Ghita

2018-04-01

We describe the genesis, design and evolution of a computing platform designed and built to improve the success rate of biomedical translational research. The eTRIKS project platform was developed with the aim of building a platform that can securely host heterogeneous types of data and provide an optimal environment to run tranSMART analytical applications. Many types of data can now be hosted, including multi-OMICS data, preclinical laboratory data and clinical information, including longitudinal data sets. During the last two years, the platform has matured into a robust translational research knowledge management system that is able to host other data mining applications and support the development of new analytical tools. Copyright © 2018 Elsevier Ltd. All rights reserved.

Bridging the translational gap: collaborative drug development and dispelling the stigma of commercialization.

PubMed

Yu, Helen W H

2016-02-01

The current drug discovery and development process is stalling the translation of basic science into lifesaving products. Known as the 'Valley of Death', the traditional technology transfer model fails to bridge the gap between early-stage discoveries and preclinical research to advance innovations beyond the discovery phase. In addition, the stigma associated with 'commercialization' detracts from the importance of efficient translation of basic research. Here, I introduce a drug discovery model whereby the respective expertise of academia and industry are brought together to take promising discoveries through to proof of concept as a way to derisk the drug discovery and development process. Known as the 'integrated drug discovery model', I examine here the extent to which existing legal frameworks support this model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical Problem Solving Exercises for Pre-Clinical Medical Education: A Design, Implementation and Preliminary Evaluation.

ERIC Educational Resources Information Center

Bordage, Georges

Clinical problem solving exercises for preclinical medical education that were developed at Michigan State University School of Osteopathic Medicine are described. Two types of outcomes were set as priorities in the design and implementation of the problem solving sessions: small group peer interactions as instructional and evaluative resources;…

Students' Opinions about the Effects of Preclinical Patient Contacts on Their Learning

ERIC Educational Resources Information Center

Diemers, Agnes D.; Dolmans, Diana H. J. M.; Verwijnen, Maarten G. M.; Heineman, Erik; Scherpbier, Albert J. J. A.

2008-01-01

Several reasons have been given why students should have contacts with real patients early in the undergraduate medical curriculum, i.e., in the preclinical phase. However, it is not clear exactly what effects early patient contacts have with regard to knowledge construction and the development of clinical reasoning skills. We sought students'…

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

PubMed

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

2017-11-01

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

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.

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.

Computerized Virtual Reality Simulation in Preclinical Dentistry: Can a Computerized Simulator Replace the Conventional Phantom Heads and Human Instruction?

PubMed

Plessas, Anastasios

2017-10-01

In preclinical dental education, the acquisition of clinical, technical skills, and the transfer of these skills to the clinic are paramount. Phantom heads provide an efficient way to teach preclinical students dental procedures safely while increasing their dexterity skills considerably. Modern computerized phantom head training units incorporate features of virtual reality technology and the ability to offer concurrent augmented feedback. The aims of this review were to examine and evaluate the dental literature for evidence supporting their use and to discuss the role of augmented feedback versus the facilitator's instruction. Adjunctive training in these units seems to enhance student's learning and skill acquisition and reduce the required faculty supervision time. However, the virtual augmented feedback cannot be used as the sole method of feedback, and the facilitator's input is still critical. Well-powered longitudinal randomized trials exploring the impact of these units on student's clinical performance and issues of cost-effectiveness are warranted.

Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.

PubMed

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-04-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (Δ(9)-THC)) Cannabis spp.

Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.

PubMed

Chad, David A; Bidichandani, Sanjay; Bruijn, Lucie; Capra, J Donald; Dickie, Brian; Ferguson, John; Figlewicz, Denise; Forsythe, Melissa; Kaufmann, Petra; Kirshner, Annette; Monti, William

2013-05-01

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community.

Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers.

PubMed

Rusk, Anthony; McKeegan, Evelyn; Haviv, Fortuna; Majest, Sandra; Henkin, Jack; Khanna, Chand

2006-12-15

The angiogenic phenotype of malignant cancers has been established as a target for cancer therapy. ABT-526 and ABT-510, two peptide mimetics of thrombospondin-1 (TSP-1), block angiogenesis in vitro and in vivo and slow tumor growth in mice. To guide the clinical development of these drugs, translational studies in dogs with naturally occurring cancers were initiated. A prospective open-label trial using ABT-510 or ABT-526 in pet dogs with measurable malignant spontaneously arising tumors. Endpoints included safety, pharmacokinetics, antitumor activity, and preliminary assessment of changes in circulating endothelial cell populations. Two-hundred and forty-two dogs were sequentially entered to this open-label trial. The elimination half-life for ABT-510 and ABT-526 was 0.7 and 0.8 h, respectively (range, 0.5-1 h). No dose-limiting toxicities were seen in any dogs (N = 242). Forty-two dogs receiving peptide had objective responses (>50% reduction in tumor size; n = 6) or significant disease stabilization. Most objective responses were seen after 60 days of exposure to the TSP-1 peptide. Antitumor activity was similar for both peptides and was seen in several histologies, including mammary carcinoma, head and neck carcinoma, soft tissue sarcoma, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma. Assessment of circulating endothelial cell populations in a small subset of dogs suggested that effective exposure to TSP-1 peptides may be associated with reductions in circulating endothelial cells. These results support the safety and activity of ABT-526 and ABT-510 in dogs with naturally occurring malignant cancers. Data from this preclinical trial support the development of TSP-1 mimetic peptides as anticancer agents.

Bridging the Gap in Neurotherapeutic Discovery and Development: The Role of the National Institute of Neurological Disorders and Stroke in Translational Neuroscience.

PubMed

Mott, Meghan; Koroshetz, Walter

2015-07-01

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS supports early- and late-stage therapy development funding programs to accelerate preclinical discovery and the development of new therapeutic interventions for neurological disorders. The NINDS Office of Translational Research facilitates and funds the movement of discoveries from the laboratory to patients. Its grantees include academics, often with partnerships with the private sector, as well as small businesses, which, by Congressional mandate, receive > 3% of the NINDS budget for small business innovation research. This article provides an overview of NINDS-funded therapy development programs offered by the NINDS Office of Translational Research.

Innate signaling by mycobacterial cell wall components and relevance for development of adjuvants for subunit vaccines.

PubMed

Tima, Hermann Giresse; Huygen, Kris; Romano, Marta

2016-11-01

Pathogen recognition receptors (PRRs) recognize pathogen-associated molecular patterns, triggering the induction of inflammatory innate responses and contributing to the development of specific adaptive immune responses. Novel adjuvants have been developed based on agonists of PRRs. Areas covered: Lipid pathogen-associated molecular patterns (PAMPs) present in the cell wall of mycobacteria are revised, with emphasis on agonists of C-type lectin receptors, signaling pathways, and preclinical data supporting their use as novel adjuvants inducing cell-mediated immune responses. Their potential use as lipid antigens in novel tuberculosis subunit vaccines is also discussed. Expert commentary: Few adjuvants are licensed for human use and mainly favour antibody-mediated protective immunity. Use of lipid PAMPs that trigger cell-mediated immune responses could lead to the development of adjuvants for vaccines against intracellular pathogens and cancer.

How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

PubMed Central

Laverty, HG; Benson, C; Cartwright, EJ; Cross, MJ; Garland, C; Hammond, T; Holloway, C; McMahon, N; Milligan, J; Park, BK; Pirmohamed, M; Pollard, C; Radford, J; Roome, N; Sager, P; Singh, S; Suter, T; Suter, W; Trafford, A; Volders, PGA; Wallis, R; Weaver, R; York, M; Valentin, JP

2011-01-01

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: Fully characterize the incidence, prevalence and impact of drug-induced cardiovascular issues at all stages of the drug development process. Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers. PMID:21306581

Translational research in addiction: toward a framework for the development of novel therapeutics.

PubMed

Paterson, Neil E

2011-06-15

The development of novel substance use disorder (SUD) therapeutics is insufficient to meet the medical needs of a growing SUD patient population. The identification of translatable SUD models and tests is a crucial step in establishing a framework for SUD therapeutic development programs. The present review begins by identifying the clinical features of SUDs and highlights the narrow regulatory end-point required for approval of a novel SUD therapeutic. A conceptual overview of dependence is provided, followed by identification of potential intervention targets in the addiction cycle. The main components of the addiction cycle provide the framework for a discussion of preclinical models and their clinical analogs, all of which are focused on isolated behavioral end-points thought to be relevant to the persistence of compulsive drug use. Thus, the greatest obstacle to successful development is the gap between the multiplicity of preclinical and early clinical end-points and the regulatory end-point of sustained abstinence. This review proposes two pathways to bridging this gap: further development and validation of the preclinical extended access self-administration model; inclusion of secondary end-points comprising all of the measures highlighted in the present discussion in Phase 3 trials. Further, completion of the postdictive validation of analogous preclinical and clinical assays is of high priority. Ultimately, demonstration of the relevance and validity of a variety of end-points to the ultimate goal of abstinence will allow researchers to identify truly relevant therapeutic mechanisms and intervention targets, and establish a framework for SUD therapeutic development that allows optimal decision-making and resource allocation. 2011 Elsevier Inc. All rights reserved.

Best Practices in Stability Indicating Method Development and Validation for Non-clinical Dose Formulations.

PubMed

Henry, Teresa R; Penn, Lara D; Conerty, Jason R; Wright, Francesca E; Gorman, Gregory; Pack, Brian W

2016-11-01

Non-clinical dose formulations (also known as pre-clinical or GLP formulations) play a key role in early drug development. These formulations are used to introduce active pharmaceutical ingredients (APIs) into test organisms for both pharmacokinetic and toxicological studies. Since these studies are ultimately used to support dose and safety ranges in human studies, it is important to understand not only the concentration and PK/PD of the active ingredient but also to generate safety data for likely process impurities and degradation products of the active ingredient. As such, many in the industry have chosen to develop and validate methods which can accurately detect and quantify the active ingredient along with impurities and degradation products. Such methods often provide trendable results which are predictive of stability, thus leading to the name; stability indicating methods. This document provides an overview of best practices for those choosing to include development and validation of such methods as part of their non-clinical drug development program. This document is intended to support teams who are either new to stability indicating method development and validation or who are less familiar with the requirements of validation due to their position within the product development life cycle.

Molecular and clinical implementations of ovarian cancer mouse avatar models.

PubMed

Zayed, Amira A; Mandrekar, Sumithra J; Haluska, Paul

2015-09-01

Innovation in oncology drug development has been hindered by lack of preclinical models that reliably predict clinical activity of novel therapies in cancer patients. Increasing desire for individualize treatment of patients with cancer has led to an increase in the use of patient-derived xenografts (PDX) engrafted into immune-compromised mice for preclinical modeling. Large numbers of tumor-specific PDX models have been established and proved to be powerful tools in pre-clinical testing. A subset of PDXs, referred to as Avatars, establish tumors in an orthotopic and treatment naïve fashion that may represent the most clinical relevant model of individual human cancers. This review will discuss ovarian cancer (OC) PDX models demonstrating the opportunities and limitations of these models in cancer drug development, and describe concepts of clinical trials design in Avatar guided therapy.

Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325.

PubMed

Carew, Jennifer S; Nawrocki, Steffan T

2017-04-03

Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in vitro and in vivo studies in preclinical models of renal cell carcinoma demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy inhibition, was very well tolerated, and exhibited significant superiority with respect to autophagy inhibition and anticancer activity over hydroxychloroquine. Our findings support the clinical investigation of the safety and preliminary efficacy of ROC-325 in patients with autophagy-dependent malignancies and other disorders where aberrant autophagy contributes to disease pathogenesis.

Latest development on RNA-based drugs and vaccines.

PubMed

Lundstrom, Kenneth

2018-06-01

Drugs and vaccines based on mRNA and RNA viruses show great potential and direct translation in the cytoplasm eliminates chromosomal integration. Limitations are associated with delivery and stability issues related to RNA degradation. Clinical trials on RNA-based drugs have been conducted in various disease areas. Likewise, RNA-based vaccines for viral infections and various cancers have been subjected to preclinical and clinical studies. RNA delivery and stability improvements include RNA structure modifications, targeting dendritic cells and employing self-amplifying RNA. Single-stranded RNA viruses possess self-amplifying RNA, which can provide extreme RNA replication in the cytoplasm to support RNA-based drug and vaccine development. Although oligonucleotide-based approaches have demonstrated potential, the focus here is on mRNA- and RNA virus-based methods.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

PubMed

Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

2012-03-01

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Leveraging model-based study designs and serial micro-sampling techniques to understand the oral pharmacokinetics of the potent LTB4 inhibitor, CP-105696, for mouse pharmacology studies.

PubMed

Spilker, Mary E; Chung, Heekyung; Visswanathan, Ravi; Bagrodia, Shubha; Gernhardt, Steven; Fantin, Valeria R; Ellies, Lesley G

2017-07-01

1. Leukotriene B4 (LTB4) is a proinflammatory mediator important in the progression of a number of inflammatory diseases. Preclinical models can explore the role of LTB4 in pathophysiology using tool compounds, such as CP-105696, that modulate its activity. To support preclinical pharmacology studies, micro-sampling techniques and mathematical modeling were used to determine the pharmacokinetics of CP-105696 in mice within the context of systemic inflammation induced by a high-fat diet (HFD). 2. Following oral administration of doses > 35 mg/kg, CP-105696 kinetics can be described by a one-compartment model with first order absorption. The compound's half-life is 44-62 h with an apparent volume of distribution of 0.51-0.72 L/kg. Exposures in animals fed an HFD are within 2-fold of those fed a normal chow diet. Daily dosing at 100 mg/kg was not tolerated and resulted in a >20% weight loss in the mice. 3. CP-105696's long half-life has the potential to support a twice weekly dosing schedule. Given that most chronic inflammatory diseases will require long-term therapies, these results are useful in determining the optimal dosing schedules for preclinical studies using CP-105696.

Meniscal Scaffolds - Preclinical Evidence to Support their Use: A Systematic Review

PubMed Central

Di Matteo, Berardo; Perdisa, Francesco; Gostynska, Natalia; Kon, Elizaveta; Filardo, Giuseppe; Marcacci, Maurilio

2015-01-01

Arthroscopic meniscal treatment is the most common procedure performed in the orthopedic practice. Current management of meniscal pathology relies on different therapeutic options, ranging from selective meniscectomy, suturing, and to meniscal replacement by using either allografts or scaffolds. The progresses made in the field of regenerative medicine and biomaterials allowed to develop several meniscal substitutes, some of those currently used in the clinical practice. Before reaching the clinical application, these devices necessarily undergo accurate testing in the animal model: the aim of the present manuscript is to systematically review the scientific evidence derived by animal model results for the use of meniscal scaffolds, in order to understand the current state of research in this particular field and to identify the trends at preclinical level that may influence in the near future the clinical practice. Thirty-four papers were included in the present analysis. In 12 cases the meniscal scaffolds were used with cells to further stimulate tissue regeneration. With the exception of some negative reports regarding dacron-based scaffolds, the majority of the trials highlighted that biomaterials and bio-engineered scaffolds are safe and could play a beneficial role in stimulating meniscal healing and in chondral protection. With regard to the benefits of cell augmentation, the evidence is limited to a small number of studies and no conclusive evidence is available. However, preclinical evidence seems to suggest that cells could enhance tissue regeneration with respect to the use of biomaterials alone, and further research should confirm the translational potential of cell-based approach. PMID:26157531

Treatment planning and 3D dose verification of whole brain radiation therapy with hippocampal avoidance in rats

NASA Astrophysics Data System (ADS)

Yoon, S. W.; Miles, D.; Cramer, C.; Reinsvold, M.; Kirsch, D.; Oldham, M.

2017-05-01

Despite increasing use of stereotactic radiosurgery, whole brain radiotherapy (WBRT) continues to have a therapeutic role in a selected subset of patients. Selectively avoiding the hippocampus during such treatment (HA-WBRT) emerged as a strategy to reduce the cognitive morbidity associated with WBRT and gave rise to a recently published the phase II trial (RTOG 0933) and now multiple ongoing clinical trials. While conceptually hippocampal avoidance is supported by pre-clinical evidence showing that the hippocampus plays a vital role in memory, there is minimal pre-clinic data showing that selectively avoiding the hippocampus will reduce radiation-induced cognitive decline. Largely the lack of pre-clinical evidence can be attributed to the technical hurdles associated with delivering precise conformal treatment the rat brain. In this work we develop a novel conformal HA-WBRT technique for Wistar rats, utilizing a 225kVp micro-irradiator with precise 3D-printed radiation blocks designed to spare hippocampus while delivering whole brain dose. The technique was verified on rodent-morphic Presage® 3D dosimeters created from micro-CT scans of Wistar rats with Duke Large Field-of-View Optical Scanner (DLOS) at 1mm isotropic voxel resolution. A 4-field box with parallel opposed AP-PA and two lateral opposed fields was explored with conformal hippocampal sparing aided by 3D-printed radiation blocks. The measured DVH aligned reasonably well with that calculated from SmART Plan Monte Carlo simulations with simulated blocks for 4-field HA-WBRT with both demonstrating hippocampal sparing of 20% volume receiving less than 30% the prescription dose.

Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences.

PubMed

Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J; Granero, Luis; Polache, Ana; Zornoza, Teodoro

2017-01-01

Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism.

Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences

PubMed Central

Orrico, Alejandro; Martí-Prats, Lucía; Cano-Cebrián, María J.; Granero, Luis; Polache, Ana; Zornoza, Teodoro

2017-01-01

Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethanol relapse-like drinking behavior as well as in chronic alcohol consumption. In this sense, one of the most explored interventions has been the administration of D-Penicillamine (DP). These pre-clinical studies, that we critically summarize in this article, are considered a critical step for the potential development of a novel pharmacotherapeutic strategy for alcohol addiction treatment that could improve the outcomes of current ones. Thus, on one hand, several experimental findings provide the rationale for using DP as a novel therapeutic intervention alone and/or in combination to prevent relapse into alcohol seeking and consumption. On the other hand, its effectiveness in reducing voluntary ethanol consumption in long-term experienced animals still remains unclear. Finally, this drug offers the additional advantage that has already been approved for use in humans, hence it could be easily implemented as a new therapeutic intervention for relapse prevention in alcoholism. PMID:28326026

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

Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review.

PubMed

Park, Angela; Barrera-Ramirez, Juliana; Ranasinghe, Indee; Pilon, Sophie; Sy, Richmond; Fergusson, Dean; Allan, David S

2016-06-01

Mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) are used in cell-based regenerative therapy. HMG CoA reductase inhibitors (statins) appear promising in blocking apoptosis, prolonging progenitor cell survival and improving their capacity to repair organ function. We performed a systematic review of preclinical and clinical studies to clarify whether statins can improve cell-based repair of organ injury. MEDLINE, EMBASE, and PUBMED databases were searched (1947 to June 25, 2013). Controlled clinical and pre-clinical studies were included that evaluated statin therapy used alone or in combination with MSCs or EPCs in patients or animals with organ injury. After screening 771 citations, 100 records underwent full eligibility screening of which 38 studies met eligibility and were included in the review: Studies were grouped into pre-clinical studies that involved statin treatment in combination with cell therapy (18 studies), preclinical studies of statin therapy alone (13 studies) and clinical studies of statin therapy (7 studies). Studies addressed cardiac injury (14 studies), vascular disorders (15 studies), neurologic conditions (8 studies) and bone fractures (1 study). Pre-clinical studies of statins in combination with MSC infusion (15 studies) or EPC therapy (3 studies) were described and despite marked heterogeneity in reporting outcomes of cellular analysis and organ function, all of these cell-based pre-clinical studies reported improved organ recovery with the addition of statin therapy. Moreover, 13 pre-clinical studies involved the administration of a statin drug alone to animals. An increase in EPC number and/or function (no studies of MSCs) was reported in 11 of these studies (85 %) and improved organ function in 12 studies (92 %). We also identified 7 clinical studies and none involved the administration of cells but described an increased number and/or function of EPCs (no studies of MSCs) and improved organ function with statin therapy (1.2-fold to 35-fold improvement over controls) in all 7 studies. Our systematic review provides a foundation of encouraging results that support further study of statins in regenerative therapy to augment the number and/or function of MSCs used in cell-based repair and to augment the number and function of EPCs in vivo to repair damaged tissues. Larger studies are needed to ensure safety and confirm clinical benefits.

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

PubMed

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

2018-03-07

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

Micro-Dose Calibrator for Pre-clinical Radiotracer Assays | NCI Technology Transfer Center | TTC

Cancer.gov

Pre-clinical radiotracer biomedical research involves the use of compounds labeled with radioisotopes, including cell binding studies, immune cell labeling techniques, and radio-ligand bio-distribution studies. Before this Micro-Dose Calibrator, measurement of pre-clinical level dosage for small animal studies was inaccurate and unreliable. This dose calibrator is a prototype ready for manufacturing. It is designed to accurately measure radioactive doses in the range of 50 nCi (1.8 kBq) to 100 µCi (3.7 MBq) with 1% precision. The NCI seeks co-development or licensing to commercialize it. Alternative uses will be considered.

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.

Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer's disease: a selective review.

PubMed

Rentz, Dorene M; Parra Rodriguez, Mario A; Amariglio, Rebecca; Stern, Yaakov; Sperling, Reisa; Ferris, Steven

2013-01-01

Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer's disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer's disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer's disease in presymptomatic individuals.

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.

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

Integrity, standards, and QC-related issues with big data in pre-clinical drug discovery.

PubMed

Brothers, John F; Ung, Matthew; Escalante-Chong, Renan; Ross, Jermaine; Zhang, Jenny; Cha, Yoonjeong; Lysaght, Andrew; Funt, Jason; Kusko, Rebecca

2018-06-01

The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data. Copyright © 2018 Elsevier Inc. All rights reserved.

Strategies to predict rheumatoid arthritis development in at-risk populations

PubMed Central

van der Helm-van Mil, Annette H.

2016-01-01

The development of RA is conceived as a multiple hit process and the more hits that are acquired, the greater the risk of developing clinically apparent RA. Several at-risk phases have been described, including the presence of genetic and environmental factors, RA-related autoantibodies and biomarkers and symptoms. Intervention in these preclinical phases may be more effective compared with intervention in the clinical phase. One prerequisite for preventive strategies is the ability to estimate an individual’s risk adequately. This review evaluates the ability to predict the risk of RA in the various preclinical stages. Present data suggest that a combination of genetic and environmental factors is helpful to identify persons at high risk of RA among first-degree relatives. Furthermore, a combination of symptoms, antibody characteristics and environmental factors has been shown to be relevant for risk prediction in seropositive arthralgia patients. Large prospective studies are needed to validate and improve risk prediction in preclinical disease stages. PMID:25096602

Targeting miRNAs by polyphenols: Novel therapeutic strategy for cancer.

PubMed

Pandima Devi, Kasi; Rajavel, Tamilselvam; Daglia, Maria; Nabavi, Seyed Fazel; Bishayee, Anupam; Nabavi, Seyed Mohammad

2017-10-01

In the recent years, polyphenols have gained significant attention in scientific community owing to their potential anticancer effects against a wide range of human malignancies. Epidemiological, clinical and preclinical studies have supported that daily intake of polyphenol-rich dietary fruits have a strong co-relationship in the prevention of different types of cancer. In addition to direct antioxidant mechanisms, they also regulate several therapeutically important oncogenic signaling and transcription factors. However, after the discovery of microRNA (miRNA), numerous studies have identified that polyphenols, including epigallocatechin-3-gallate, genistein, resveratrol and curcumin exert their anticancer effects by regulating different miRNAs which are implicated in all the stages of cancer. MiRNAs are short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression. However, cancer associated miRNAs has emerged only in recent years to support its applications in cancer therapy. Preclinical experiments have suggested that deregulation of single miRNA is sufficient for neoplastic transformation of cells. Indeed, the widespread deregulation of several miRNA profiles of tumor and healthy tissue samples revealed the involvement of many types of miRNA in the development of numerous cancers. Hence, targeting the miRNAs using polyphenols will be a novel and promising strategy in anticancer chemotherapy. Herein, we have critically reviewed the potential applications of polyphenols on various human miRNAs, especially which are involved in oncogenic and tumor suppressor pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mucosal Vaccination for Prevention of HIV Infection and AIDS.

PubMed

Aldovini, Anna

2016-01-01

Most of HIV infections occur via the genital tract or the rectum and HIV replicates at high levels in lymphoid organs and intestinal mucosa, likely requiring a more diversified immunity than pathogens restricted to a single mucosal site, such as the gastrointestinal tract for Vibrio cholera, or the respiratory airways for the influenza virus. Numerous AIDS vaccine candidates are under development and a general observation obtained from preclinical trials in non-human primates that failed to provide sterilizing immunity is that some infection protection or delayed onset of disease is observed in the presence of anti-SIV immunity. Recent clinical trials support difficulties to reproduce in humans the results observed in simian models, but at least one of them indicated that some protection of infection can be achieved. However, given the limited efficacy observed in the RV144 trial and concerns voiced in its statistical interpretation, preclinical trials should explore more effective immunogens, whether new or as combinations of existing ones, and mucosal routes of vaccinations in addition to the systemic routes, with the goal to maximize vaccination-mediated protection. The rationale for generating both strong mucosal and systemic immunity comes from animal experiments, recent clinical trials, and other successful vaccines currently in use. Mucosal responses against SIV have been induced with a variety of SIV antigens and via different mucosal routes with a spectrum of effects on protection. This review covers the rational and the experimental data that support the validity to explore mucosal immunization for HIV infection and AIDS prevention.

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

PubMed Central

Walker, Suellen M.; Yaksh, Tony L.

2015-01-01

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

The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum.

PubMed

Lucieer, Susanna M; van der Geest, Jos N; Elói-Santos, Silvana M; de Faria, Rosa M Delbone; Jonker, Laura; Visscher, Chris; Rikers, Remy M J P; Themmen, Axel P N

2016-03-01

Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

Drugs for solid cancer: the productivity crisis prompts a rethink

PubMed Central

Rösel, Daniel; Brábek, Jan; Veselý, Pavel; Fernandes, Michael

2013-01-01

Despite remarkable progress in cancer-drug discovery, the delivery of novel, safe, and sustainably effective products to the clinic has stalled. Using Src as a model, we examine key steps in drug development. The preclinical evidence on the relationship between Src and solid cancer is in sharp contrast with the modest anticancer effect noted in conventional clinical trials. Here, we consider Src inhibitors as an example of a promising drug class directed to invasion and metastasis and identify roadblocks in translation. We question the assumption that a drug-induced tumor shrinkage in preclinical and clinical studies predicts a successful outcome. Our analysis indicates that the key areas requiring attention are related, and include preclinical models (in vitro and mouse models), meaningful clinical trial end points, and an appreciation of the role of metastasis in morbidity and mortality. Current regulations do not reflect the natural history of the disease, and may be unrelated to the key complications: local invasion, metastasis, and the development of resistance. Alignment of preclinical and clinical studies and regulations based on mechanistic trial end points and platforms may help in overcoming these roadblocks. Viewed kaleidoscopically, most elements necessary and sufficient for a novel translational paradigm are in place. PMID:23836990

[The role of biotechnology in pharmaceutical drug design].

PubMed

Gaisser, Sibylle; Nusser, Michael

2010-01-01

Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

Collaborative learning in pre-clinical dental hygiene education.

PubMed

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

2013-04-01

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

Vitamin D: Considerations in the Continued Development as an Agent for Cancer Prevention and Therapy

PubMed Central

Trump, Donald L.; Deeb, Kristen; Johnson, Candace S.

2010-01-01

Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression and therapy of cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps the most robust of these epidemiologic studies is that of Giovannucci and colleagues who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among more than 40,000 individuals in the Health professionals Study an increase in 25(OH) cholecalciferol level of 62.5ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers and acute leukemia by >50%. Unfortunately very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells – as well as vascular endothelial cells derived from tumors - to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor “bioavailability” of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that very high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that very high doses of calcitriol (>100mcg weekly, intravenously and 0.15mcg/kg weekly orally) can be given safely. The maximum tolerated dose (MTD) of calcitriol is unclear. While a 250 patient trial in men with castration resistant prostate cancer (CRPC) comparing docetaxel (36mg/sqm weekly) +/- calcitriol 0.15mcg/kg indicated that calcitriol was very safe, may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol vs q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or MTD of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated. PMID:20164683

Can Rheumatoid Arthritis Be Prevented?

PubMed Central

Deane, Kevin

2013-01-01

The discovery of elevations of rheumatoid arthritis (RA)-related biomarkers prior to the onset of clinically apparent RA raises hopes that individuals who are at risk for future RA can be identified in a preclinical phase of disease that is defined as abnormalities of RA-related immune activity prior to the clinically apparent onset of joint disease. Additionally, there is a growing understanding of the immunologic processes that are occurring in preclinical RA, as well as a growing understanding of risk factors that may be mechanistically related to RA development. Furthermore, there are data supporting that treatment of early RA can lead to drug free remission. Taken as a whole, these findings suggest that it may be possible to use biomarkers and other factors to accurately identify the likelihood and timing of onset of future RA, and intervene with immunomodulatory therapies and/or risk factor modification to prevent the future onset of RA in at-risk individuals. Importantly, several clinical prevention trials for RA have already been tried, and one is underway. However, while our understanding of the growing understanding of the mechanisms and natural history of RA development may be leading us to the implementation of prevention strategies for RA, there are still several challenges to be met. These include developing sufficiently accurate methods of predicting those at high risk for future RA so that clinical trials can be developed based on accurate rates of development of arthritis and subjects can be adequately informed of their risk for disease, identifying the appropriate interventions and biologic targets for optimal prevention, and addressing the psychosocial and economic aspects that are crucial to developing broadly applicable prevention measures for RA. These issues notwithstanding, prevention of RA may be within reach in the near future. PMID:24315049

The therapeutic potential of Na+ and Ca2+ channel blockers in pain management.

PubMed

Sabido-David, Cibele; Faravelli, Laura; Salvati, Patricia

2004-10-01

Chronic pain affects a large percentage of the population, representing a socio-economic burden. Current treatments are characterised by suboptimal efficacy and/or side effects that limit their use. Among several approaches to treating chronic pain, voltage-sensitive Ca(2+) and Na(+) channels are promising targets. This review evaluates the preclinical evidence that supports the involvement of these targets, with specific attention to those subtypes that appear more strictly correlated with pain generation and sustainment, as well as those compounds that modulate the activity of Ca(2+) and/or Na(+) channels that are currently in clinical development for chronic pain conditions.

Bioengineered vascular constructs as living models for in vitro cardiovascular research.

PubMed

Wolf, Frederic; Vogt, Felix; Schmitz-Rode, Thomas; Jockenhoevel, Stefan; Mela, Petra

2016-09-01

Cardiovascular diseases represent the most common cause of morbidity and mortality worldwide. In this review, we explore the potential of bioengineered vascular constructs as living models for in vitro cardiovascular research to advance the current knowledge of pathophysiological processes and support the development of clinical therapies. Bioengineered vascular constructs capable of recapitulating the cellular and mechanical environment of native vessels represent a valuable platform to study cellular interactions and signaling cascades, test drugs and medical devices under (patho)physiological conditions, with the additional potential benefit of reducing the number of animals required for preclinical testing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Advances in bioartificial liver assist devices.

PubMed

Patzer, J F

2001-11-01

Rapid advances in development of bioartificial liver assist devices (BLADs) are exciting clinical interest in the application of BLAD technology for support of patients with acute liver failure. Four devices (Circe Biomedical HepatAssist, Vitagen ELAD, Gerlach BELS, and Excorp Medical BLSS) that rely on hepatocytes cultured in hollow-fiber membrane technology are currently in various stages of clinical evaluation. Several alternative approaches for culture and perfusion of hepatocytes have been evaluated in preclinical, large animal models of liver failure, or at a laboratory scale. Engineering design issues with respect to xenotransplantation, BLAD perfusion, hepatocyte functionality and culture maintenance, and ultimate distribution of a BLAD to a clinical site are delineated.

The National Institutes of Health Investment in Research on Botanicals

PubMed Central

Coates, Paul M.; Meyers, Catherine M.

2010-01-01

The Office of Dietary Supplements (ODS) and the National Center for Complementary and Alternative Medicine (NCCAM) were both established by Congress in the 1990’s. ODS aims to strengthen knowledge and understanding of dietary supplements (DS). NCCAM promotes exploration of complementary and alternative medicine in the context of rigorous science. Together, they developed the Botanical Research Centers Program to promote interdisciplinary study of botanicals, particularly those found in DS, by supporting research activities ranging from plant and characterization to preclinical and early-phase clinical studies. These Centers are part of the coordinated efforts of ODS and NCCAM to enhance botanical research. PMID:21075178

Testing Experimental Therapies in a Guinea Pig Model for Hemorrhagic Fever.

PubMed

Wong, Gary; Bi, Yuhai; Kobinger, Gary; Gao, George F; Qiu, Xiangguo

2018-01-01

Hemorrhagic fever viruses are among the deadliest pathogens known to humans, and often, licensed medical countermeasures are unavailable to prevent or treat infections. Guinea pigs are a commonly used animal for the preclinical development of any experimental candidates, typically to confirm data generated in mice and as a way to validate and support further testing in nonhuman primates. In this chapter, we use Sudan virus (SUDV), a lethal filovirus closely related to Ebola virus, as an example of the steps required for generating a guinea pig-adapted isolate that is used to test a monoclonal antibody-based therapy against viral hemorrhagic fevers.

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

[Machine Learning-based Prediction of Seizure-inducing Action as an Adverse Drug Effect].

PubMed

Gao, Mengxuan; Sato, Motoshige; Ikegaya, Yuji

2018-01-01

　During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.

Machine learning-based prediction of adverse drug effects: An example of seizure-inducing compounds.

PubMed

Gao, Mengxuan; Igata, Hideyoshi; Takeuchi, Aoi; Sato, Kaoru; Ikegaya, Yuji

2017-02-01

Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Preclinical activity of melflufen (J1) in ovarian cancer.

PubMed

Carlier, Charlotte; Strese, Sara; Viktorsson, Kristina; Velander, Ebba; Nygren, Peter; Uustalu, Maria; Juntti, Therese; Lewensohn, Rolf; Larsson, Rolf; Spira, Jack; De Vlieghere, Elly; Ceelen, Wim P; Gullbo, Joachim

2016-09-13

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

The Neurotensin NTS1 Receptor Agonist PD149163 Produces Antidepressant-Like Effects in the Forced Swim Test: Further Support for Neurotensin as a Novel Pharmacologic Strategy for Antidepressant Drugs.

PubMed

Carey, Lawrence M; Rice, Remington J; Prus, Adam J

2017-08-01

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS 1 receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS 1 receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Preclinical activity of melflufen (J1) in ovarian cancer

PubMed Central

Viktorsson, Kristina; Velander, Ebba; Nygren, Peter; Uustalu, Maria; Juntti, Therese; Lewensohn, Rolf; Larsson, Rolf; Spira, Jack; De Vlieghere, Elly; Ceelen, Wim P.; Gullbo, Joachim

2016-01-01

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra- and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration. PMID:27528037

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C.

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of non-small cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify two major lessons from the outcomes of these trials: 1) The antioxidant hypothesis was tested in wrong subjects or patient populations. 2) The selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to re-vitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials. PMID:26595411

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges.

PubMed

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.

Thirty years on: examination performance and career success of the 1950-1 intake of Cambridge medical students.

PubMed Central

Wakeford, R; Roberts, S

1983-01-01

The relation between preclinical tripos and clinical examination results and subsequent career success of 188 medical graduates of Cambridge University was measured using five indicators of success. A generally positive relation was found, but this was not specific enough to make accurate individual predictions. Present levels of appointment were more closely related to clinical than preclinical results. No support was found for the local assertion that "2.1s" do better than "firsts" in clinical medicine. Since undergraduate examination results seem to be inaccurate predictors of later performance they should not be used as the principal evidence in making selection decisions. PMID:6407573

Testing therapeutic potency of anticancer drugs in animal studies: a commentary.

PubMed

Den Otter, Willem; Steerenberg, Peter A; Van der Laan, Jan Willem

2002-04-01

Regulatory authorities for medicines in European countries deal with many applications for admission to the market of anticancer drugs. Each application must be supported by preclinical and clinical data, among which testing of the therapeutic activity of drugs in animals is important. Recently, the Committee for Proprietary Medicinal Products (CPMP) has released a note for guidance on the preclinical evaluation of anticancer medicinal products. This note provides only general statements regarding tests of anticancer drugs in rodents. This stimulates considerations on how to organize and how to evaluate these tests. In this article we describe our considerations regarding these items based on our experience with applications in The Netherlands since 1993. (c) 2002 Elsevier Science (USA).

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

PubMed

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

2010-02-15

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

Optimizing Chemotherapy Dose and Schedule by Norton-Simon Mathematical Modeling

PubMed Central

Traina, Tiffany A.; Dugan, Ute; Higgins, Brian; Kolinsky, Kenneth; Theodoulou, Maria; Hudis, Clifford A.; Norton, Larry

2011-01-01

Background To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14 - 7). Results The model predicted that 7 days of treatment followed by a 7-day rest (7 - 7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development. PMID:20519801

Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma.

PubMed

Martin, Matthew J; Eberlein, Cath; Taylor, Molly; Ashton, Susan; Robinson, David; Cross, Darren

2016-12-27

Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment. However experience with targeted therapies suggests that acquired resistance may emerge. Thus there is a need to characterize resistance mechanisms and to devise ways to prevent, delay or overcome osimertinib resistance. We show here that osimertinib suppresses glycolysis in parental EGFR-mutant lung adenocarcinoma lines, but has not in osimertinib-resistant cell lines. Critically, we show osimertinib treatment induces a strict dependence on mitochondrial oxidative phosphorylation (OxPhos), as OxPhos inhibitors significantly delay the long-term development of osimertinib resistance in osimertinib-sensitive lines. Accordingly, growth conditions which promote a less glycolytic phenotype confer a degree of osimertinib resistance. Our data support a model in which the combination of osimertinib and OxPhos inhibitors can delay or prevent resistance in osimertinib-naïve tumour cells, and represents a novel strategy that warrants further pre-clinical investigation.

Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma

PubMed Central

Martin, Matthew J.; Eberlein, Cath; Taylor, Molly; Ashton, Susan; Robinson, David; Cross, Darren

2016-01-01

Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment. However experience with targeted therapies suggests that acquired resistance may emerge. Thus there is a need to characterize resistance mechanisms and to devise ways to prevent, delay or overcome osimertinib resistance. We show here that osimertinib suppresses glycolysis in parental EGFR-mutant lung adenocarcinoma lines, but has not in osimertinib-resistant cell lines. Critically, we show osimertinib treatment induces a strict dependence on mitochondrial oxidative phosphorylation (OxPhos), as OxPhos inhibitors significantly delay the long-term development of osimertinib resistance in osimertinib-sensitive lines. Accordingly, growth conditions which promote a less glycolytic phenotype confer a degree of osimertinib resistance. Our data support a model in which the combination of osimertinib and OxPhos inhibitors can delay or prevent resistance in osimertinib-naïve tumour cells, and represents a novel strategy that warrants further pre-clinical investigation. PMID:27861144

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.

Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor

PubMed Central

Yingling, Jonathan M.; McMillen, William T.; Yan, Lei; Huang, Huocong; Sawyer, J. Scott; Graff, Jeremy; Clawson, David K.; Britt, Karen S.; Anderson, Bryan D.; Beight, Douglas W.; Desaiah, Durisala; Lahn, Michael M.; Benhadji, Karim A.; Lallena, Maria J.; Holmgaard, Rikke B.; Xu, Xiaohong; Zhang, Faming; Manro, Jason R.; Iversen, Philip W.; Iyer, Chandrasekar V.; Brekken, Rolf A.; Kalos, Michael D.; Driscoll, Kyla E.

2018-01-01

Transforming growth factor-β (TGFβ) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFβ receptor I (TGFβRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFβRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFβ-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFβ-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects. Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFβ-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFβ pathway inhibitors. PMID:29467918

Zinc dependent Histone deacetylase inhibitors in cancer therapeutics: Recent update.

PubMed

Georgianos, Panagiotis I; Divani, Maria; Eleftheriadis, Theodoros; Mertens, Peter R; Liakopoulos, Vassilios

2018-05-23

Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensin-aldosterone-system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. A systematic literature search of bibliographic databases to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. SGLT-2 inhibition emerges as a novel therapeutic approach of type 2 diabetes with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies.

PubMed

Guizzetti, Marina; Davies, Daryl L; Egli, Mark; Finn, Deborah A; Molina, Patricia; Regunathan, Soundar; Robinson, Donita L; Sohrabji, Farida

2016-06-01

In May 2014, Dr. Francis Collins, the director of U.S. National Institutes of Health (NIH), and Dr. Janine Clayton, the director of the U.S. National Institutes of Health Office of Research on Women's Health, published a commentary in the journal Nature announcing new policies to ensure that preclinical research funded by the NIH considers both males and females. While these policies are still developing, they have already generated great interest by the scientific community and triggered both criticism and applause. This review provides a description and interpretation of the NIH guidelines, and it traces the history that led to their implementation. As expected, this NIH initiative generated some anxiety in the scientific community. The use of female animals in the investigation of basic mechanisms is perceived to increase variability in the results, and the use of both sexes has been claimed to slow the pace of scientific discoveries and to increase the cost at a time characterized by declining research support. This review discusses issues related to the study of sex as a biological variable (SABV) in alcohol studies and provides examples of how researchers have successfully addressed some of them. A practical strategy is provided to include both sexes in biomedical research while maintaining control of the research direction. The inclusion of sex as an important biological variable in experimental design, analysis, and reporting of preclinical alcohol research is likely to lead to a better understanding of alcohol pharmacology and the development of alcohol use disorder, may promote drug discovery for new pharmacotherapies by increasing scientific rigor, and may provide clinical benefit to women's health. This review aims to promote the understanding of the NIH's SABV guidelines and to provide alcohol researchers with a theoretical and practical framework for working with both sexes in preclinical research. Copyright © 2016 by the Research Society on Alcoholism.

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.

Perceived sources and levels of stress, general self-efficacy and coping strategies in preclinical dental students.

PubMed

Ersan, Nilüfer; Dölekoğlu, Semanur; Fişekçioğlu, Erdoğan; İlgüy, Mehmet; Oktay, İnci

2018-06-01

Dental education programs are known to be highly stressful and stress can affect general health. The aims were to identify sources of stress among preclinical students and to evaluate their perceived levels of stress, self-efficacy and effective coping strategies in a private dental school. One hundred preclinical students in a Turkish private dental school were surveyed using dental environment stress (DES), perceived stress (PSS), general self-efficacy (G-SES) and brief coping scales (Brief-COPE). Age, gender, history of psychiatric treatment, factors that affected the choice of dentistry, choice rank of dental school, scholarship and income was recorded. 'Exams and grades' followed by 'Fear of failing course or year' were found to be the most stressprovoking factors. The most and the least stressprovoking DES domains were 'Workload' and 'Social stressors', respectively. 'Social stressors' affected male more than female (p < .05). The most and the least common coping strategies were found to be 'Planning', and 'Drug', respectively. Female used 'Instrumental support' more than male (p < .05). Demographic factors had impact on the perceived stress factors and levels, as well as coping strategies. Unlike previous studies establishing high stress levels in dental students, preclinical students displayed moderate level of stress. Clinical dental education might be more responsible for creating stress.

Sex Differences in Stroke Therapies

PubMed Central

Sohrabji, Farida; Park, Min Jung; Mahnke, Amanda H

2016-01-01

Stroke is the 5th leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these were found to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few therapeutics, both preclinically and clinically, take into account possible sex differences in treatment. Reanalysis of data from the only currently FDA-approved stroke therapy, tPA, has shown to not only improve stroke outcomes for both sexes, but to also show sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (IGF-1), and inhibitors of cell death pathways (pharmacological inhibition of PARP-1, NO production, and caspase activation), as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analyses in clinical trials, as well as in preclinical studies, must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systemized/structured way to translate promising therapies to both sexes and increase stroke recovery. PMID:27870437

Development of Sanofi Pasteur tetravalent dengue vaccine.

PubMed

Guy, Bruno; Saville, Melanie; Lang, Jean

2010-09-16

The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of 4 recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies also showed that the TV dengue vaccine induced controlled stimulation in human dendritic cells and significant immune responses in monkeys. TV dengue vaccine reactogenicity, viraemia induction and antibody responses were investigated in three Phase I trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. Results showed that the majority of adverse events were mild to moderate and transient in nature. Viraemia was transient and low, and was not increased after initial dengue TV administration, even in the case of incomplete responses. ϕSeropositivity [≥10 in a PRNT 50 assay] was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of TV dengue vaccine in the USA. Similarly, seropositivity was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue TV injection in the Philippines where baseline flavivirus immunity was high. Responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such TV dengue vaccines will also be discussed in the last part of this review. In conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue TV vaccine. An extensive clinical development program for dengue TV is underway including completion of the enrollment of 4,000 4-11 years old children in an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.

Overview of genetically engineered mouse models of colorectal carcinoma to enable translational biology and drug development.

PubMed

Roper, Jatin; Martin, Eric S; Hung, Kenneth E

2014-06-16

Preclinical models for colorectal cancer (CRC) are critical for translational biology and drug development studies to characterize and treat this condition. Mouse models of human cancer are particularly popular because of their relatively low cost, short life span, and ease of use. Genetically engineered mouse models (GEMMs) of CRC are engineered from germline or somatic modification of critical tumor suppressor genes and/or oncogenes that drive mutations in human disease. Detailed in this overview are the salient features of several useful colorectal cancer GEMMs and their value as tools for translational biology and preclinical drug development. Copyright © 2014 John Wiley & Sons, Inc.

Legalising medical use of cannabis in South Africa: Is the empirical evidence sufficient to support policy shifts in this direction?

PubMed

Parry, Charles D H; Myers, Bronwyn J

2014-03-12

Inkatha Freedom Party MP Mario Oriani-Ambrosini's impassioned plea to legalise the medical use of cannabis must be understood in the context of his own condition as well as legislative changes in at least ten countries. This article argues that any decisions to shift policy must be based on a consideration of the evidence on the risks and benefits associated with the medical use of cannabis for the individual and broader society. It concludes that there are important gaps in the evidence base, particularly in human trials supporting the efficacy of cannabis use for treating and preventing medical conditions and alleviating negative symptoms associated with these conditions. South African researchers should be enabled actively to support development of the necessary evidence base actively by conducting preclinical and clinical research in this area. Human trials to establish the efficacy of the use of cannabis/cannabinoids in addressing AIDS wasting syndrome and other negative sequelae of HIV and AIDS are especially needed.

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

PubMed

Westerdahl, Daniel E; Chang, David H; Hamilton, Michele A; Nakamura, Mamoo; Henry, Timothy D

2016-09-01

Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date

PubMed Central

Fung, Lawrence K.; Hardan, Antonio Y.

2015-01-01

Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in preclinical and clinical studies are described. Finally, we will discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD. PMID:26104862

Neuropeptide Y, resilience, and PTSD therapeutics.

PubMed

Kautz, Marin; Charney, Dennis S; Murrough, James W

2017-05-10

Resilience to traumatic stress is a complex psychobiological process that protects individuals from developing posttraumatic stress disorder (PTSD) or other untoward consequences of exposure to extreme stress, including depression. Progress in translational research points toward the neuropeptide Y (NPY) system - among others - as a key mediator of stress response and as a potential therapeutic focus for PTSD. Substantial preclinical evidence supports the role of NPY in the modulation of stress response and in the regulation of anxiety in animal models. Clinical studies testing the safety and efficacy of modulating the NPY system in humans, however, have lagged behind. In the current article, we review the evidence base for targeting the NPY system as a therapeutic approach in PTSD, and consider impediments and potential solutions to therapeutic development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations.

PubMed

Chang, Rong-Kun; Mathias, Neil; Hussain, Munir A

2017-09-01

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.

Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

PubMed

Ioset, Jean-Robert; Chang, Shing

2011-09-01

The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

Growth/differentiation factor-5: pre-clinical and clinical evaluations of periodontal regeneration and alveolar augmentation--review.

PubMed

Lee, Jaebum; Wikesjö, Ulf M E

2014-08-01

Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Intraspinal Stem Cell Transplantation for Amyotrophic Lateral Sclerosis

PubMed Central

Chen, Kevin S.; Sakowski, Stacey A.; Feldman, Eva L.

2015-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only FDA approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS since they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. While various stem cell types are being evaluated in preclinical and early clinical applications, here we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of the Phase I and IIa clinical trials involving direct intraspinal transplantation in humans. PMID:26696091

The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.

PubMed

Eaton, Joshua Seth; Miller, Paul E; Bentley, Ellison; Thomasy, Sara M; Murphy, Christopher J

2017-12-01

To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development. Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science. The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species. The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.

[Development of a New Scholastic Program for Medication Counseling Practice in Preclinical Training, Constructed for Junior Students by Senior Students Based on Their Experiences of On-site Practice].

PubMed

Suzuki, Sayo; Aono, Izumi; Imai, Natsumi; Kuwabara, Aki; Kenda, Yuki; Matsumoto, Minako; Yoshida, Aya; Watanabe, Asuka; Takagi, Akinori; Kobayashi, Noriko; Saeki, Haruko; Ohtani, Hisakazu; Nakamura, Tomonori; Kizu, Junko

2017-01-01

 Long-term practical on-site training, based on the Model Core Curriculum for Pharmaceutical Education, is a core program of the 6-year course of pharmaceutical education, introduced in Japan in 2010. In particular, medication counseling in practical training in 5th-year provides valuable opportunities for communication with real patients rather than simulated patients (SPs). However, it can also cause anxiety in 4th-year students before practical training. To address such concerns, upperclassmen (5th- and 6th-year students), who have already completed practical training, constructed and conducted a new educational program for medication counseling practice in preclinical training based on their experiences. They also developed case scenarios and played the role of patients themselves to create more realistic clinical settings. Advice from professional SPs was also provided. The 5-step program is composed of 1st counseling, 1st small group discussion (SGD) for improving counseling, 2nd revised counseling based on the 1st SGD, 2nd SGD, and development of a counseling plan and presentation. Educational effects of the program were evaluated by questionnaire survey after preclinical training in 4th-year students and after their practical training in 5th-year students. This new program, the Advanced Medication Counseling Practice, was found to be useful to reduce anxiety about communication with patients among 4th-year students (about 90%). Even after their practical training in 5th-year, they still appreciated usefulness of this program (about 80%). This program is still valued 4 years after its development. We developed the Advanced Medication Counseling Practice in preclinical training for junior students by senior students.

Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

PubMed Central

Mazcko, Christina; Hanna, Engy; Kachala, Stefan; LeBlanc, Amy; Newman, Shelley; Vail, David; Henry, Carolyn; Thamm, Douglas; Sorenmo, Karin; Hajitou, Amin; Pasqualini, Renata; Arap, Wadih

2009-01-01

Background Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5×1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies. PMID:19330034

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics.

PubMed

Knezevic, Nebojsa Nick; Yekkirala, Ajay; Yaksh, Tony L

2017-11-01

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor-targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | Poster

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. The mice were developed to tolerate often-used light-emitting molecules, such as luciferase from fireflies and green fluorescent protein

The Flipped Classroom for pre-clinical dental skills teaching - a reflective commentary.

PubMed

Crothers, A J; Bagg, J; McKerlie, R

2017-05-12

A Flipped Classroom method for teaching of adult practical pre-clinical dental skills was introduced to the BDS curriculum in Glasgow during the 2015/2016 academic session. This report provides a commentary of the first year of employing this method - from the identification of the need to optimise teaching resources, through the planning, implementation and development of the method, with an early indication of performance.

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.

Premise for Standardized Sepsis Models.

PubMed

Remick, Daniel G; Ayala, Alfred; Chaudry, Irshad; Coopersmith, Craig M; Deutschman, Clifford; Hellman, Judith; Moldawer, Lyle; Osuchowski, Marcin

2018-06-05

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cancer, malaria, obesity and cardiovascular diseases have used standardized, preclinical models that allow laboratories to compare results. Standardized models accelerate the pace of research and such models have been used to test new therapies or changes in treatment guidelines. The National Institutes of Health (NIH) mandated that investigators increase data reproducibility and the rigor of scientific experiments and has also issued research funding announcements about the development and refinement of standardized models. Our premise is that refinement and standardization of preclinical sepsis models may accelerate the development and testing of potential therapeutics for human sepsis, as has been the case with preclinical models for other disorders. As a first step towards creating standardized models, we suggest 1) standardizing the technical standards of the widely used cecal ligation and puncture model and 2) creating a list of appropriate organ injury and immune dysfunction parameters. Standardized sepsis models could enhance reproducibility and allow comparison of results between laboratories and may accelerate our understanding of the pathogenesis of sepsis.

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

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.

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

Modeling the Western Diet for Preclinical Investigations.

PubMed

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

2018-05-01

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

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.

Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders

PubMed Central

Heidbreder, Christian A.; Newman, Amy H.

2011-01-01

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. PMID:20201845

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.

PubMed

Tiphaine, Adam de Beaumais; Hjalgrim, Lisa Lynqsie; Nersting, Jacob; Breitkreutz, Joerg; Nelken, Brigitte; Schrappe, Martin; Stanulla, Martin; Thomas, Caroline; Bertrand, Yves; Leverger, Guy; Baruchel, André; Schmiegelow, Kjeld; Jacqz-Aigrain, Evelyne

2016-02-15

6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination. The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred. Pharmacokinetic, palatability and safety data support the use of Loulla in children. Copyright © 2015 Elsevier B.V. All rights reserved.

Is immunotherapy an opportunity for effective treatment of drug addiction?

PubMed

Zalewska-Kaszubska, Jadwiga

2015-11-27

Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?

PubMed

Choy, Hak; Milas, Luka

2003-10-01

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.

Psychosocial impact, perceived stress and learning effect in undergraduate dental students during transition from pre-clinical to clinical education.

PubMed

Frese, C; Wolff, D; Saure, D; Staehle, H J; Schulte, A

2018-04-10

This study aimed to develop a suitable instrument for a comprehensive quantitative and qualitative assessment of perceived psychosocial impact, levels of stress and learning effect in undergraduate dental students during the transition from pre-clinical to clinical education. These findings might improve curricular structures and didactic organisation during this period. At the beginning of their first clinical year, undergraduate dental students were asked to complete an anonymous forty-item questionnaire. Two hundred and seventy-six undergraduate dental students were willing to participate and completed the questionnaire and participated during the years 2011-2016. The response rate was between 45% and 96%. Correlational analysis (Spearman-Rho) in the field of psychosocial impact showed the dental teacher to be the most important multiplier of students' feelings. If the students feel that their teacher acts cooperatively, positive items increase and negative items decrease significantly (P < .0001). Also, students who report high levels of stress are affected significantly in their psychosocial interaction (P < .0001). Wilcoxon test yielded highest levels of stress in endodontology during the first weeks (P < .0001). During the same period, the greatest learning increment was seen for diagnostics and caries excavation. In conclusion, teaching of undergraduate dental students during the transition period from pre-clinical to clinical education can be positively influenced by a supportive learning environment and by specific chronological modifications in the curriculum. Students should start their clinical training with diagnostics, preventive dentistry and initial periodontal treatment. Due to high levels of perceived stress, endodontology should be introduced later in the clinical curriculum. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.

PubMed

Heidbreder, Christian A; Newman, Amy H

2010-02-01

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides.

PubMed

Engelhardt, Jeffery A; Fant, Pierluigi; Guionaud, Silvia; Henry, Scott P; Leach, Michael W; Louden, Calvert; Scicchitano, Marshall S; Weaver, James L; Zabka, Tanja S; Frazier, Kendall S

2015-10-01

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies. © 2015 by The Author(s).

Anatomy meets dentistry! Linking anatomy and clinical practice in the preclinical dental curriculum.

PubMed

Rafai, Nicole; Lemos, Martin; Kennes, Lieven Nils; Hawari, Ayichah; Gerhardt-Szép, Susanne; Classen-Linke, Irmgard

2016-11-25

Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes. For the curricular development of the expanded course module, Kern's 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes. The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study. The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.

SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

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

Ellens, N; Farahani, K

2015-06-15

Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precisionmore » of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many preclinical applications including focused drug delivery and thermal therapy. Funding support provided by Philips Healthcare.« less

The Science of Cancer Prevention

Cancer.gov

The science of cancer prevention is described by Dr. Barnett S. Kramer, M.D., M.P.H., director of the Division of Cancer Prevention, National Cancer Institute (NCI). The Division of Cancer Prevention administers a broad spectrum of research that spans basic pre-clinical, laboratory research, supportive and palliative care research, early detection, and randomized controlled clinical trials. The Division also supports the Cancer Prevention Fellowship Program and is devoted to the balanced communication of scientific results.

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

PubMed

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

2018-01-01

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

Enzastaurin: A lesson in drug development.

PubMed

Bourhill, T; Narendran, A; Johnston, R N

2017-04-01

Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic. Copyright © 2017 Elsevier B.V. All rights reserved.

The current status of biomarkers for predicting toxicity

PubMed Central

Campion, Sarah; Aubrecht, Jiri; Boekelheide, Kim; Brewster, David W; Vaidya, Vishal S; Anderson, Linnea; Burt, Deborah; Dere, Edward; Hwang, Kathleen; Pacheco, Sara; Saikumar, Janani; Schomaker, Shelli; Sigman, Mark; Goodsaid, Federico

2013-01-01

Introduction There are significant rates of attrition in drug development. A number of compounds fail to progress past preclinical development due to limited tools that accurately monitor toxicity in preclinical studies and in the clinic. Research has focused on improving tools for the detection of organ-specific toxicity through the identification and characterization of biomarkers of toxicity. Areas covered This article reviews what we know about emerging biomarkers in toxicology, with a focus on the 2012 Northeast Society of Toxicology meeting titled ‘Translational Biomarkers in Toxicology.’ The areas covered in this meeting are summarized and include biomarkers of testicular injury and dysfunction, emerging biomarkers of kidney injury and translation of emerging biomarkers from preclinical species to human populations. The authors also provide a discussion about the biomarker qualification process and possible improvements to this process. Expert opinion There is currently a gap between the scientific work in the development and qualification of novel biomarkers for nonclinical drug safety assessment and how these biomarkers are actually used in drug safety assessment. A clear and efficient path to regulatory acceptance is needed so that breakthroughs in the biomarker toolkit for nonclinical drug safety assessment can be utilized to aid in the drug development process. PMID:23961847

Organs-on-chips at the frontiers of drug discovery

PubMed Central

Esch, Eric W.; Bahinski, Anthony; Huh, Dongeun

2016-01-01

Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology. PMID:25792263

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

PubMed Central

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery.

PubMed

Coussens, Nathan P; Sittampalam, G Sitta; Guha, Rajarshi; Brimacombe, Kyle; Grossman, Abigail; Chung, Thomas D Y; Weidner, Jeffrey R; Riss, Terry; Trask, O Joseph; Auld, Douglas; Dahlin, Jayme L; Devanaryan, Viswanath; Foley, Timothy L; McGee, James; Kahl, Steven D; Kales, Stephen C; Arkin, Michelle; Baell, Jonathan; Bejcek, Bruce; Gal-Edd, Neely; Glicksman, Marcie; Haas, Joseph V; Iversen, Philip W; Hoeppner, Marilu; Lathrop, Stacy; Sayers, Eric; Liu, Hanguan; Trawick, Bart; McVey, Julie; Lemmon, Vance P; Li, Zhuyin; McManus, Owen; Minor, Lisa; Napper, Andrew; Wildey, Mary Jo; Pacifici, Robert; Chin, William W; Xia, Menghang; Xu, Xin; Lal-Nag, Madhu; Hall, Matthew D; Michael, Sam; Inglese, James; Simeonov, Anton; Austin, Christopher P

2018-06-07

The Assay Guidance Manual (AGM) is an eBook of best-practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through pre-clinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Nonuniform cardiac denervation observed by 11C-meta-hydroxyephedrine PET in 6-OHDA-treated monkeys.

PubMed

Joers, Valerie; Seneczko, Kailie; Goecks, Nichole C; Kamp, Timothy J; Hacker, Timothy A; Brunner, Kevin G; Engle, Jonathan W; Barnhart, Todd E; Nickles, R Jerome; Holden, James E; Emborg, Marina E

2012-01-01

Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg). The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog (11)C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps) revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001) and 14 weeks (P<0.01) relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05), epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01) were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia.

The eTOX data-sharing project to advance in silico drug-induced toxicity prediction.

PubMed

Cases, Montserrat; Briggs, Katharine; Steger-Hartmann, Thomas; Pognan, François; Marc, Philippe; Kleinöder, Thomas; Schwab, Christof H; Pastor, Manuel; Wichard, Jörg; Sanz, Ferran

2014-11-14

The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that reach the market, but the majority of studies are never made public and are often difficult to access in an automated way, even sometimes within the owning company itself. It is evident from many academic and industrial examples, that useful data mining and model development requires large and representative data sets and careful curation of the collected data. In 2010, under the auspices of the Innovative Medicines Initiative, the eTOX project started with the objective of extracting and sharing preclinical study data from paper or pdf archives of toxicology departments of the 13 participating pharmaceutical companies and using such data for establishing a detailed, well-curated database, which could then serve as source for read-across approaches (early assessment of the potential toxicity of a drug candidate by comparison of similar structure and/or effects) and training of predictive models. The paper describes the efforts undertaken to allow effective data sharing intellectual property (IP) protection and set up of adequate controlled vocabularies) and to establish the database (currently with over 4000 studies contributed by the pharma companies corresponding to more than 1400 compounds). In addition, the status of predictive models building and some specific features of the eTOX predictive system (eTOXsys) are presented as decision support knowledge-based tools for drug development process at an early stage.

Applications of pathology-assisted image analysis of immunohistochemistry-based biomarkers in oncology.

PubMed

Shinde, V; Burke, K E; Chakravarty, A; Fleming, M; McDonald, A A; Berger, A; Ecsedy, J; Blakemore, S J; Tirrell, S M; Bowman, D

2014-01-01

Immunohistochemistry-based biomarkers are commonly used to understand target inhibition in key cancer pathways in preclinical models and clinical studies. Automated slide-scanning and advanced high-throughput image analysis software technologies have evolved into a routine methodology for quantitative analysis of immunohistochemistry-based biomarkers. Alongside the traditional pathology H-score based on physical slides, the pathology world is welcoming digital pathology and advanced quantitative image analysis, which have enabled tissue- and cellular-level analysis. An automated workflow was implemented that includes automated staining, slide-scanning, and image analysis methodologies to explore biomarkers involved in 2 cancer targets: Aurora A and NEDD8-activating enzyme (NAE). The 2 workflows highlight the evolution of our immunohistochemistry laboratory and the different needs and requirements of each biological assay. Skin biopsies obtained from MLN8237 (Aurora A inhibitor) phase 1 clinical trials were evaluated for mitotic and apoptotic index, while mitotic index and defects in chromosome alignment and spindles were assessed in tumor biopsies to demonstrate Aurora A inhibition. Additionally, in both preclinical xenograft models and an acute myeloid leukemia phase 1 trial of the NAE inhibitor MLN4924, development of a novel image algorithm enabled measurement of downstream pathway modulation upon NAE inhibition. In the highlighted studies, developing a biomarker strategy based on automated image analysis solutions enabled project teams to confirm target and pathway inhibition and understand downstream outcomes of target inhibition with increased throughput and quantitative accuracy. These case studies demonstrate a strategy that combines a pathologist's expertise with automated image analysis to support oncology drug discovery and development programs.

Cost-effective teaching of radiology with preclinical anatomy.

PubMed

Wilson, James S; Alvarez, Jacqueline; Davis, Bonnie C; Duerinckx, Andre J

2018-03-01

Graduating physicians in all subspecialties have an increased need for competency in radiology, particularly since the use of diagnostic imaging continues to grow. To integrate the teaching of radiology with anatomy during the first year of medical school at Howard University, a novel approach was developed to overcome the limitations of resources including funding, faculty, and curricular time. The resulting program relies on self-study and peer-to-peer interactions to develop proficiency at manipulating free versions of medical image viewer software (using the DICOM standard), identifying normal anatomy in medical images, and applying critical thinking skills to understand common clinical conditions. An effective collaborative relationship between a radiologist and anatomist was necessary to develop and implement the program of anatomic-radiographic instruction which consists of five tiers: (1) initial exposure to anatomy through dissection which provides a foundation of knowledge; (2) study of annotated radiographs from atlases; (3) a radiology quiz open to group discussions; (4) small group study of clinical cases with diagnostic images; and (5) radiographic tests. Students took all quizzes and tests by working from image datasets preloaded on their personal computers, mimicking the approach by which radiologists analyze medical images. In addition to stimulating student support of a new teaching initiative, the strengths of Howard's program are that it can be introduced into an existing preclinical curriculum in almost any medical school with minimal disruption, it requires few additional resources to implement and run, and its design is consistent with the principles of modern education theory. Anat Sci Educ 11: 196-206. © 2017 American Association of Anatomists. © 2017 American Association of Anatomists.

TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development.

PubMed

Kaufmann, Stefan H E; Dockrell, Hazel M; Drager, Nick; Ho, Mei Mei; McShane, Helen; Neyrolles, Olivier; Ottenhoff, Tom H M; Patel, Brij; Roordink, Danielle; Spertini, François; Stenger, Steffen; Thole, Jelle; Verreck, Frank A W; Williams, Ann

2017-01-01

TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.

TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development

PubMed Central

Kaufmann, Stefan H. E.; Dockrell, Hazel M.; Drager, Nick; Ho, Mei Mei; McShane, Helen; Neyrolles, Olivier; Ottenhoff, Tom H. M.; Patel, Brij; Roordink, Danielle; Spertini, François; Stenger, Steffen; Thole, Jelle; Verreck, Frank A. W.; Williams, Ann; Britton, Warwick

2017-01-01

TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal. PMID:29046674

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

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

PubMed

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

2017-02-01

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

Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside.

PubMed

Shabbir, Munira; Stuart, Robert

2010-03-01

Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population. An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade. The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent. Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.

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

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

PubMed Central

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

2010-01-01

Introduction Global health education is becoming more important for developing well-rounded physicians and may encourage students toward a career in primary care. Many medical schools, however, lack adequate and structured opportunities for students beginning the curriculum. Methods Second-year medical students initiated, designed, and facilitated a pass–fail international health elective, providing a curricular framework for preclinical medical students wishing to gain exposure to the clinical and cultural practices of a developing country. Results All course participants (N=30) completed a post-travel questionnaire within one week of sharing their experiences. Screening reflection essays for common themes that fulfill university core competencies yielded specific global health learning outcomes, including analysis of health care determinants. Conclusion Medical students successfully implemented a sustainable global health curriculum for preclinical student peers. Financial constraints, language, and organizational burdens limit student participation. In future, long-term studies should analyze career impact and benefits to the host country. PMID:20186283

Nanoparticles in targeted cancer therapy: mesoporous silica nanoparticles entering preclinical development stage.

PubMed

Rosenholm, Jessica M; Mamaeva, Veronika; Sahlgren, Cecilia; Lindén, Mika

2012-01-01

Nanotechnology may help overcome persisting limitations of current cancer treatment and thus contribute to the creation of more effective, safer and more affordable therapies. While some nanotechnology-based drug delivery systems are already being marketed and others are in clinical trial, most still remain in the preclinical development stage. Mesoporous silica nanoparticles have been highlighted as an interesting drug delivery platform, due to their flexibility and high drug load potential. Although numerous reports demonstrate sophisticated drug delivery mechanisms in vitro, the therapeutic benefit of these systems for in vivo applications have been under continuous debate. This has been due to nontranslatable conditions used in the in vitro studies, as well as contradictory conclusions drawn from preclinical (in vivo) studies. However, recent studies have indicated that the encouraging cellular studies could in fact be repeated also in vivo. Here, we report on these recent advances regarding therapeutic efficacy, targeting and safety issues related to the application of mesoporous silica nanoparticles in cancer therapy.

Toward the development of effective transmission-blocking vaccines for malaria.

PubMed

Nikolaeva, Daria; Draper, Simon J; Biswas, Sumi

2015-05-01

The continued global burden of malaria can in part be attributed to a complex lifecycle, with both human hosts and mosquito vectors serving as transmission reservoirs. In preclinical models of vaccine-induced immunity, antibodies to parasite sexual-stage antigens, ingested in the mosquito blood meal, can inhibit parasite survival in the insect midgut as judged by ex vivo functional studies such as the membrane feeding assay. In an era of renewed political momentum for malaria elimination and eradication campaigns, such observations have fueled support for the development and implementation of so-called transmission-blocking vaccines. While leading candidates are being evaluated using a variety of promising vaccine platforms, the field is also beginning to capitalize on global '-omics' data for the rational genome-based selection and unbiased characterization of parasite and mosquito proteins to expand the candidate list. This review covers the progress and prospects of these recent developments.

Outsourcing bioanalytical services at Janssen Research and Development: the sequel anno 2017.

PubMed

Dillen, Lieve; Verhaeghe, Tom

2017-08-01

The strategy of outsourcing bioanalytical services at Janssen has been evolving over the last years and an update will be given on the recent changes in our processes. In 2016, all internal GLP-related activities were phased out and this decision lead to the re-orientation of the in-house bioanalytical activities. As a consequence, in-depth experience with the validated bioanalytical assays for new drug candidates is currently gained together with the external partner, since development and validation of the assay and execution of GLP preclinical studies are now transferred to the CRO. The evolution to externalize more bioanalytical support has created opportunities to build even stronger partnerships with the CROs and to refocus internal resources. Case studies are presented illustrating challenges encountered during method development and validation at preferred partners when limited internal experience is obtained or with introduction of new technology.

Innovative financing for late-stage global health research and development: the Global Health Investment Fund.

PubMed

Fitchett, Joseph Robert; Fan Li, Julia; Atun, Rifat

2016-01-01

Innovative financing strategies for global health are urgently needed to reinvigorate investment and new tools for impact. Bottleneck areas along the research and development (R&D) pipeline require particular attention, such as the transitions from preclinical discovery to clinical study, and product development to implementation and delivery. Successful organizations mobilizing and disbursing resources through innovating financing mechanisms include UNITAID, the Global Fund, and Gavi, the Vaccine Alliance. Although precise numbers are poorly documented, estimated investment in low-income settings falls seriously short of local need. This commentary discusses the newly established Global Health Investment Fund as a case study to support late-stage global health R&D. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Developing therapeutic microRNAs for cancer

PubMed Central

Bader, AG; Brown, D; Stoudemire, J; Lammers, P

2014-01-01

Despite substantial progress in understanding the cancer-signaling network, effective therapies remain scarce due to insufficient disruption of oncogenic pathways, drug resistance and drug-induced toxicity. This complexity of cancer defines an urgent goal for researchers and clinicians to develop novel therapeutic strategies. The discovery of microRNAs (miRNAs) provides new hope for accomplishing this task. Supported by solid evidence for a critical role in cancer and bolstered by a unique mechanism of action, miRNAs are likely to yield a new class of targeted therapeutics. In contrast to current cancer medicines, miRNA-based therapies function by subtle repression of gene expression on a yet large number of oncogenic factors and are, therefore, anticipated to be highly efficacious. After the completion of target validation for several candidates, the development of therapeutic miRNAs is now moving to a new stage that involves pharmacological drug delivery, preclinical toxicology and regulatory guidelines. PMID:21633392

Conference Report: 6th Annual International Symposium on Regenerative Rehabilitation.

PubMed

Loghmani, M Terry; Roche, Joseph A

2018-04-03

The 6th International Symposium on Regenerative Rehabilitation, hosted by the Alliance for Regenerative Rehabilitation Research and Training (AR 3 T), included a preconference meeting of institutional representatives of the International Consortium of Regenerative Rehabilitation, keynote talks from distinguished scientists, platform and poster presentations from experts and trainees, panel discussions and postconference workshops. The following priorities were identified: increasing rigor in basic, preclinical and clinical studies, especially the use of better controls; developing better outcome measures for preclinical and clinical trials; focusing on developing more tissue-based interventions versus cell-based interventions; including regenerative rehabilitation in curricula of professional programs like occupational and physical therapy; and developing better instruments to quantify rehabilitative interventions.

The development of the rotigotine transdermal patch: a historical perspective.

PubMed

Waters, Cheryl

2013-08-01

The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. Copyright © 2013 Elsevier Inc. All rights reserved.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

PubMed

Washington, Patricia M; Villapol, Sonia; Burns, Mark P

2016-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should it be classified together as traumatic encephalopathy?

PubMed Central

Washington, Patricia M.; Villapol, Sonia; Burns, Mark P.

2015-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer’s disease (AD), while mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position—examining epidemiological and case-control human studies, neuropathological evidence, and preclinical studies. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson’s disease. Further, human post-mortem studies on either single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a ‘polypathology’. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI are viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. PMID:26091850

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

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

Welch, M; Jaffray, D; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MRmore » and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century at CIHR and the Gifford Ontario Student Opportunity Trust Fund.« less

Differential Cued-Stroop Performance in Cognitively Asymptomatic Older Adults with Biomarker-Identified Risk for Alzheimer's Disease: A Pilot Study.

PubMed

Patten, Ryan Van; Fagan, Anne M; Kaufman, David A S

2018-04-04

There exists a need for more sensitive measures, capable of detecting subtle cognitive decline due to Alzheimer's disease. To advance the literature in Alzheimer's disease by demonstrating that performance on a cued-Stroop task is impacted by preclinical Alzheimer's disease neuropathology. Twenty-nine cognitively asymptomatic older adults completed a computerized, cued-Stroop task in which accuracy rates and intraindividual variability in reaction times were the outcomes of interest. Cerebrospinal fluid biomarkers of Aβ42 and tau were measured and participants were then grouped according to a published p-tau/Aβ42 cutoff reflecting risk for Alzheimer's disease (preclinical Alzheimer's disease = 14; control = 15). ANOVAs indicated that accuracy rates did not differ between the groups but 4-second delay incongruent color-naming Stroop coefficient of variation reaction times were higher in the preclinical Alzheimer's disease group compared to the control group, reflecting increased within-person variability. Moreover, partial correlations showed no relationships between cerebrospinal fluid biomarkers and accuracy rates. However, increases in coefficient of variation reaction times correlated with decreased Aβ42 and increases in p-tau and the p-tau/Aβ42 ratio. Results supported the ability of the computerized, cued-Stroop task to detect subtle Alzheimer's disease neuropathology using a small cohort of cognitively asymptomatic older adults. The ongoing measurement of cued-Stroop coefficient of variation reaction times has both scientific and clinical utility in preclinical Alzheimer's disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sex differences in stroke therapies.

PubMed

Sohrabji, Farida; Park, Min Jung; Mahnke, Amanda H

2017-01-02

Stroke is the fifth leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these have been shown to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few preclinical or clinical therapeutics take into account possible sex differences in treatment. Reanalysis of data from studies of tissue plasminogen activator (tPA), the only currently FDA-approved stroke therapy, has shown that tPA improves stroke outcomes for both sexes and also shows sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (insulin-like growth factor-1), and inhibitors of cell death pathways (pharmacological inhibition of poly[ADP-ribose] polymerase-1, nitric oxide production, and caspase activation) as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analysis in clinical trials as well as in preclinical studies must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systematic/structured ways to allow promising therapies for both sexes and increase stroke recovery. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

PubMed

Ogwang, P E; Nyafuono, J; Agwaya, Moses; Omujal, F; Tumusiime, H R; Kyakulaga, A H

2011-09-01

Medicinal plants in Uganda and other developing countries have been scientifically demonstrated to have medicinal benefits but few or none have been translated to products for clinical use. Most herbal products developed by local herbalists and sold to the public are not standardized and lack efficacy and safety data to support use. To formulate from two Ugandan medicinal plants a herbal product for wound management and test its preclinical safety and efficacy using rat models. Thirty (30) Wistar albino rats were randomly divided into three groups and wounds were surgically created on the mid-dorsal region. The wounds were treated topically with distilled water (group I), Jena(®) (group II)and Neomycin sulfate cream (group III). The effects of the treatments on rate of wound closure, epithelialisation time and histological organization of tissue were assessed. The herbal formulation (Jena) had a significantly higher rate of wound closure than neomycin (p<0.05) which itself was better than distilled water. Epithelialisation time was also significantly shorter for the herbal product (p<0.01). Histological picture revealed more collagen fibers, less inflammation and better tissue remodeling for rats treated with herbal product. The herbal formulation Jena(®) systematically designed and formulated based on two Ugandan medicinal plants is according to this study better than neomycin and probably other imported products for wound management in Uganda. We recommend its trial in a clinical setting as an alternative in wound management.

Novel glutamatergic drugs for the treatment of mood disorders

PubMed Central

Lapidus, Kyle AB; Soleimani, Laili; Murrough, James W

2013-01-01

Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders. PMID:23976856

Ten-year NEDO BVAD development program: moving forward to the clinical arena.

PubMed

Motomura, Tadashi; Okubo, Hisashi; Oda, Takeshi; Ogawa, Daisuke; Okahisa, Toshiya; Igo, Stephen; Shinohara, Toshiyuki; Yamamoto, Yoshiro; Noguchi, Chikaya; Ishizuka, Tsukasa; Okamoto, Eiji; Nosé, Yukihiko

2006-01-01

Since 1995, the Baylor Group has been developing a totally implantable NEDO BVAD system. This 10-year program was completed in March 2005, and preparation for clinical trials is underway. This article summarizes the entire 10-year NEDO program and describes the strategy for clinical trials. The project aimed to achieve: (1) dual centrifugal pumps with the ability of full biventricular support, (2) a compact system implantable into small adults, (3) a totally implantable system with transcutaneous energy transmission system (TETS), (4) a durable system with a lifetime of over 5 years, and (5) a system free of thrombus and with minimal hemolysis. The final goals are to complete preclinical system evaluations and commence the clinical trials in the near future. In vitro studies have demonstrated a pump capacity of over 8.5 l/min and an Index of Hemolysis of <0.004 g/100 l. The pump-bearing life expectancy was over 5 years. To date, eight pumps endured in vivo studies of over 3 months without complications, including thromboembolic events. The in vitro endurance studies of eight pumps are longer than 1 year. There were no mechanical malfunctions or pump failure. A stepwise clinical trial is being planned: Step1, a wearable BVAD/VAD will be clinically studied; Step 2, the BVAD/VAD will be implanted intracorporeally without TETS; and, Step 3, a totally implantable system will be clinically evaluated. The NEDO BVAD system has completed preclinical testing. Clinical trial preparation is underway.

Methods for the In Vitro Characterization of Nanomedicines—Biological Component Interaction

PubMed Central

Fornaguera, Cristina; Solans, Conxita

2017-01-01

The design of colloidal nanosystems intended for biomedical applications, specifically in the field of personalized medicine, has increased notably in the last years. Consequently, a variety of characterization techniques devoted to studying nanomedicine interactions with proteins and cells have been developed, since a deep characterization of nanosystems is required before starting preclinical and clinical studies. In this context, this review aims to summarize the main techniques used to assess the interaction of nanomedicines with biological systems, highlighting their advantages and disadvantages. Testing designed nanomaterials with these techniques is required in order to have more information about their behavior on a physiological environment. Moreover, techniques used to study the interaction of nanomedicines with proteins, such as albumin and fibrinogen, are summarized. These interactions are not desired, since they usually are the first signal to the body for the activation of the immune system, which leads to the clearance of the exogenous components. On the other hand, techniques for studying the cell toxicity of nanosystems are also summarized, since this information is required before starting preclinical steps. The translation of knowledge from novel designed nanosystems at a research laboratory scale to real human therapies is usually a limiting or even a final point due to the lack of systematic studies regarding these two aspects: nanoparticle interaction with biological components and nanoparticle cytotoxicity. In conclusion, this review will be a useful support for those scientists aiming to develop nanosystems for nanomedicine purposes. PMID:28134833

Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury

PubMed Central

Robertson, Courtney L.; Fidan, Emin; Stanley, Rachel M.; MHSA; Noje, Corina; Bayir, Hülya

2016-01-01

Objective To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury (TBI), and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric TBI. Data Sources National Library of Medicine PubMed literature review. Data Selection The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of TBI are summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult TBI is reviewed. Data Extraction and Synthesis Progesterone is a pleotropic agent with beneficial effects on secondary injury cascades that occur after TBI, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after TBI in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human Phase II trials of progesterone for adult TBI have been published, and two multi-center Phase III trials are underway. Conclusions The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of TBI. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children, and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, statue epilepticus). PMID:25581631

Determination of a deuterohemin-peptide conjugate in rat plasma by liquid chromatography-tandem mass spectrometry and application to a preclinical pharmacokinetic study.

PubMed

Wang, Hao; Sun, Yantong; Guo, Wei; Fang, Chunxue; Fawcett, J Paul; Li, Wei; Gao, Yin; Yang, Yan; Gu, Jingkai

2014-09-01

The deuterohemin-peptide conjugate (DhHP-6) is a microperoxidase mimetic, which has demonstrated substantial benefits in vivo as a scavenger of reactive oxygen species. This paper reports the development of a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of DhHP-6 in rat plasma using triptorelin as an internal standard (IS). 50μL plasma was used in sample preparation, and a simple protein precipitation procedure with acetonitrile was involved. Satisfactory peak shapes of analyte and IS were obtained on an Agilent HC-C18 column by using a gradient elution with 10mM ammonium acetate-0.5% formic acid (v:v) and acetonitrile, there was no significant interference impacting the determination. A calibration curve obtained from this method was linear within the concentration range 10-3000ng/mL with intra- and inter-day precisions of 4.2-6.8% and 3.2-8.9%, respectively and accuracy of -1.3% to 2.1%. The recovery was above 80% with low matrix effects. The method was successfully applied to support a preclinical pharmacokinetic study in rat. Copyright © 2014 Elsevier B.V. All rights reserved.

Enhancing positive attitudes towards disability: evaluation of an integrated physiotherapy program.

PubMed

Morgan, Prue Elizabeth; Lo, Kristin

2013-02-01

This study explored whether attitudes towards disability in second year undergraduate physiotherapy students could be enhanced by an on-campus integrated curriculum program. A pre-post design was used. Year 2 (pre-clinical) students participated in a 12-week program focused on optimising attitudes towards people with acquired or developmental neurological disability. The Discomfort subscale of the Interaction with Disabled Persons scale, rated on a six-point Likert scale, was applied prior to and at completion of the 12-week program, and compared to year 4 students, just prior to graduation. Qualitative data from year 2 reflective narratives was also gathered. Forty-seven second year and 45 fourth year physiotherapy students participated. The difference in Discomfort subscale scores between weeks 1 and 12 of year 2 was statistically significant (p = 0.0016). The difference in Discomfort subscale scores between year 2 week 1 and year 4 students was also statistically significant (p = 0.040). There was no significant difference in attitudes between students at the end of year 2 and the end of year 4 (p = 0.703). Qualitative data supported the development of more positive attitudes towards neurological disability across the 12 week year 2 pre-clinical program. Student attitudes towards people with acquired and/or developmental neurological disabilities can be enhanced through an on campus integrated curriculum program.

Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.

PubMed

Sangiolo, Dario; Mesiano, Giulia; Gammaitoni, Loretta; Leuci, Valeria; Todorovic, Maja; Giraudo, Lidia; Cammarata, Cristina; Dell'Aglio, Carmine; D'Ambrosio, Lorenzo; Pisacane, Alberto; Sarotto, Ivana; Miano, Sara; Ferrero, Ivana; Carnevale-Schianca, Fabrizio; Pignochino, Ymera; Sassi, Francesco; Bertotti, Andrea; Piacibello, Wanda; Fagioli, Franca; Aglietta, Massimo; Grignani, Giovanni

2014-01-01

Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.

Cell therapy for spinal cord injuries: what is really going on?

PubMed

Granger, Nicolas; Franklin, Robin J M; Jeffery, Nick D

2014-12-01

During the last two decades, many experiments have examined the ability of cell transplants to ameliorate the loss of function after spinal cord injuries, with the hope of developing interventions to benefit patients. Although many reports suggest positive effects, there is growing concern over the quality of the available preclinical data. It is therefore important to ask whether this worldwide investigative process is close to defining a cell transplant protocol that could be translated into human patients with a realistic chance of success. This review systematically examines the strength of the preclinical evidence and outlines mechanisms by which transplanted cells may mediate their effects in spinal cord injuries. First, we examined changes in voluntary movements in the forelimb associated with cell transplants after partial cervical lesions. Second, we examined the efficacy of transplanted cells to restore electrophysiological conduction across a complete thoracic lesion. We postulated that cell therapies found to be successful in both models could reasonably have potential to treat human patients. We conclude that although there are data to support a beneficial effect of cell transplantation, most reports provide only weak evidence because of deficits in experimental design. The mechanisms by which transplanted cells mediate their functional effects remain unclear. © The Author(s) 2014.

Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

PubMed Central

Kelly, John R.; Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Hyland, Niall P.

2015-01-01

The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID:26528128

"Psychogeritechnology" in Japan: Exemplars from a super-aged society.

PubMed

Leroi, Iracema; Watanabe, Kentaro; Hird, Nick; Sugihara, Taro

2018-05-31

The burgeoning field of gerontechnology, which is the interdisciplinary field of applying technology to ageing issues, has focused primarily on "active ageing" and maintaining independence for older adults. To date, there has been less focus on people who develop dementia. Here, we argue for the field of gerontechnology to have a greater emphasis on clinical applications for dementia. This can be captured under the rubric of "psychogeritechnology," a term we have coined to describe the range of technology approaches to the prevention, prediction, screening, assessment, diagnosis, management, and monitoring of people at risk of, or living with, dementia. Using Japan as the world's leading "super-aged' nation as a paradigm, the purpose of this paper is to provide a narrative review of the use of innovative technology for the diagnosis, management and support of people at risk of, or living with, dementia. By following the "life course" of dementia, we will use clinical exemplars and case studies of psychogeritechnological applications from a Japanese context, specific to each stage of dementia, from the preclinical to the advanced stage. In the preclinical stage, the focus will be on prevention and early detection of degenerative cognitive-functional trajectories. In the early-stage of dementia, we will outline examples of screening, assessment, diagnosis, and clinical monitoring, as well as the use of technology to support independent living and autonomy. In the moderate stage, examples of safety monitoring systems, and assistive technology to foster independence, quality of life will be outlined. Finally, in the advanced stage of dementia, our focus will be on assistive technology in the care home setting, and the need to foster secure and efficient communication among care providers. We will discuss these applications in terms of the evolution of the "technological roadmap" for dementia, and the need for a theoretical underpinning for the field, a meaningful and flexible evaluation framework, and consideration of the "wider perspective" including safety-critical issues, ethical issues, and the relation to policy and health economics. Japan, as a rapidly ageing society, is on the forefront of developing technology to support people with dementia. The new field of psychogeritechnology must harness the potential of such developments, while furthering the methodology to implement and evaluate the changes. Copyright © 2018 John Wiley & Sons, Ltd.

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, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement. Conclusions The study has commenced, but it is too early to provide results or conclusions. PMID:28254733

Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review

PubMed Central

Regner, Gabriela G.; Pereira, Patrícia; Leffa, Douglas T.; de Oliveira, Carla; Vercelino, Rafael; Fregni, Felipe; Torres, Iraci L. S.

2018-01-01

Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002–2017) using the keywords “tDCS,” “epilepsy,” “clinical trials,” and “animal models.” Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy. PMID:29623027

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

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.

Is tapentadol different from classical opioids? A review of the evidence

PubMed Central

Langford, Richard M; Knaggs, Roger; Farquhar-Smith, Paul; Dickenson, Anthony H

2016-01-01

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids. PMID:27867511

Is tapentadol different from classical opioids? A review of the evidence.

PubMed

Langford, Richard M; Knaggs, Roger; Farquhar-Smith, Paul; Dickenson, Anthony H

2016-11-01

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.

Large animal models for vaccine development and testing.

PubMed

Gerdts, Volker; Wilson, Heather L; Meurens, Francois; van Drunen Littel-van den Hurk, Sylvia; Wilson, Don; Walker, Stewart; Wheler, Colette; Townsend, Hugh; Potter, Andrew A

2015-01-01

The development of human vaccines continues to rely on the use of animals for research. Regulatory authorities require novel vaccine candidates to undergo preclinical assessment in animal models before being permitted to enter the clinical phase in human subjects. Substantial progress has been made in recent years in reducing and replacing the number of animals used for preclinical vaccine research through the use of bioinformatics and computational biology to design new vaccine candidates. However, the ultimate goal of a new vaccine is to instruct the immune system to elicit an effective immune response against the pathogen of interest, and no alternatives to live animal use currently exist for evaluation of this response. Studies identifying the mechanisms of immune protection; determining the optimal route and formulation of vaccines; establishing the duration and onset of immunity, as well as the safety and efficacy of new vaccines, must be performed in a living system. Importantly, no single animal model provides all the information required for advancing a new vaccine through the preclinical stage, and research over the last two decades has highlighted that large animals more accurately predict vaccine outcome in humans than do other models. Here we review the advantages and disadvantages of large animal models for human vaccine development and demonstrate that much of the success in bringing a new vaccine to market depends on choosing the most appropriate animal model for preclinical testing. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Connecting drug delivery reality to smart materials design.

PubMed

Grainger, David W

2013-09-15

Inflated claims to both design and mechanistic novelty in drug delivery and imaging systems, including most nanotechnologies, are not supported by the generally poor translation of these systems to clinical efficacy. The "form begets function" design paradigm is seductive but perhaps over-simplistic in translation to pharmaceutical efficacy. Most innovations show few clinically important distinctions in their therapeutic benefits in relevant preclinical disease and delivery models, despite frequent claims to the contrary. Long-standing challenges in drug delivery issues must enlist more realistic, back-to-basics approaches to address fundamental materials properties in complex biological systems, preclinical test beds, and analytical methods to more reliably determine fundamental pharmaceutical figures of merit, including drug carrier purity and batch-batch variability, agent biodistribution, therapeutic index (safety), and efficacy. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

Vitamin D in prostate cancer.

PubMed

Trump, Donald L; Aragon-Ching, Jeanny B

2018-01-01

Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.

Diagnostic and prognostic role of semantic processing in preclinical Alzheimer's disease.

PubMed

Venneri, Annalena; Jahn-Carta, Caroline; Marco, Matteo De; Quaranta, Davide; Marra, Camillo

2018-06-13

Relatively spared during most of the timeline of normal aging, semantic memory shows a subtle yet measurable decline even during the pre-clinical stage of Alzheimer's disease. This decline is thought to reflect early neurofibrillary changes and impairment is detectable using tests of language relying on lexical-semantic abilities. A promising approach is the characterization of semantic parameters such as typicality and age of acquisition of words, and propositional density from verbal output. Seminal research like the Nun Study or the analysis of the linguistic decline of famous writers and politicians later diagnosed with Alzheimer's disease supports the early diagnostic value of semantic processing and semantic memory. Moreover, measures of these skills may play an important role for the prognosis of patients with mild cognitive impairment.

Patient-derived xenografts as preclinical neuroblastoma models.

PubMed

Braekeveldt, Noémie; Bexell, Daniel

2018-05-01

The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing.

Perspective: moving students beyond an organ-based approach when teaching medical interviewing and physical examination skills.

PubMed

Alexander, Erik K

2008-10-01

Medical interviewing and physical examination skills are core pillars of clinical medicine. Though nearly all U.S. medical students participate in preclinical courses designed to teach these skills, medical school faculty often comment that students' abilities remain limited on entering their clinical clerkships. The reason for this contention is not clear.The author briefly describes the current preclinical curricula at most medical schools that are designed to teach patient interviewing and examination. An organ-based curriculum is commonly employed, although the limitations of such an approach readily become apparent. For example, many hospitalized patients do not suffer from single-organ illnesses, but rather from infections or metabolic derangements, which cause numerous abnormalities to several body systems. Furthermore, clinical reasoning skills are rarely taught in such preclinical courses, though these abilities form the foundation for effective doctoring. These findings suggest an opportunity for content development surrounding patient interviewing and examination. The author proposes an educational approach that depicts how the confluence of both content knowledge skills and clinical reasoning skills can work synergistically to enhance preclinical teaching of the medical interview and physical examination.

New Kids on the Block: RNA-Based Influenza Virus Vaccines.

PubMed

Scorza, Francesco Berlanda; Pardi, Norbert

2018-04-01

RNA-based immunization strategies have emerged as promising alternatives to conventional vaccine approaches. A substantial body of published work demonstrates that RNA vaccines can elicit potent, protective immune responses against various pathogens. Consonant with its huge impact on public health, influenza virus is one of the best studied targets of RNA vaccine research. Currently licensed influenza vaccines show variable levels of protection against seasonal influenza virus strains but are inadequate against drifted and pandemic viruses. In recent years, several types of RNA vaccines demonstrated efficacy against influenza virus infections in preclinical models. Additionally, comparative studies demonstrated the superiority of some RNA vaccines over the currently used inactivated influenza virus vaccines in animal models. Based on these promising preclinical results, clinical trials have been initiated and should provide valuable information about the translatability of the impressive preclinical data to humans. This review briefly describes RNA-based vaccination strategies, summarizes published preclinical and clinical data, highlights the roadblocks that need to be overcome for clinical applications, discusses the landscape of industrial development, and shares the authors' personal perspectives about the future of RNA-based influenza virus vaccines.

Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers.

PubMed

Petok, Jessica R; Myers, Catherine E; Pa, Judy; Hobel, Zachary; Wharton, David M; Medina, Luis D; Casado, Maria; Coppola, Giovanni; Gluck, Mark A; Ringman, John M

2018-05-01

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD. Copyright © 2018 Elsevier Inc. 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

Degron Protease Blockade Sensor to Image Epigenetic Histone Protein Methylation in Cells and Living Animals

PubMed Central

2015-01-01

Lysine methylation of histone H3 and H4 has been identified as a promising therapeutic target in treating various cellular diseases. The availability of an in vivo assay that enables rapid screening and preclinical evaluation of drugs that potentially target this cellular process will significantly expedite the pace of drug development. This study is the first to report the development of a real-time molecular imaging biosensor (a fusion protein, [FLuc2]-[Suv39h1]-[(G4S)3]-[H3-K9]-[cODC]) that can detect and monitor the methylation status of a specific histone lysine methylation mark (H3-K9) in live animals. The sensitivity of this sensor was assessed in various cell lines, in response to down-regulation of methyltransferase EHMT2 by specific siRNA, and in nude mice with lysine replacement mutants. In vivo imaging in response to a combination of methyltransferase inhibitors BIX01294 and Chaetocin in mice reveals the potential of this sensor for preclinical drug evaluation. This biosensor thus has demonstrated its utility in the detection of H3-K9 methylations in vivo and potential value in preclinical drug development. PMID:25489787

A novel suction/coagulation integrated probe for achieving better hemostasis: development and clinical use.

PubMed

Takahashi, Hidekazu; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Matsuda, Chu; Yamamoto, Hirofumi; Mizushima, Tsunekazu; Mori, Masaki; Doki, Yuichiro; Nakajima, Kiyokazu

2018-06-01

Modern electrosurgical tools have a specific coagulation mode called "soft coagulation". However, soft coagulation has not been widely accepted for surgical operations. To optimize the soft coagulation environment, we developed a novel suction device integrated with an electrosurgical probe, called the "Suction ball coagulator" (SBC). In this study, we aimed to optimize the SBC design with a prototyping process involving a bench test and preclinical study; then, we aimed to demonstrate the feasibility, safety, and potential effectiveness of the SBC for laparoscopic surgery in clinical settings. SBC prototyping was performed with a bench test. Device optimization was performed in a preclinical study with a domestic swine bleeding model. Then, SBC was tested in a clinical setting during 17 clinical laparoscopic colorectal surgeries. In the bench tests, two tip hole sizes and patterns showed a good suction capacity. The preclinical study indicated the best tip shape for accuracy. In clinical use, no device-related adverse event was observed. Moreover, the SBC was feasible for prompt hemostasis and blunt dissections. In addition, SBC could evacuate vapors generated by tissue ablation using electroprobe during laparoscopic surgery. We successfully developed a novel, integrated suction/coagulation probe for hemostasis and commercialized it.

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology.

PubMed

Kaddi, Chanchala D; Niesner, Bradley; Baek, Rena; Jasper, Paul; Pappas, John; Tolsma, John; Li, Jing; van Rijn, Zachary; Tao, Mengdi; Ortemann-Renon, Catherine; Easton, Rachael; Tan, Sharon; Puga, Ana Cristina; Schuchman, Edward H; Barrett, Jeffrey S; Azer, Karim

2018-06-19

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Developing translational research infrastructure and capabilities associated with cancer clinical trials.

PubMed

Hall, Jacqueline A; Brown, Robert

2013-09-27

The integration of molecular information in clinical decision making is becoming a reality. These changes are shaping the way clinical research is conducted, and as reality sets in, the challenges in conducting, managing and organising multi-disciplinary research become apparent. Clinical trials provide a platform to conduct translational research (TR) within the context of high quality clinical data accrual. Integrating TR objectives in trials allows the execution of pivotal studies that provide clinical evidence for biomarker-driven treatment strategies, targeting early drug development trials to a homogeneous and well defined patient population, supports the development of companion diagnostics and provides an opportunity for deepening our understanding of cancer biology and mechanisms of drug action. To achieve these goals within a clinical trial, developing translational research infrastructure and capabilities (TRIC) plays a critical catalytic role for translating preclinical data into successful clinical research and development. TRIC represents a technical platform, dedicated resources and access to expertise promoting high quality standards, logistical and operational support and unified streamlined procedures under an appropriate governance framework. TRIC promotes integration of multiple disciplines including biobanking, laboratory analysis, molecular data, informatics, statistical analysis and dissemination of results which are all required for successful TR projects and scientific progress. Such a supporting infrastructure is absolutely essential in order to promote high quality robust research, avoid duplication and coordinate resources. Lack of such infrastructure, we would argue, is one reason for the limited effect of TR in clinical practice beyond clinical trials.

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax.

PubMed

Leverson, Joel D; Sampath, Deepak; Souers, Andrew J; Rosenberg, Saul H; Fairbrother, Wayne J; Amiot, Martine; Konopleva, Marina; Letai, Anthony

2017-12-01

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax. Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376-93. ©2017 AACR. ©2017 American Association for Cancer Research.

Recent early clinical drug development for acute kidney injury.

PubMed

Gallagher, Kevin M; O'neill, Stephen; Harrison, Ewen M; Ross, James A; Wigmore, Stephen J; Hughes, Jeremy

2017-02-01

Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated. There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI. Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI. We summarise the development of the agents recently in clinical trial, update on their trial progress, consider reasons for failed efficacy of two agents, and discuss new paradigms in pre-clinical targets for AKI. Agents covered include- QPI-1002, THR-184, BB-3, heme arginate, human recombinant alkaline phosphatase (recAP), ciclosporin A, AB103, levosimendan, AC607 and ABT-719. Expert opinion: Due to the heterogenous nature of AKI, agents with the widest pleiotropic effects on multiple pathophysiological pathways are likely to be most effective. Linking preclinical models to clinical indication and improving AKI definition and diagnosis are key areas for improvement in future clinical trials.

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.

From research to practice: an integrative framework for the development of interventions for children with fetal alcohol spectrum disorders.

PubMed

Kodituwakku, Piyadasa W; Kodituwakku, E Louise

2011-06-01

Since fetal alcohol syndrome was first described over 35 years ago, considerable progress has been made in the delineation of the neurocognitive profile in children with prenatal alcohol exposure. Preclinical investigators have made impressive strides in elucidating the mechanisms of alcohol teratogenesis and in testing the effectiveness of pharmacological agents and dietary supplementation in the amelioration of alcohol-induced deficits. Despite these advances, only limited progress has been made in the development of evidence-based comprehensive interventions for functional impairment in alcohol-exposed children. Having performed a search in PubMed and PsycINFO using key words, interventions, treatment, fetal alcohol syndrome, prenatal alcohol exposure, and fetal alcohol spectrum disorders, we found only 12 papers on empirically-based interventions. Only two of these interventions had been replicated and none met the criteria of "well-established," as defined by Chambless and Hollon (Journal of Consulting and Clinical Psychology 66(1):7-18, 1998). There has been only limited cross-fertilization of ideas between preclinical and clinical research with regard to the development of interventions. Therefore, we propose a framework that allows integrating data from preclinical and clinical investigations to develop comprehensive intervention programs for children with fetal alcohol spectrum disorders. This framework underscores the importance of multi-level evaluations and interventions.

Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer's disease.

PubMed

Jimenez, Amanda; Pegueroles, Jordi; Carmona-Iragui, María; Vilaplana, Eduard; Montal, Victor; Alcolea, Daniel; Videla, Laura; Illán-Gala, Ignacio; Pané, Adriana; Casajoana, Anna; Belbin, Olivia; Clarimón, Jordi; Moizé, Violeta; Vidal, Josep; Lleó, Alberto; Fortea, Juan; Blesa, Rafael

2017-12-01

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer´s Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ 42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ 42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD.

Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer's disease

PubMed Central

Carmona-Iragui, María; Vilaplana, Eduard; Montal, Victor; Alcolea, Daniel; Videla, Laura; Illán-Gala, Ignacio; Pané, Adriana; Casajoana, Anna; Belbin, Olivia; Clarimón, Jordi; Moizé, Violeta; Vidal, Josep; Lleó, Alberto; Fortea, Juan; Blesa, Rafael

2017-01-01

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer´s Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD. PMID:29285207

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

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

Grant, Claire, E-mail: claire.grant@astrazeneca.com; Ewart, Lorna; Muthas, Daniel

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility ofmore » integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used to confirm and quantify the risk.« less

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 procedures and new biomaterials.

Found in translation: how preclinical research is guiding the clinical development of the BCL-2-selective inhibitor venetoclax

PubMed Central

Leverson, Joel D.; Sampath, Deepak; Souers, Andrew J.; Rosenberg, Saul H.; Fairbrother, Wayne J.; Amiot, Martine; Konopleva, Marina; Letai, Anthony

2017-01-01

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax. PMID:29146569

A matrix approach to guide IHC-based tissue biomarker development in oncology drug discovery.

PubMed

Smith, Neil R; Womack, Christopher

2014-01-01

Immunohistochemistry (IHC) is a core platform for the analysis of tissue samples, and there is an increasing demand for reliable and quantitative IHC-based tissue biomarkers in oncology clinical research and development (R&D) environments. Biomarker assay and drug development proceed in parallel. Furthermore, biomarker assay requirements change with each phase of drug development. We have therefore developed a matrix tool to enable researchers to evaluate whether a particular IHC biomarker assay is fit for purpose. Experience gained from the development of 130 IHC biomarkers, supporting a large number of oncology drug projects, was used to formulate a practical approach to IHC assay development. The resultant matrix grid and accompanying work flow incorporates 16 core decision points that link antibody and assay specificity and sensitivity, and assay performance in preclinical and clinical samples, with stages of drug development. The matrix provides a means to ensure that relevant information on an IHC assay in development is recorded and communicated consistently and that minimum assay validation requirements are met. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

Parathyroid Hormone-Related Peptide (PTHrP) as a New Target for Metastatic Breast Cancer: Evaluation in Preclinical Models

DTIC Science & Technology

2016-10-01

in PTHrP-ablated and non-ablated animals. Using CRISPr technology, we are developing pre-clinical PTHrP-ablated human triple-negative breast cancer...3.2.2.1 KO of human TNBC cells by Clustered Regularly Interspaced Short Palindromic Repeats ( Crispr ): % COMPLETED: 90% OF TASK. (ON TIME). A unique... CRISPR sequence for PTHrP was chosen from pre-designed sites in the human genome using online tools (Sigma-Aldrich). The sites are designed to

Clinical development of Ebola vaccines

PubMed Central

Sridhar, Saranya

2015-01-01

The ongoing outbreak of Ebola virus disease in West Africa highlighted the lack of a licensed drug or vaccine to combat the disease and has renewed the urgency to develop a pipeline of Ebola vaccines. A number of different vaccine platforms are being developed by assessing preclinical efficacy in animal models and expediting clinical development. Over 15 different vaccines are in preclinical development and 8 vaccines are now in different stages of clinical evaluation. These vaccines include DNA vaccines, virus-like particles and viral vectors such as live replicating vesicular stomatitis virus (rVSV), human and chimpanzee adenovirus, and vaccinia virus. Recently, in preliminary results reported from the first phase III trial of an Ebola vaccine, the rVSV-vectored vaccine showed promising efficacy. This review charts this rapidly advancing area of research focusing on vaccines in clinical development and discusses the future opportunities and challenges faced in the licensure and deployment of Ebola vaccines. PMID:26668751

Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.

PubMed

Serabian, M A; Pilaro, A M

1999-01-01

Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unnecessary use of animals.

Chemoprevention of Oral Cancer by Topical Application of Black Raspberries on High At-Risk Mucosa

PubMed Central

Warner, Blake M.; Casto, Bruce C.; Knobloch, Thomas J.; Accurso, Brent T.; Weghorst, Christopher M.

2014-01-01

Objective To evaluate the preclinical efficacy of topical administration of freeze-dried black raspberries (BRBs) to inhibit the progression of premalignant oral lesions and modulate biomarkers of cancer development in high at-risk mucosa (HARM). Study Design Hamster cheek pouches (HCPs) were treated with carcinogen for six weeks to initiate a HARM microenvironment. Subsequently, right HCPs were topically administered a BRB suspension in short-term or long-term studies. After 12 weeks, SCC multiplicity, SCC incidence, and cell proliferation rates were evaluated. mRNA expression was measured in short-term treated pouches for selected oral cancer biomarkers. Results SCC multiplicity (−41.3%), tumor incidence (−37.1%), and proliferation rate (−6.9%) were reduced in HCPs receiving BRBs. Topical BRBs correlated with an increase in Rb1 expression in developing oral lesions. Conclusion Topical BRBs inhibit SCC development when targeted to HARM tissues. These results support the translational role of BRBs to prevent oral cancer development in humans. PMID:25457886

Basic Science Evidence for the Link Between Erectile Dysfunction and Cardiometabolic Dysfunction

PubMed Central

Musicki, Biljana; Bella, Anthony J.; Bivalacqua, Trinity J.; Davies, Kelvin P.; DiSanto, Michael E.; Gonzalez-Cadavid, Nestor F.; Hannan, Johanna L.; Kim, Noel N.; Podlasek, Carol A.; Wingard, Christopher J.; Burnett, Arthur L.

2016-01-01

Introduction Although clinical evidence supports an association between cardiovascular/metabolic diseases (CVMD) and erectile dysfunction (ED), scientific evidence for this link is incompletely elucidated. Aim This study aims to provide scientific evidence for the link between CVMD and ED. Methods In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current literature on basic scientific support for a mechanistic link between ED and CVMD, and deficiencies in this regard with a critical assessment of current preclinical models of disease. Results A link exists between ED and CVMD on several grounds: the endothelium (endothelium-derived nitric oxide and oxidative stress imbalance); smooth muscle (SM) (SM abundance and altered molecular regulation of SM contractility); autonomic innervation (autonomic neuropathy and decreased neuronal-derived nitric oxide); hormones (impaired testosterone release and actions); and metabolics (hyperlipidemia, advanced glycation end product formation). Conclusion Basic science evidence supports the link between ED and CVMD. The Committee also highlighted gaps in knowledge and provided recommendations for guiding further scientific study defining this risk relationship. This endeavor serves to develop novel strategic directions for therapeutic interventions. PMID:26646025

Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk

PubMed Central

Lauretta, Rosa; Lanzolla, Giulia; Vici, Patrizia; Mariani, Luciano; Moretti, Costanzo

2016-01-01

Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. PMID:27725832

Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy.

PubMed

Barnes, Samuel A; Sheffler, Douglas J; Semenova, Svetlana; Cosford, Nicholas D P; Bespalov, Anton

2018-06-01

The ability of novel pharmacological compounds to improve outcomes in preclinical models is often not translated into clinical efficacy. Psychiatric disorders do not have biological boundaries, and identifying mechanisms to improve the translational bottleneck between preclinical and clinical research domains is an important and challenging task. Glutamate transmission is disrupted in several neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors represent a diverse class of receptors that contribute to excitatory neurotransmission. Given the wide, yet region-specific manner of expression, developing pharmacological compounds to modulate mGlu receptor activity provides an opportunity to subtly and selectively modulate excitatory neurotransmission. This review focuses on the potential involvement of mGlu5 receptor disruption in major depressive disorder and substance and/or alcohol use disorders. We provide an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarize the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for major depressive disorders and nicotine dependence, and highlight the outcomes of recent clinical trials. While the evidence of mGlu5 receptor negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we identify key challenges that may contribute to poor clinical translation and provide suggested approaches moving forward to potentially improve the translation from preclinical to clinical domains. Such approaches may increase the success of clinical trials and may reduce the translational bottleneck that exists in drug discovery for psychiatric disorders. Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Maternal intake of fatty acids and their food sources during lactation and the risk of preclinical and clinical type 1 diabetes in the offspring.

PubMed

Niinistö, S; Takkinen, H-M; Uusitalo, L; Rautanen, J; Vainio, N; Ahonen, S; Nevalainen, J; Kenward, M G; Lumia, M; Simell, O; Veijola, R; Ilonen, J; Knip, M; Virtanen, S M

2015-08-01

We examined maternal dietary intake of fatty acids and foods which are sources of fatty acids during lactation and whether they are associated with the risk of preclinical and clinical type 1 diabetes in the offspring. The subjects comprised a cohort of 2,939 mother-child pairs from the prospective Type 1 Diabetes Prediction and Prevention Study. Composition of maternal diet during the third month of lactation was assessed by a validated food frequency questionnaire. Among the children with HLA-conferred susceptibility to type 1 diabetes, 172 developed preclinical and 81 clinical diabetes. Average follow-up for preclinical type 1 diabetes was 7.5 years (range 0.2-14.0 years) and for clinical type 1 diabetes 7.7 years (0.2-14.0 years). Maternal intake of fatty acids during lactation was not associated with the risk of type 1 diabetes in the offspring. After adjusting for putative confounders, maternal total consumption of red meat and meat products during lactation was associated both with increased risk for preclinical [hazard ratio (HR) 1.19, 95 % CI 1.02-1.40, p = 0.038] and clinical type 1 diabetes (HR 1.27, 95 % CI 1.06-1.52, p = 0.025). In particular, consumption of processed meat products showed an association with increased risk for type 1 diabetes (HR 1.23, 95 % CI 1.02-1.48, p = 0.045). Maternal use of vegetable oils was associated with increased risk for preclinical type 1 diabetes (HR 1.21, 95 % CI 1.03-1.41, p = 0.023). Maternal consumption of red meat, especially processed meat, during lactation may increase the risk of type 1 diabetes.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

PubMed Central

Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

2015-01-01

Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases. PMID:25767435

Proteomic Data Resources for EDRN Ovary Cancer Researchers within the EDRN — EDRN Public Portal

Cancer.gov

This project will generate a highly valuable data resource and make it available to all EDRN ovarian cancer researchers. The resource will include comprehensive proteomic (tandem mass spectrometry, MS/MS) data generated from plasma samples that have been collected between four months and four years prior to clinical detection of ovarian cancer. These pre-clinical samples, provided from the Beta Carotene and Retinol Efficacy Trial (CARET) prospective study, will be interrogated using IPAS, the proteomic profiling method developed by the Hanash Laboratory and with the quantitative methods developed by the McIntosh laboratory. In addition, we will combine these pre-clinical data with already completed IPAS interrogations of plasma collected at the time of ovarian cancer diagnosis. Thus together we will provide information on both pre-clinical and clinical behavior of a large number of proteins. Based on our preliminary work we are able to quantify over 500 plasma proteins in each of these experiments, many of which are putative ovarian cancer biomarkers, showing the platform is capable of providing useful information regarding biomarker candidates.

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

PubMed Central

Gasparini, Fabrizio; Di Paolo, Thérèse; Gomez-Mancilla, Baltazar

2013-01-01

Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD. PMID:23853735

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

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

Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance.

PubMed

Lanzi, Cinzia; Zaffaroni, Nadia; Cassinelli, Giuliana

2017-01-01

Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of effort from academia and industry has led to the development of agents mimicking HS, and/or inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and two heparanase inhibitors/HS mimics (roneparstat, PG545) are currently under early clinical investigation. In this review, we summarized preclinical studies in experimental tumor models of the main chemical classes of Sulf-2 and heparanase inhibitors. We described examples of different mechanisms through which heparanase and HSPGs, often in cooperation, may impact tumor sensitivity to various antitumor agents. Finally, we reported a few preclinical studies showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in combination regimens. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies

PubMed Central

Hooijmans, Carlijn R.; de Vries, Rob B. M.; Ritskes-Hoitinga, Merel; Rovers, Maroeska M.; Leeflang, Mariska M.; IntHout, Joanna; Wever, Kimberley E.; Hooft, Lotty; de Beer, Hans; Kuijpers, Ton; Macleod, Malcolm R.; Sena, Emily S.; ter Riet, Gerben; Morgan, Rebecca L.; Thayer, Kristina A.; Rooney, Andrew A.; Guyatt, Gordon H.; Schünemann, Holger J.

2018-01-01

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE’s indirectness domain as a tool to predict translation from animal models to humans. PMID:29324741

Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies.

PubMed

Hooijmans, Carlijn R; de Vries, Rob B M; Ritskes-Hoitinga, Merel; Rovers, Maroeska M; Leeflang, Mariska M; IntHout, Joanna; Wever, Kimberley E; Hooft, Lotty; de Beer, Hans; Kuijpers, Ton; Macleod, Malcolm R; Sena, Emily S; Ter Riet, Gerben; Morgan, Rebecca L; Thayer, Kristina A; Rooney, Andrew A; Guyatt, Gordon H; Schünemann, Holger J; Langendam, Miranda W

2018-01-01

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

Molecular basis of the potential of vitamin D to prevent cancer.

PubMed

Ingraham, Betty A; Bragdon, Beth; Nohe, Anja

2008-01-01

To review current research findings in cell biology, epidemiology, preclinical, and clinical trials on the protective effects of vitamin D against the development of cancers of the breast, colon, prostate, lung, and ovary. Current recommendations for optimal vitamin D status, the movement towards revision of standards, and reflections on healthy exposure to sunlight are also reviewed. Search methodology: A literature search was conducted in April and updated in September 2007. The Medline and Web of Knowledge databases were searched for primary and review articles published between 1970 and 2007, using the search terms 'vitamin D', 'calcitriol', 'cancer', 'chemoprevention', 'nuclear receptor', 'vitamin D receptor', 'apoptosis', 'cell cycle', 'epidemiology', and 'cell adhesion molecule'. Articles that focused on epidemiological, preclinical, and clinical evidence for vitamin D's effects were selected and additional articles were obtained from reference lists of the retrieved articles. An increasing body of research supports the hypothesis that the active form of vitamin D has significant, protective effects against the development of cancer. Epidemiological studies show an inverse association between sun exposure, serum levels of 25(OH)D, and intakes of vitamin D and risk of developing and/or surviving cancer. The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer. A significant number of individuals have serum vitamin D levels lower than what appears to protect against cancer, and the research community is currently revising the guidelines for optimal health. This will lead to improved public health policies and to reduced risk of cancer. Research strongly supports the view that efforts to improve vitamin D status would have significant protective effects against the development of cancer. The clinical research community is currently revising recommendations for optimal serum levels and for sensible levels of sun exposure, to levels greater than previously thought. Currently, most experts in the field believe that intakes of between 1000 and 4000 IU will lead to a more healthy level of serum 25(OH)D, at approximately 75 nmol/L that will offer significant protection effects against cancers of the breast, colon, prostate, ovary, lungs, and pancreas. The first randomized trial has shown significant protection against breast cancer, and other clinical trials will follow and ultimately lead to improved public health policies and significantly fewer cancers.

Pharmacological Strategies to Retard Cardiovascular Aging.

PubMed

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

2016-05-13

Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health. © 2016 American Heart Association, Inc.

Pharmacological Strategies to Retard Cardiovascular Aging

PubMed Central

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

2016-01-01

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

[CERN-MEDICIS (Medical Isotopes Collected from ISOLDE): a new facility].

PubMed

Viertl, David; Buchegger, Franz; Prior, John O; Forni, Michel; Morel, Philippe; Ratib, Osman; Bühler Léo H; Stora, Thierry

2015-06-17

CERN-MEDICIS is a facility dedicated to research and development in life science and medical applications. The research platform was inaugurated in October 2014 and will produce an increasing range of innovative isotopes using the proton beam of ISOLDE for fundamental studies in cancer research, for new imaging and therapy protocols in cell and animal models and for preclinical trials, possibly extended to specific early phase clinical studies (phase 0) up to phase I trials. CERN, the University Hospital of Geneva (HUG), the University Hospital of Lausanne (CHUV), the Swiss Institute for Experimental Cancer (ISREC) at Swiss Federal Institutes of Technology (EPFL) that currently support the project will benefit of the initial production that will then be extended to other centers.

Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.

PubMed

West, Andrew B

2017-12-01

In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues. In some PD models, small molecule LRRK2 kinase inhibitors that block these activities also provide neuroprotection. Herein, the genetic and biochemical evidence that supports the involvement of LRRK2 kinase activity in PD susceptibility is reviewed. Issues related to the definition of a therapeutic window for LRRK2 inhibition and the safety of chronic dosing are discussed. Finally, recommendations are given for a biomarker-guided initial entry of LRRK2 kinase inhibitors in PD patients. Four key areas must be considered for achieving neuroprotection with LRRK2 kinase inhibitors in PD: 1) identification of patient populations most likely to benefit from LRRK2 kinase inhibitors, 2) prioritization of superior LRRK2 small molecule inhibitors based on open disclosures of drug performance, 3) incorporation of biomarkers and empirical measures of LRRK2 kinase inhibition in clinical trials, and 4) utilization of appropriate efficacy measures guided in part by rigorous pre-clinical modeling. Meticulous and rational development decisions can potentially prevent incredibly costly errors and provide the best chances for LRRK2 inhibitors to slow the progression of PD. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

At the bedside: adoptive cell therapy for melanoma-clinical development.

PubMed

Weber, Jeffrey S

2014-06-01

Adoptive cell therapy for melanoma, particularly using TIL, consists of a complex and difficult set of procedures, although it has a strong preclinical background and justification and has been pursued clinically by one small group of investigators over the last 20 years. More recent developments and a better understanding of the molecular basis of the anti-tumor immune response have led to the conduct of clinical trials that use lymphoid depletion with chemotherapy and/or TBI to exploit the favorable immune milieu of homeostatic lymphoid reconstitution during transfer of effector T cells. Improved ways of propagating T cells ex vivo have also simplified and shortened the cell-growth process. Current TIL trials have now been expanded beyond the initial center where it was developed, reproducing excellent objective response rates of 40-50% in previously treated melanoma patients and more importantly, demonstrating that a significant proportion of patients will be alive and free of disease 3-5 years after treatment, raising the possibility that those patients may be cured of their disease. Newer methods for growing the infiltrating T cells using immune-checkpoint antibodies or other agents to condition the tumor before harvest and improved technology to simplify the complex and often cumbersome cell-growth process suggest that this technology may be able to be disseminated to a wide selection of cancer centers and may be a candidate for testing in a randomized Phase III trial to show definitively its benefit in patients with metastatic melanoma. In the accompanying review, the preclinical work that supports the idea of adoptive cell therapy with TIL and expands the concept in promising new ways will be explored. © 2014 Society for Leukocyte Biology.

Using data from drug discovery and development to aid the aquatic environmental risk assessment of human pharmaceuticals: concepts, considerations, and challenges.

PubMed

Winter, Matthew J; Owen, Stewart F; Murray-Smith, Richard; Panter, Grace H; Hetheridge, Malcolm J; Kinter, Lewis B

2010-01-01

Over recent years, human pharmaceuticals have been detected in the aquatic environment. This, combined with the fact that many are (by design) biologically active compounds, has raised concern about potential impacts in wildlife species. This concern was realized with two high-profile cases of unforeseen environmental impact (i.e., estrogens and diclofenac), which have led to a flurry of work addressing how best to predict such effects in the future. One area in which considerable research effort has been made, partially in response to regulatory requirements, has been on the potential use of preclinical and clinical pharmacological and toxicological data (generated during drug development from nonhuman mammals and humans) to predict possible effects in nontarget, environmentally relevant species: so-called read across. This approach is strengthened by the fact that many physiological systems are conserved between mammals and certain environmentally relevant species. Consequently, knowledge of how a pharmaceutical works (the “mode-of-action,” or MoA) in nonclinical species and humans could assist in the selection of appropriate test species, study designs, and endpoints, in an approach referred to as “intelligent testing.” Here we outline the data available from the human drug development process and suggest how this might be used to design a testing strategy best suited to the specific characteristics of the drug in question. In addition, we review published data that support this type of approach, discuss the potential pitfalls associated with read across, and identify knowledge gaps that require filling to ensure accuracy in the extrapolation of data from preclinical and clinical studies, for use in the environmental risk assessment of human pharmaceuticals.

Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.

PubMed

Clark, Amy S; Karasic, Thomas B; DeMichele, Angela; Vaughn, David J; O'Hara, Mark; Perini, Rodolfo; Zhang, Paul; Lal, Priti; Feldman, Michael; Gallagher, Maryann; O'Dwyer, Peter J

2016-02-01

Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.

Art of Analysis: A Cooperative Program between a Museum and Medicine

ERIC Educational Resources Information Center

Jacques, Andrew; Trinkley, Rachel; Stone, Linda; Tang, Richard; Hudson, William Andy; Khandelwal, Sorabh

2012-01-01

Art of Analysis (AoA) is a cooperative effort of the Ohio State University College of Medicine (OSUCOM) and Columbus Museum of Art (CMA) aimed at medical students who are participating in learning communities, groups formed in pre-clinical medical student education to emotionally support and encourage students through the arduous process of…

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.

Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat

PubMed Central

Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.

2010-01-01

Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model. PMID:20526189

Validation of a preclinical spinal safety model: effects of intrathecal morphine in the neonatal rat.

PubMed

Westin, B David; Walker, Suellen M; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L

2010-07-01

Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat. Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model.

Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia.

PubMed

Dhanesha, Nirav; Vázquez-Rosa, Edwin; Cintrón-Pérez, Coral J; Thedens, Daniel; Kort, Alexa J; Chuong, Vicky; Rivera-Dompenciel, Adriana M; Chauhan, Anil K; Leira, Enrique C; Pieper, Andrew A

2018-05-01

Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. To address this need, we subjected 7- to 9-week old ovariectomized female mice to filament-induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke. Published by Elsevier Inc.

Prediction of Human Intestinal Absorption of Compounds Using Artificial Intelligence Techniques.

PubMed

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2017-01-01

Information about Pharmacokinetics of compounds is an essential component of drug design and development. Modeling the pharmacokinetic properties require identification of the factors effecting absorption, distribution, metabolism and excretion of compounds. There have been continuous attempts in the prediction of intestinal absorption of compounds using various Artificial intelligence methods in the effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are large numbers of individual predictive models available for absorption using machine learning approaches. Six Artificial intelligence methods namely, Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis were used for prediction of absorption of compounds. Prediction accuracy of Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis for prediction of intestinal absorption of compounds was found to be 91.54%, 88.33%, 84.30%, 86.51%, 79.07% and 80.08% respectively. Comparative analysis of all the six prediction models suggested that Support vector machine with Radial basis function based kernel is comparatively better for binary classification of compounds using human intestinal absorption and may be useful at preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

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.

Better self-management and meaningful activities thanks to tablets? Development of a person-centered program to support people with mild dementia and their carers through use of hand-held touch screen devices.

PubMed

Kerkhof, Yvonne J F; Graff, Maud J L; Bergsma, Ad; de Vocht, Hilde H M; Dröes, Rose-Marie

2016-11-01

To offer good support to people with dementia and their carers in an aging and Internet society the deployment of hand-held touch screen devices, better known as tablets, and its applications (apps) can be viable and desirable. However, at the moment it is not clear which apps are usable for supporting people with dementia in daily life. Also, little is known about how people with dementia can be coached to learn to use a tablet and its apps. A person-centered program, with tools and training, will be developed that aims to support people with mild dementia and their (in)formal carers in how to use the tablet for self-management and meaningful activities. The program will be developed in accordance with the Medical Research Council's (MRC) framework for developing and evaluating complex interventions and the study will cover the following phases: a preclinical or theoretical (0) phase; a modeling phase (I) and the exploratory trial phase (II). The users (people with dementia and their carers) will be involved intensively during all these phases, by means of individual interviews, workshops, focus groups, and case studies. The iterative process inherent to this framework makes it possible to develop a user-oriented intervention, in this case a person-centered program, for the use of tablets in dementia care. Preparatory work will be done to perform a methodologically sound randomized controlled trial (RCT) in the near future, which aims to investigate the contribution of this person-centered program for tablet use to the quality of life of people with dementia and their carers.

In Vivo Imaging of Influenza Virus Infection in Immunized Mice

PubMed Central

Czakó, Rita; Vogel, Leatrice; Lamirande, Elaine W.; Bock, Kevin W.; Moore, Ian N.; Ellebedy, Ali H.; Ahmed, Rafi

2017-01-01

ABSTRACT Immunization is the cornerstone of seasonal influenza control and represents an important component of pandemic preparedness strategies. Using a bioluminescent reporter virus, we demonstrate the application of noninvasive in vivo imaging system (IVIS) technology to evaluate the preclinical efficacy of candidate vaccines and immunotherapy in a mouse model of influenza. Sequential imaging revealed distinct spatiotemporal kinetics of bioluminescence in groups of mice passively or actively immunized by various strategies that accelerated the clearance of the challenge virus at different rates and by distinct mechanisms. Imaging findings were consistent with conclusions derived from virus titers in the lungs and, notably, were more informative than conventional efficacy endpoints in some cases. Our findings demonstrate the reliability of IVIS as a qualitative approach to support preclinical evaluation of candidate medical countermeasures for influenza in mice. PMID:28559489

Vitamin D in prostate cancer

PubMed Central

Trump, Donald L; Aragon-Ching, Jeanny B

2018-01-01

Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited. PMID:29667615

Dietary Nitrate Lowers Blood Pressure: Epidemiological, Pre-clinical Experimental and Clinical Trial Evidence.

PubMed

Gee, Lorna C; Ahluwalia, Amrita

2016-02-01

Nitric oxide (NO), a potent vasodilator critical in maintaining vascular homeostasis, can reduce blood pressure in vivo. Loss of constitutive NO generation, for example as a result of endothelial dysfunction, occurs in many pathological conditions, including hypertension, and contributes to disease pathology. Attempts to therapeutically deliver NO via organic nitrates (e.g. glyceryl trinitrate, GTN) to reduce blood pressure in hypertensives have been largely unsuccessful. However, in recent years inorganic (or 'dietary') nitrate has been identified as a potential solution for NO delivery through its sequential chemical reduction via the enterosalivary circuit. With dietary nitrate found in abundance in vegetables this review discusses epidemiological, pre-clinical and clinical data supporting the idea that dietary nitrate could represent a cheap and effective dietary intervention capable of reducing blood pressure and thereby improving cardiovascular health.

Implementation of a configurable laboratory information management system for use in cellular process development and manufacturing.

PubMed

Russom, Diana; Ahmed, Amira; Gonzalez, Nancy; Alvarnas, Joseph; DiGiusto, David

2012-01-01

Regulatory requirements for the manufacturing of cell products for clinical investigation require a significant level of record-keeping, starting early in process development and continuing through to the execution and requisite follow-up of patients on clinical trials. Central to record-keeping is the management of documentation related to patients, raw materials, processes, assays and facilities. To support these requirements, we evaluated several laboratory information management systems (LIMS), including their cost, flexibility, regulatory compliance, ongoing programming requirements and ability to integrate with laboratory equipment. After selecting a system, we performed a pilot study to develop a user-configurable LIMS for our laboratory in support of our pre-clinical and clinical cell-production activities. We report here on the design and utilization of this system to manage accrual with a healthy blood-donor protocol, as well as manufacturing operations for the production of a master cell bank and several patient-specific stem cell products. The system was used successfully to manage blood donor eligibility, recruiting, appointments, billing and serology, and to provide annual accrual reports. Quality management reporting features of the system were used to capture, report and investigate process and equipment deviations that occurred during the production of a master cell bank and patient products. Overall the system has served to support the compliance requirements of process development and phase I/II clinical trial activities for our laboratory and can be easily modified to meet the needs of similar laboratories.

Positioning, labelling, and medical information control of co-artemether tablets (CPG 56697): a fixed novel combination of artemether and benflumetol. Novartis Co-Artemether International Development Team.

PubMed

Skelton-Stroud, P; Mull, R

1998-01-01

Coartemether is a fixed 1:6 ratio of artemether and lumefantrine (benflumetol), a joint development between Novartis Pharma and the Academy of Military Medical Sciences (Beijing, China). It is well tolerated and has a high efficacy against uncomplicated and drug resistant falciparum malaria by oral administration. The preclinical profile of coartemether revealed no prohibitive toxicological, teratogenic or mutagenic findings. No evidence of neurotoxicity was seen in oral preclinical studies. It shows a negative response to the induction of resistance and prevents recrudescence. Clinically, coartemether shows a rapid onset of antiparasitic action, resolution of symptoms, no clinical neurotoxicity and excellent parasite clearance.

Analytical Chemistry in the Regulatory Science of Medical Devices.

PubMed

Wang, Yi; Guan, Allan; Wickramasekara, Samanthi; Phillips, K Scott

2018-06-12

In the United States, regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all Food and Drug Administration-regulated products. Good regulatory science facilitates consumer access to innovative medical devices that are safe and effective throughout the Total Product Life Cycle (TPLC). Because the need to measure things is fundamental to the regulatory science of medical devices, analytical chemistry plays an important role, contributing to medical device technology in two ways: It can be an integral part of an innovative medical device (e.g., diagnostic devices), and it can be used to support medical device development throughout the TPLC. In this review, we focus on analytical chemistry as a tool for the regulatory science of medical devices. We highlight recent progress in companion diagnostics, medical devices on chips for preclinical testing, mass spectrometry for postmarket monitoring, and detection/characterization of bacterial biofilm to prevent infections.

Blast TBI Models, Neuropathology, and Implications for Seizure Risk

PubMed Central

Kovacs, S. Krisztian; Leonessa, Fabio; Ling, Geoffrey S. F.

2014-01-01

Traumatic brain injury (TBI) due to explosive blast exposure is a leading combat casualty. It is also implicated as a key contributor to war related mental health diseases. A clinically important consequence of all types of TBI is a high risk for development of seizures and epilepsy. Seizures have been reported in patients who have suffered blast injuries in the Global War on Terror but the exact prevalence is unknown. The occurrence of seizures supports the contention that explosive blast leads to both cellular and structural brain pathology. Unfortunately, the exact mechanism by which explosions cause brain injury is unclear, which complicates development of meaningful therapies and mitigation strategies. To help improve understanding, detailed neuropathological analysis is needed. For this, histopathological techniques are extremely valuable and indispensable. In the following we will review the pathological results, including those from immunohistochemical and special staining approaches, from recent preclinical explosive blast studies. PMID:24782820

Innovative strategies for early clinical R&D.

PubMed

Butz, Robert F; Morelli, Gaetano

2008-01-01

Developments in translational medicine and regulatory initiatives associated with the FDA's Critical Path Initiative are creating new opportunities for innovation in early clinical R&D. The introduction of the exploratory IND process allows small, 'phase 0' clinical trials to be conducted prior to traditional phase I trials - sometimes requiring considerably less chemistry, manufacturing and controls, or preclinical support. Phase 0 clinical trials involving subtherapeutic, yet pharmacologically active, dose levels can provide an early demonstration of clinical proof of concept; such demonstration is of particular importance to small pharmaceutical and early-stage biotechnology companies. However, these opportunities for rapid entry into the clinic must be balanced by a consideration of the unique risks associated with first-in-human clinical trials, and by accounting for public concerns regarding drug safety in general. This feature review discusses how innovative clinical strategies can be used effectively in early drug development.

In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging.

PubMed

Zhao, Yue; Raichle, Marcus E; Wen, Jie; Benzinger, Tammie L; Fagan, Anne M; Hassenstab, Jason; Vlassenko, Andrei G; Luo, Jie; Cairns, Nigel J; Christensen, Jon J; Morris, John C; Yablonskiy, Dmitriy A

2017-03-01

Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Aβ) biomarker Aβ 42 . A subset of 19 participants also underwent PET PiB studies to assess their brain Aβ burden. According to the Aβ status, cognitively normal participants were divided into normal (Aβ negative; n=13) and preclinical (Aβ positive; n=10) groups. GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta-amyloid (Aβ) burden defined by positron emission tomography (PET) - the current in vivo gold standard for detection of cortical Aβ, thus supporting GEPCI as a potential surrogate marker for Aβ imaging - a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high Aβ accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where Aβ accumulation is relatively low. We have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD-related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease-modifying therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Quantifying lead-time bias in risk factor studies of cancer through simulation.

PubMed

Jansen, Rick J; Alexander, Bruce H; Anderson, Kristin E; Church, Timothy R

2013-11-01

Lead-time is inherent in early detection and creates bias in observational studies of screening efficacy, but its potential to bias effect estimates in risk factor studies is not always recognized. We describe a form of this bias that conventional analyses cannot address and develop a model to quantify it. Surveillance Epidemiology and End Results (SEER) data form the basis for estimates of age-specific preclinical incidence, and log-normal distributions describe the preclinical duration distribution. Simulations assume a joint null hypothesis of no effect of either the risk factor or screening on the preclinical incidence of cancer, and then quantify the bias as the risk-factor odds ratio (OR) from this null study. This bias can be used as a factor to adjust observed OR in the actual study. For this particular study design, as average preclinical duration increased, the bias in the total-physical activity OR monotonically increased from 1% to 22% above the null, but the smoking OR monotonically decreased from 1% above the null to 5% below the null. The finding of nontrivial bias in fixed risk-factor effect estimates demonstrates the importance of quantitatively evaluating it in susceptible studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Preclinical safety testing for cell-based products using animals.

PubMed

McBlane, James W

2015-09-01

The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation. Copyright © 2015.

Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer’s Disease

PubMed Central

Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Mañanas, Miguel Angel; Lopera, Francisco; Hernández, Alher Mauricio

2016-01-01

Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD. PMID:27792014

A real-time respiration position based passive breath gating equipment for gated radiotherapy: A preclinical evaluation

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

Hu Weigang; Xu Anjie; Li Guichao

2012-03-15

Purpose: To develop a passive gating system incorporating with the real-time position management (RPM) system for the gated radiotherapy. Methods: Passive breath gating (PBG) equipment, which consists of a breath-hold valve, a controller mechanism, a mouthpiece kit, and a supporting frame, was designed. A commercial real-time positioning management system was implemented to synchronize the target motion and radiation delivery on a linear accelerator with the patient's breathing cycle. The respiratory related target motion was investigated by using the RPM system for correlating the external markers with the internal target motion while using PBG for passively blocking patient's breathing. Six patientsmore » were enrolled in the preclinical feasibility and efficiency study of the PBG system. Results: PBG equipment was designed and fabricated. The PBG can be manually triggered or released to block or unblock patient's breathing. A clinical workflow was outlined to integrate the PBG with the RPM system. After implementing the RPM based PBG system, the breath-hold period can be prolonged to 15-25 s and the treatment delivery efficiency for each field can be improved by 200%-400%. The results from the six patients showed that the diaphragm motion caused by respiration was reduced to less than 3 mm and the position of the diaphragm was reproducible for difference gating periods. Conclusions: A RPM based PBG system was developed and implemented. With the new gating system, the patient's breath-hold time can be extended and a significant improvement in the treatment delivery efficiency can also be achieved.« less

Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice

PubMed Central

Mazziotti, Raffaele; Lupori, Leonardo; Sagona, Giulia; Gennaro, Mariangela; Della Sala, Grazia; Putignano, Elena

2017-01-01

Abstract CDKL5 disorder is a neurodevelopmental disorder still without a cure. Murine models of CDKL5 disorder have been recently generated raising the possibility of preclinical testing of treatments. However, unbiased, quantitative biomarkers of high translational value to monitor brain function are still missing. Moreover, the analysis of treatment is hindered by the challenge of repeatedly and non-invasively testing neuronal function. We analyzed the development of visual responses in a mouse model of CDKL5 disorder to introduce visually evoked responses as a quantitative method to assess cortical circuit function. Cortical visual responses were assessed in CDKL5 null male mice, heterozygous females, and their respective control wild-type littermates by repeated transcranial optical imaging from P27 until P32. No difference between wild-type and mutant mice was present at P25-P26 whereas defective responses appeared from P27-P28 both in heterozygous and homozygous CDKL5 mutant mice. These results were confirmed by visually evoked potentials (VEPs) recorded from the visual cortex of a different cohort. The previously imaged mice were also analyzed at P60–80 using VEPs, revealing a persistent reduction of response amplitude, reduced visual acuity and defective contrast function. The level of adult impairment was significantly correlated with the reduction in visual responses observed during development. Support vector machine showed that multi-dimensional visual assessment can be used to automatically classify mutant and wt mice with high reliability. Thus, monitoring visual responses represents a promising biomarker for preclinical and clinical studies on CDKL5 disorder. PMID:28369421

Ewing’s Sarcoma: Overcoming the Therapeutic Plateau

PubMed Central

Subbiah, Vivek; Kurzrock, Razelle

2013-01-01

The hallmark of Ewing’s sarcoma (EWS) is a translocation -- t(11;22)(q24;q12) -- that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS. PMID:22742646

The therapeutic impact of new migraine discoveries.

PubMed

Vécsei, Laszlo; Lukács, Melinda; Tajti, Janos; Fülöp, Ferenc; Toldi, Jozsef; Edvinsson, Lars

2018-05-29

Migraine is one the most disabling neurological conditions and associates with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. The present study is a review of the current literature regarding new therapeutic lines in migraine research. A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in migraine published until July 2017. Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

PubMed Central

Ostenfeld, Thor; Beaumont, Claire; Bullman, Jonathan; Beaumont, Maria; Jeffrey, Phillip

2012-01-01

AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg). METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction. RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (Vss) and terminal elimination half-life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey). CONCLUSION For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development. PMID:22497298

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

PubMed

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

2017-03-01

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

Transparency in the reporting of in vivo pre-clinical pain research: The relevance and implications of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.

PubMed

Rice, Andrew S C; Morland, Rosemary; Huang, Wenlong; Currie, Gillian L; Sena, Emily S; Macleod, Malcolm R

2017-12-29

Clear reporting of research is crucial to the scientific process. Poorly designed and reported studies are damaging not only to the efforts of individual researchers, but also to science as a whole. Standardised reporting methods, such as those already established for reporting randomised clinical trials, have led to improved study design and facilitated the processes of clinical systematic review and meta-analysis. Such standards were lacking in the pre-clinical field until the development of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. These were prompted following a survey which highlighted a widespread lack of robust and consistent reporting of pre-clinical in vivo research, with reports frequently omitting basic information required for study replication and quality assessment. The resulting twenty item checklist in ARRIVE covers all aspects of experimental design with particular emphasis on bias reduction and methodological transparency. Influential publishers and research funders have already adopted ARRIVE. Further dissemination and acknowledgement of the importance of these guidelines is vital to their widespread implementation. Conclusions and implications Wide implementation of the ARRIVE guidelines for reporting of in vivo preclinical research, especially pain research, are essential for a much needed increased transparency and quality in publishing such research. ARRIVE will also positively influence improvements in experimental design and quality, assist the conduct of accurate replication studies of important new findings and facilitate meta-analyses of preclinical research.

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 of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development of transplantable human chordoma xenograft for preclinical assessment of novel therapeutic strategies.

PubMed

Bozzi, Fabio; Manenti, Giacomo; Conca, Elena; Stacchiotti, Silvia; Messina, Antonella; Dagrada, GianPaolo; Gronchi, Alessandro; Panizza, Pietro; Pierotti, Marco A; Tamborini, Elena; Pilotti, Silvana

2014-01-01

Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies. In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor. All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and post treatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors. Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies.

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

PubMed Central

Kim, Michelle B.; Giesler, Kyle E.; Tahirovic, Yesim A.; Truax, Valarie M.; Liotta, Dennis C.; Wilson, Lawrence J.

2018-01-01

Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests. PMID:27791451

Impaired limb reaction to displacement of center of gravity in rats with unilateral striatal ischemic injury.

PubMed

Nobile, Cameron W; Palmateer, Julie M; Kane, Jackie; Hurn, Patricia D; Schallert, Timothy; Adkins, DeAnna L

2014-10-01

Clinical stroke often results in impaired balance and increased vulnerability to severe injuries due to falling. To evaluate potential preclinical treatments that might target these deficits, it will be important to include tests capable of assessing these impairments chronically in animal models. Previously, we developed a postural instability test (PIT) that revealed chronic, unilateral impairments in postural stability in rat models of hemi-Parkinson's disease (PD) and of unilateral cervical spinal cord injury. Here, we investigated whether this test was also capable of revealing long-term stroke-induced impairments in postural support in rats. Additionally, we examined the ability of more common tests of sensorimotor function to detect chronic impairments. We found that the PIT detected chronic deficits in postural stability/balance enduring for up to 6 weeks post-stroke, outlasting impairments detected in other tests of forelimb sensorimotor function, including asymmetries in upright postural support (cylinder test) and vibrissae-evoked forelimb placing.

The preparation of students of medical faculties and other public colleges for educative activities within the national programme of health support.

PubMed

Kukurova, E; Bernadic, M; Kralova, E; Bernadicova, H; Traubner, P

2005-01-01

The tradition of education of physicians at the Medical Faculty of Comenius University (MFCU) has been developing for more than 85 years. Currently, the education has been widened by non-medical fields of study (nursing, obstetrical assistance, rehabilitation, public health care and laboratory and examination methods). After joining EU, the accreditation study programmes have been subject to transformation in compliance with current world trends in education. In accord with the transformation of content and forms of medical physics training, the authors demonstrate the main objectives and goals of this process. The goal is to prepare the graduates on high theoretical and practical levels, to teach them to work in team, and to prepare them for whole-life education. Practical skills in pre-clinical and clinical disciplines are being strengthened. One of the important outputs of pre-graduate education is the readiness of graduates for educative activities in favour of the National Programme of Health Support. (Tab. 1, Fig. 1, Ref. 7.)

Human Data Supporting Glyburide in Ischemic Stroke

PubMed Central

Sheth, Kevin N.; Simard, J. Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W. Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous (IV) formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. Early phase II study of MRI and plasma biomarkers support the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase IIb study and definitive efficacy studies are urgently needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative. PMID:26463916

Human Data Supporting Glyburide in Ischemic Stroke.

PubMed

Sheth, Kevin N; Simard, J Marc; Elm, Jordan; Kronenberg, Golo; Kunte, Hagen; Kimberly, W Taylor

2016-01-01

The SUR1-TRPM4 channel is a critical determinant of edema and hemorrhagic transformation after focal ischemia. Blockade of this channel by the small molecule glyburide results in improved survival and neurological outcome in multiple preclinical models of ischemic stroke. A robust, compelling body of evidence suggests that an intravenous formulation of glyburide, RP-1127, can prevent swelling and improve outcome in patients with stroke. Retrospective studies of diabetic stroke patients show improved outcomes in patients who are continued on sulfonylureas after stroke onset. An early phase II study using magnetic resonance imaging and plasma biomarkers supports the conclusion that RP-1127 may decrease swelling and hemorrhagic transformation. Finally, the ongoing phase II RP-1127 development program has demonstrated continued safety as well as feasibility of enrollment and tolerability of the intervention. Continued efforts to complete the ongoing phase II study and definitive efficacy studies are needed to bring a candidate pharmacotherapy to a population of severe stroke patients that currently have no alternative.

Mechanistic Insights of Vitamin D Anticancer Effects.

PubMed

Ma, Yingyu; Johnson, Candace S; Trump, Donald L

2016-01-01

Vitamin D is a secosteroid hormone that regulates many biological functions in addition to its classical role in maintaining calcium homeostasis and bone metabolism. Vitamin D deficiency appears to predispose individuals to increased risk of developing a number of cancers. Compelling epidemiological and experimental evidence supports a role for vitamin D in cancer prevention and treatment in many types of cancers. Preclinical studies show that 1,25D3, the active metabolite of vitamin D, and its analogs have antitumor effects in vitro and in vivo through multiple mechanisms including the induction of cell cycle arrest, apoptosis, differentiation and the suppression of inflammation, angiogenesis, invasion, and metastasis. 1,25D3 also potentiates the effect of chemotherapeutic agents and other agents in the combination treatment. In this review, the antitumor effects of 1,25D3 and the potential underlying mechanisms will be discussed. The current findings support the application of 1,25D3 in cancer prevention and treatment. © 2016 Elsevier Inc. All rights reserved.

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

PubMed Central

Nitrini, Ricardo

2010-01-01

The diagnosis of Alzheimer’s disease (AD) for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer’s Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD’s dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD. PMID:29213696

Ischaemic conditioning: pitfalls on the path to clinical translation

PubMed Central

Przyklenk, Karin

2015-01-01

The development of novel adjuvant strategies capable of attenuating myocardial ischaemia-reperfusion injury and reducing infarct size remains a major, unmet clinical need. A wealth of preclinical evidence has established that ischaemic ‘conditioning’ is profoundly cardioprotective, and has positioned the phenomenon (in particular, the paradigms of postconditioning and remote conditioning) as the most promising and potent candidate for clinical translation identified to date. However, despite this preclinical consensus, current phase II trials have been plagued by heterogeneity, and the outcomes of recent meta-analyses have largely failed to confirm significant benefit. As a result, the path to clinical application has been perceived as ‘disappointing’ and ‘frustrating’. The goal of the current review is to discuss the pitfalls that may be stalling the successful clinical translation of ischaemic conditioning, with an emphasis on concerns regarding: (i) appropriate clinical study design and (ii) the choice of the ‘right’ preclinical models to facilitate clinical translation. PMID:25560903

Adoptive immunotherapy against ovarian cancer.

PubMed

Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

2016-05-17

The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting.

Ibandronate treatment for osteoporosis: rationale, preclinical, and clinical development of extended dosing regimens.

PubMed

Epstein, Solomon

2006-03-01

Ibandronate is a potent nitrogen-containing bisphosphonate available as a once-monthly oral formulation for the treatment and prevention of osteoporosis. Preclinical experiments with estrogen-depleted rats, dogs, and monkeys demonstrated the efficacy of daily and intermittent ibandronate dosing. Initial clinical trials explored the optimal dosing regimens for oral administration in humans. The Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) and Monthly Oral Ibandronate in Ladies (MOBILE) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density, reducing markers of bone turnover, and preventing fractures, while maintaining bone quality. These preclinical and clinical ibandronate trials provided progressive evidence that a simple, long interval dosing regimen could offer efficacy and safety comparable with currently available bisphosphonates. It is anticipated that once-monthly ibandronate may have a positive impact on patient adherence, and ultimately, on fracture protection in osteoporotic women.

The Potential of Adaptive Design in Animal Studies.

PubMed

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-10-12

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.

The Potential of Adaptive Design in Animal Studies

PubMed Central

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-01-01

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research. PMID:26473839

Maternal dietary fatty acid intake during pregnancy and the risk of preclinical and clinical type 1 diabetes in the offspring.

PubMed

Niinistö, Sari; Takkinen, Hanna-Mari; Uusitalo, Liisa; Rautanen, Jenna; Nevalainen, Jaakko; Kenward, Michael G; Lumia, Mirka; Simell, Olli; Veijola, Riitta; Ilonen, Jorma; Knip, Mikael; Virtanen, Suvi M

2014-03-14

The aim of the present study was to examine the associations between the maternal intake of fatty acids during pregnancy and the risk of preclinical and clinical type 1 diabetes in the offspring. The study included 4887 children with human leucocyte antigen (HLA)-conferred type 1 diabetes susceptibility born during the years 1997-2004 from the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal diet was assessed with a validated FFQ. The offspring were observed at 3- to 12-month intervals for the appearance of type 1 diabetes-associated autoantibodies and development of clinical type 1 diabetes (average follow-up period: 4·6 years (range 0·5-11·5 years)). Altogether, 240 children developed preclinical type 1 diabetes and 112 children developed clinical type 1 diabetes. Piecewise linear log-hazard survival model and Cox proportional-hazards regression were used for statistical analyses. The maternal intake of palmitic acid (hazard ratio (HR) 0·82, 95 % CI 0·67, 0·99) and high consumption of cheese during pregnancy (highest quarter v. intermediate half HR 0·52, 95 % CI 0·31, 0·87) were associated with a decreased risk of clinical type 1 diabetes. The consumption of sour milk products (HR 1·14, 95 % CI 1·02, 1·28), intake of protein from sour milk (HR 1·15, 95 % CI 1·02, 1·29) and intake of fat from fresh milk (HR 1·43, 95 % CI 1·04, 1·96) were associated with an increased risk of preclinical type 1 diabetes, and the intake of low-fat margarines (HR 0·67, 95 % CI 0·49, 0·92) was associated with a decreased risk. No conclusive associations between maternal fatty acid intake or food consumption during pregnancy and the development of type 1 diabetes in the offspring were detected.

Black raspberries in cancer clinical trials: Past, present and future.

PubMed

Kresty, Laura A; Mallery, Susan R; Stoner, Gary D

Black raspberries (BRB) inhibit a broad range of cancers in preclinical models, including in vivo models of oral, esophageal, colon, breast and skin cancer. Promising preclinical results have led to clinical evaluations in cancer patients or patients at increased risk for cancer development. To summarize clinical investigations targeting cancer or precancerous lesions with BRB and discuss future directions. A thorough literature search was conducted through December 1, 2015 to identify all published studies evaluating BRB in cancer focused clinical trials. Research investigating BRB in clinical settings report positive effects on preneoplastic lesions or cancers of the oral cavity, esophagus and colon. BRB treatment resulted in: histologic regression of oral intraepithelial neoplasia associated with improved histologic grade and significantly reduced loss of heterozygosity at tumor suppressor gene loci, modulated genes linked to RNA processing and growth factor recycling; in the colon, BRB inhibited FAP-associated polyp progression, demethylated tumor suppressor genes and improved plasma cytokine profiles; in Barrett's patients, BRB consumption increased tissue levels of GST-pi and decreased 8-isoprostane, a marker of lipid peroxidation/oxidative stress. The precise dose, duration and optimum mode of BRB delivery for cancer inhibition remains to be fully elucidated. Common themes across studies support that BRB are anti-proliferative, anti- inflammatory, reduce oxidative stress and restore tumor suppressive activity. Future directions are included in the conclusions section.

A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20.

PubMed

Mata López, Sara; Hammond, James J; Rigsby, Madison B; Balog-Alvarez, Cynthia J; Kornegay, Joe N; Nghiem, Peter P

2018-05-29

Boys with Duchenne muscular dystrophy (DMD) have DMD gene mutations, with associated loss of the dystrophin protein and progressive muscle degeneration and weakness. Corticosteroids and palliative support are currently the best treatment options. The long-term benefits of recently approved compounds such as eteplirsen and ataluren remain to be seen. Dogs with naturally occurring dystrophinopathies show progressive disease akin to that of DMD. Accordingly, canine DMD models are useful for studies of pathogenesis and preclinical therapy development. A dystrophin-deficient, male border collie dog was evaluated at the age of 5 months for progressive muscle weakness and dysphagia. Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L) were seen on a biochemistry panel. Histopathologic changes characteristic of dystrophinopathy were seen. Dystrophin was absent in the skeletal muscle on immunofluorescence microscopy and western blot. Whole genome sequencing, polymerase chain reaction, and Sanger sequencing revealed a frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream. Semen was archived for future line perpetuation. This spontaneous canine dystrophinopathy occurred due to a novel mutation in the minor DMD mutation hotspot (between exons 2 through 20). Perpetuating this line could allow for preclinical testing of genetic therapies targeted to this area of the DMD gene.

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

PubMed Central

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

2012-01-01

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

Constituents and functional implications of the rat default mode network.

PubMed

Hsu, Li-Ming; Liang, Xia; Gu, Hong; Brynildsen, Julia K; Stark, Jennifer A; Ash, Jessica A; Lin, Ching-Po; Lu, Hanbing; Rapp, Peter R; Stein, Elliot A; Yang, Yihong

2016-08-02

The default mode network (DMN) has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation within the network. Because preclinical models can inform translational studies of neuropsychiatric disorders, partitioning of the DMN in nonhuman species, which has previously not been reported, may inform both physiology and pathophysiology of the human DMN. In this study, we sought to identify constituents of the rat DMN using resting-state functional MRI (rs-fMRI) and diffusion tensor imaging. After identifying DMN using a group-level independent-component analysis on the rs-fMRI data, modularity analyses fractionated the DMN into an anterior and a posterior subsystem, which were further segregated into five modules. Diffusion tensor imaging tractography demonstrates a close relationship between fiber density and the functional connectivity between DMN regions, and provides anatomical evidence to support the detected DMN subsystems. Finally, distinct modulation was seen within and between these DMN subcomponents using a neurocognitive aging model. Taken together, these results suggest that, like the human DMN, the rat DMN can be partitioned into several subcomponents that may support distinct functions. These data encourage further investigation into the neurobiological mechanisms of DMN processing in preclinical models of both normal and disease states.

On-line integration of computer controlled diagnostic devices and medical information systems in undergraduate medical physics education for physicians.

PubMed

Hanus, Josef; Nosek, Tomas; Zahora, Jiri; Bezrouk, Ales; Masin, Vladimir

2013-01-01

We designed and evaluated an innovative computer-aided-learning environment based on the on-line integration of computer controlled medical diagnostic devices and a medical information system for use in the preclinical medical physics education of medical students. Our learning system simulates the actual clinical environment in a hospital or primary care unit. It uses a commercial medical information system for on-line storage and processing of clinical type data acquired during physics laboratory classes. Every student adopts two roles, the role of 'patient' and the role of 'physician'. As a 'physician' the student operates the medical devices to clinically assess 'patient' colleagues and records all results in an electronic 'patient' record. We also introduced an innovative approach to the use of supportive education materials, based on the methods of adaptive e-learning. A survey of student feedback is included and statistically evaluated. The results from the student feedback confirm the positive response of the latter to this novel implementation of medical physics and informatics in preclinical education. This approach not only significantly improves learning of medical physics and informatics skills but has the added advantage that it facilitates students' transition from preclinical to clinical subjects. Copyright © 2011 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Problem-based learning versus a traditional educational methodology: a comparison of preclinical and clinical periodontics performance.

PubMed

Rich, Sandra K; Keim, Robert G; Shuler, Charles F

2005-06-01

To evaluate efficacy of a problem-based learning (PBL) pedagogy in preclinical and clinical teaching, test scores of 234 undergraduate dental students from the conventionally taught classes of 2003 and 2004 were compared with scores of 274 dental students from the PBL classes of 2005 and 2006. Although the groups' means were close together, t-test analysis of scores revealed that PBL students performed significantly better than traditional (TRAD) students on midterm (p=.0001) and final (p=.015) examinations taken on student partner/mock patients. ANOVA comparing the classes with each other showed significant differences for the midterm and final, but not for the clinical examination. Further multiple comparison tests (Tukey HSD) for the midterm and final revealed that differences specifically reflected superior performance of PBL classes against one of the TRAD classes (2004). There was no difference in performance between PBL (n=134) and TRAD (n=233) students on examinations taken with actual clinical patients who were undergoing nonsurgical periodontal treatment. Over a two-year period, PBL students rated their program instructors at a mean of 4.41 on a Likert-type scale of 1 (not helpful) to 5 (outstanding). The program provides a PBL model for teaching preclinical and clinical skills supported by a four-year evaluation of manual skills outcomes.

Big data to smart data in Alzheimer's disease: Real-world examples of advanced modeling and simulation.

PubMed

Haas, Magali; Stephenson, Diane; Romero, Klaus; Gordon, Mark Forrest; Zach, Neta; Geerts, Hugo

2016-09-01

Many disease-modifying clinical development programs in Alzheimer's disease (AD) have failed to date, and development of new and advanced preclinical models that generate actionable knowledge is desperately needed. This review reports on computer-based modeling and simulation approach as a powerful tool in AD research. Statistical data-analysis techniques can identify associations between certain data and phenotypes, such as diagnosis or disease progression. Other approaches integrate domain expertise in a formalized mathematical way to understand how specific components of pathology integrate into complex brain networks. Private-public partnerships focused on data sharing, causal inference and pathway-based analysis, crowdsourcing, and mechanism-based quantitative systems modeling represent successful real-world modeling examples with substantial impact on CNS diseases. Similar to other disease indications, successful real-world examples of advanced simulation can generate actionable support of drug discovery and development in AD, illustrating the value that can be generated for different stakeholders. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Seeking innovation: incentive funding for biodefense biotechs.

PubMed

Nolan, John M; Samad, Emad U; Jindra, Lawrence F; Brozak, Stephen G

2010-12-01

In the current venture capital climate, it is easier to secure funding for late-stage, next-in-class therapeutic agents than for early-stage opportunities that have the potential to advance basic science and translational medicine. This funding paradigm is particularly problematic for the development of "dual-use" biothreat countermeasures such as antibiotics, vaccines, and antitoxins that target pathogens in novel ways and that have broad public health and biodefense applications. To address this issue, we propose the creation of the Drug Development Incentive Fund (DDIF), a novel funding mechanism that can stimulate the development of first-in-class agents that also possess the capability to guard against potential biothreats. This program would also support greater synergies between public funding and private venture investment. In a single act, this organization would secure science of national importance from disappearing, invest in projects that yield significant public health returns, advance the promises of preclinical and early phase research, revitalize biopharmaceutical investment, and create valuable innovation-economy jobs.

Drugs for dengue: a patent review (2010-2014).

PubMed

Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

2014-11-01

Almost half the global population is estimated to be at risk of contracting dengue infection. Of the 400 million infections estimated to occur annually, 4 million can be potentially life-threatening leading to vascular leakage and shock. The only treatment available to severe dengue patients is fluid replacement therapy and supportive care. A drug for treating dengue is an urgent need. This article endeavors to provide an overview of the experimental dengue drugs being developed around the world as reflected in the recent patent literature spanning the last few years (2010-2014). Dengue drug development is essentially in its infancy and currently hobbled by multiple factors including a poor understanding of the molecular mechanism of severe disease and lack of reliable small animal model for preclinical drug evaluation. More intense R&D coupled to setting up product development partnerships to facilitate the efficient movement of a drug molecule from the laboratory to the clinic is needed to make antiviral therapy for dengue a reality in the coming future.

An adjuvant-modulated vaccine response in human whole blood

PubMed Central

Hakimi, Jalil; Azizi, Ali; Ausar, Salvador F.; Todryk, Stephen M.; Rahman, Nausheen; Brookes, Roger H.

2017-01-01

ABSTRACT The restimulation of an immune memory response by in vitro culture of blood cells with a specific antigen has been used as a way to gauge immunity to vaccines for decades. In this commentary we discuss a less appreciated application to support vaccine process development. We report that human whole blood from pre-primed subjects can generate a profound adjuvant-modulated, antigen-specific response to several different vaccine formulations. The response is able to differentiate subtle changes in the quality of an immune memory response to vaccine formulations and can be used to select optimal conditions relating to a particular manufacture process step. While questions relating to closeness to in vivo vaccination remain, the approach is another big step nearer to the more relevant human response. It has special importance for new adjuvant development, complementing other preclinical in vivo and in vitro approaches to considerably de-risk progression of novel vaccines before and throughout early clinical development. Broader implications of the approach are discussed. PMID:28605295

Novel Cognitive Paradigms for the Detection of Memory Impairment in Preclinical Alzheimer’s Disease

PubMed Central

Loewenstein, David A.; Curiel, Rosie E.; Duara, Ranjan; Buschke, Herman

2017-01-01

In spite of advances in neuroimaging and other brain biomarkers to assess preclinical Alzheimer’s disease (AD), cognitive assessment has relied on traditional memory paradigms developed well over six decades ago. This has led to a growing concern about their effectiveness in the early diagnosis of AD which is essential to develop preventive and early targeted interventions before the occurrence of multisystem brain degeneration. We describe the development of novel tests that are more cognitively challenging, minimize variability in learning strategies, enhance initial acquisition and retrieval using cues, and exploit vulnerabilities in persons with incipient AD such as the susceptibility to proactive semantic interference, and failure to recover from proactive semantic interference. The advantages of various novel memory assessment paradigms are examined as well as how they compare with traditional neuropsychological assessments of memory. Finally, future directions for the development of more effective assessment paradigms are suggested. PMID:29214859

Preclinical development of monoclonal antibodies: considerations for the use of non-human primates.

PubMed

Chapman, Kathryn; Pullen, Nick; Coney, Lee; Dempster, Maggie; Andrews, Laura; Bajramovic, Jeffrey; Baldrick, Paul; Buckley, Lorrene; Jacobs, Abby; Hale, Geoff; Green, Colin; Ragan, Ian; Robinson, Vicky

2009-01-01

The development of mAbs remains high on the therapeutic agenda for the majority of pharmaceutical and biotechnology companies. Often, the only relevant species for preclinical safety assessment of mAbs are non-human primates (NHPs), and this raises important scientific, ethical and economic issues. To investigate evidence-based opportunities to minimize the use of NHPs, an expert working group with representatives from leading pharmaceutical and biotechnology companies, contract research organizations and institutes from Europe and the USA, has shared and analyzed data on mAbs for a range of therapeutic areas. This information has been applied to hypothetical examples to recommend scientifically appropriate development pathways and study designs for a variety of potential mAbs. The addendum of ICHS6 provides a timely opportunity for the scientific and regulatory community to embrace strategies which minimize primate use and increase efficiency of mAb development.

Huddle-coaching: a dynamic intervention for trainees and staff to support team-based care.

PubMed

Shunk, Rebecca; Dulay, Maya; Chou, Calvin L; Janson, Susan; O'Brien, Bridget C

2014-02-01

Many outpatient clinics where health professionals train will transition to a team-based medical home model over the next several years. Therefore, training programs need innovative approaches to prepare and incorporate trainees into team-based delivery systems. To address this need, educators at the San Francisco Veterans Affairs (VA) Medical Center included trainees in preclinic team "huddles," or briefing meetings to facilitate care coordination, and developed an interprofessional huddle-coaching program for nurse practitioner students and internal medicine residents who function as primary providers for patient panels in VA outpatient primary care clinics. The program aimed to support trainees' partnerships with staff and full participation in the VA's Patient Aligned Care Teams. The huddle-coaching program focuses on structuring the huddle process via scheduling, checklists, and designated huddle coaches; building relationships among team members through team-building activities; and teaching core skills to support collaborative practice. A multifaceted evaluation of the program showed positive results. Participants rated training sessions and team-building activities favorably. In interviews, trainees valued their team members and identified improvements in efficiency and quality of patient care as a result of the team-based approach. Huddle checklists and scores on the Team Development Measure indicated progress in team processes and relationships as the year progressed. These findings suggest that the huddle-coaching program was a worthwhile investment in trainee development that also supported the clinic's larger mission to deliver team-based, patient-aligned care. As more training sites shift to team-based care, the huddle-coaching program offers a strategy for successfully incorporating trainees.

Effective use of real-life events as tools for teaching-learning clinical pharmacology in a problem-based learning curriculum.

PubMed

James, Henry; Al Khaja, Khalid A; Sequeira, Reginald P

2015-01-01

This paper describes how in a problem-based learning (PBL) medical curriculum, having identified the learning outcomes, problems can be developed from real-life events for teaching-learning clinical pharmacology topics for which PBL cases might be inadequate. Such problems can be very interesting and educational. Using the story of the development and withdrawal of rofecoxib (Vioxx(®)), we developed a problem for undergraduate medical students to address important issues related to clinical pharmacology and therapeutics such as new drug development, preclinical testing, clinical trials, adverse drug reactions, professionalism, and critical appraisal of literature. These topics would otherwise be difficult to address in patient-based problems. The evaluation of the problem based on pooled feedback from 57 tutorial groups, each comprising 8-10 students, collected over 5 years, supported the effectiveness of the problem. A systematic approach described in this paper can be used for the development and validation of educational material for introducing focal topics of pharmacology/clinical pharmacology integrated with other disciplines in innovative medical (and other health profession) curricula.

Development of a chimeric Plasmodium berghei strain expressing the repeat region of the P. vivax circumsporozoite protein for in vivo evaluation of vaccine efficacy.

PubMed

Espinosa, Diego A; Yadava, Anjali; Angov, Evelina; Maurizio, Paul L; Ockenhouse, Christian F; Zavala, Fidel

2013-08-01

The development of vaccine candidates against Plasmodium vivax-the most geographically widespread human malaria species-is challenged by technical difficulties, such as the lack of in vitro culture systems and availability of animal models. Chimeric rodent Plasmodium parasites are safe and useful tools for the preclinical evaluation of new vaccine formulations. We report the successful development and characterization of chimeric Plasmodium berghei parasites bearing the type I repeat region of P. vivax circumsporozoite protein (CSP). The P. berghei-P. vivax chimeric strain develops normally in mosquitoes and produces highly infectious sporozoites that produce patent infection in mice that are exposed to the bites of as few as 3 P. berghei-P. vivax-infected mosquitoes. Using this transgenic parasite, we demonstrate that monoclonal and polyclonal antibodies against P. vivax CSP strongly inhibit parasite infection and thus support the notion that these antibodies play an important role in protective immunity. The chimeric parasites we developed represent a robust model for evaluating protective immune responses against P. vivax vaccines based on CSP.

Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice.

PubMed

Lu, Yanmei; Hoyte, Kwame; Montgomery, William H; Luk, Wilman; He, Dongping; Meilandt, William J; Zuchero, Y Joy Yu; Atwal, Jasvinder K; Scearce-Levie, Kimberly; Watts, Ryan J; DeForge, Laura E

2016-05-01

Transgenic mice that overexpress human amyloid precursor protein with Swedish or London (APPswe or APPlon) mutations have been widely used for preclinical Alzheimer's disease (AD) drug development. AD patients, however, rarely possess these mutations or overexpress APP. We developed a sensitive ELISA that specifically and accurately measures low levels of endogenous Aβ40 in mouse plasma, brain and CSF. In wild-type mice treated with a bispecific anti-TfR/BACE1 antibody, significant Aβ reductions were observed in the periphery and the brain. APPlon transgenic mice showed a slightly less reduction, whereas APPswe mice did not have any decrease. This sensitive and well-characterized mouse Aβ40 assay enables the use of wild-type mice for preclinical PK/PD and efficacy studies of potential AD therapeutics.

Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma

PubMed Central

Bassiri, Hamid; Benavides, Adriana; Haber, Michelle; Gilmour, Susan K.; Norris, Murray D.

2015-01-01

Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”) since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC. Pre-emptive blockade of polyamine synthesis is sufficient to block tumor initiation in an otherwise fully penetrant transgenic mouse model of neuroblastoma driven by MYCN, underscoring the necessity of polyamines in this process. Moreover, polyamine depletion regimens exert potent anti-tumor activity in pre-clinical models of established neuroblastoma as well, in combination with numerous chemotherapeutic agents and even in tumors with unfavorable genetic features such as MYCN, ALK or TP53 mutation. This has led to the testing of DFMO in clinical trials for children with neuroblastoma. Current trial designs include testing lower dose DFMO alone (2,000 mg/m2/day) starting at the completion of standard therapy, or higher doses combined with chemotherapy (up to 9,000 mg/m2/day) for patients with relapsed disease that has progressed. In this review we will discuss important considerations for the future design of DFMO-based clinical trials for neuroblastoma, focusing on the need to better define the principal mechanisms of anti-tumor activity for polyamine depletion regimens. Putative DFMO activities that are both cancer cell intrinsic (targeting the principal oncogenic driver, MYC) and cancer cell extrinsic (altering the tumor microenvironment to support anti-tumor immunity) will be discussed. Understanding the mechanisms of DFMO activity are critical in determining how it might be best leveraged in upcoming clinical trials. This mechanistic approach also provides a platform by which iterative pre-clinical testing using translational tumor models may complement our clinical approaches. PMID:26835380

Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies

PubMed Central

Jahangiri, Arman; Chin, Aaron T.; Flanigan, Patrick M.; Chen, Rebecca; Bankiewicz, Krystof; Aghi, Manish K.

2017-01-01

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail. PMID:27035164

Drugs' development in acute heart failure: what went wrong?

PubMed

Teneggi, Vincenzo; Sivakumar, Nithy; Chen, Deborah; Matter, Alex

2018-05-08

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

Restoring platinum sensitivity in recurrent ovarian cancer by extending the platinum-free interval: Myth or reality?

PubMed

Tomao, Federica; D'Incalci, Maurizio; Biagioli, Elena; Peccatori, Fedro A; Colombo, Nicoletta

2017-09-15

The platinum-free interval is the most important predictive factor of a response to subsequent lines of chemotherapy and the most important prognostic factor for progression-free and overall survival in patients with recurrent epithelial ovarian cancer. A nonplatinum regimen is generally considered the most appropriate approach when the disease recurs very early after the end of chemotherapy, whereas platinum-based chemotherapy is usually adopted when the platinum-free interval exceeds 12 months. However, the therapeutic management of patients with intermediate sensitivity (ie, when the relapse occurs between 6 and 12 months) remains debatable. Preclinical and clinical data suggest that the extension of platinum-free interval (using a nonplatinum-based regimen) might restore platinum sensitivity, thus allowing survival improvement. The objective of this review was to critically analyze preclinical and clinical evidences supporting this hypothesis. Cancer 2017;123:3450-9. © 2017 American Cancer Society. © 2017 American Cancer Society.

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

PubMed Central

Broekman, Winifred; Khedoe, Padmini P S J; Schepers, Koen; Roelofs, Helene; Stolk, Jan; Hiemstra, Pieter S

2018-01-01

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. PMID:29653970

Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

PubMed

Canal, Clinton E

2018-03-13

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT 2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence.

PubMed

Romeo-Guitart, David; Forés, Joaquim; Herrando-Grabulosa, Mireia; Valls, Raquel; Leiva-Rodríguez, Tatiana; Galea, Elena; González-Pérez, Francisco; Navarro, Xavier; Petegnief, Valerie; Bosch, Assumpció; Coma, Mireia; Mas, José Manuel; Casas, Caty

2018-01-30

Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma.

Recent Translational Findings on Impulsivity in Relation to Drug Abuse

PubMed Central

Weafer, Jessica; Mitchell, Suzanne H.

2015-01-01

Impulsive behavior is strongly implicated in drug abuse, as both a cause and a consequence of drug use. To understand how impulsive behaviors lead to and result from drug use, translational evidence from both human and non-human animal studies is needed. Here, we review recent (2009 or later) studies that have investigated two major components of impulsive behavior, inhibitory control and impulsive choice, across preclinical and clinical studies. We concentrate on the stop-signal task as the measure of inhibitory control and delay discounting as the measure of impulsive choice. Consistent with previous reports, recent studies show greater impulsive behavior in drug users compared with non-users. Additionally, new evidence supports the prospective role of impulsive behavior in drug abuse, and has begun to identify the neurobiological mechanisms underlying impulsive behavior. We focus on the commonalities and differences in findings between preclinical and clinical studies, and suggest future directions for translational research. PMID:25678985

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis.

PubMed

Veale, Douglas J; McGonagle, Dennis; McInnes, Iain B; Krueger, James G; Ritchlin, Christopher T; Elewaut, Dirk; Kanik, Keith S; Hendrikx, Thijs; Berstein, Gabriel; Hodge, Jennifer; Telliez, Jean-Baptiste

2018-04-03

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats.

PubMed

Rombolà, Laura; Tridico, Laura; Scuteri, Damiana; Sakurada, Tsukasa; Sakurada, Shinobu; Mizoguchi, Hirokazu; Avato, Pinarosa; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Morrone, Luigi Antonio

2017-04-11

Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders. However, only limited preclinical evidences are actually available. This study examined the anxiolytic/sedative-like effects of BEO using an open field task (OFT), an elevated plus-maze task (EPM), and a forced swimming task (FST) in rats. This study further compared behavioural effects of BEO to those of the benzodiazepine diazepam. Analysis of data suggests that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of the DZP. The present observations provide further insight to the pharmacological profile of BEO and support its rational use in aromatherapy.

Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

PubMed

Gómez-Lechón, María José; Tolosa, Laia

2016-09-01

Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

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.

Food for Thought Look Back in Anger – What Clinical Studies Tell Us About Preclinical Work

PubMed Central

Hartung, Thomas

2013-01-01

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models.

PubMed

Sharma, Sai Kiran; Chow, Andrew; Monette, Sebastien; Vivier, Delphine; Pourat, Jacob; Edwards, Kimberly J; Dilling, Thomas R; Abdel-Atti, Dalya; Zeglis, Brian M; Poirier, John T; Lewis, Jason S

2018-04-01

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric, and murine mAbs against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development. Significance: Fc/FcγR-mediated immunobiology of the experimental host is a key determinant to preclinical in vivo tumor targeting and efficacy of therapeutic antibodies. Cancer Res; 78(7); 1820-32. ©2018 AACR . ©2018 American Association for Cancer Research.

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.

Gastroenterology Curriculum in the Canadian Medical School System.

PubMed

Dang, ThucNhi Tran; Wong, Clarence; Bistritz, Lana

2017-01-01

Background and Purpose. Gastroenterology is a diverse subspecialty that covers a wide array of topics. The preclinical gastroenterology curriculum is often the only formal training that medical students receive prior to becoming residents. There is no Canadian consensus on learning objectives or instructional methods and a general lack of awareness of curriculum at other institutions. This results in variable background knowledge for residents and lack of guidance for course development. Objectives. (1) Elucidate gastroenterology topics being taught at the preclinical level. (2) Determine instructional methods employed to teach gastroenterology content. Results . A curriculum map of gastroenterology topics was constructed from 10 of the medical schools that responded. Topics often not taught included pediatric GI diseases, surgery and trauma, food allergies/intolerances, and obesity. Gastroenterology was taught primarily by gastroenterologists and surgeons. Didactic and small group teaching was the most employed teaching method. Conclusion. This study is the first step in examining the Canadian gastroenterology curriculum at a preclinical level. The data can be used to inform curriculum development so that topics generally lacking are better incorporated in the curriculum. The study can also be used as a guide for further curriculum design and alignment across the country.

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/1st communication: The contribution of clinical pharmacology].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture; genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/2nd communication: promising strategies].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture, genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

Prediction of Metabolism of Drugs using Artificial Intelligence: How far have we reached?

PubMed

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2016-01-01

Information about drug metabolism is an essential component of drug development. Modeling the drug metabolism requires identification of the involved enzymes, rate and extent of metabolism, the sites of metabolism etc. There has been continuous attempts in the prediction of metabolism of drugs using artificial intelligence in effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are number of predictive models available for metabolism using Support vector machines, Artificial neural networks, Bayesian classifiers etc. There is an urgent need to review their progress so far and address the existing challenges in prediction of metabolism. In this attempt, we are presenting the currently available literature models and some of the critical issues regarding prediction of drug metabolism.

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

PubMed

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

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study design is required to improve clinical translation of tissue engineering technologies. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Challenges in Learning Preclinical Prosthodontics: A Survey of Perceptions of Dental Undergraduates and Teaching Faculty at an Indian Dental School

PubMed Central

Jyotsna, S; Rajesh, G; Wadgave, Umesh; Sankeshwari, Banashree; Nayak, Sushma S; Vyas, Rashmi

2017-01-01

Introduction Preclinical dental education promotes development of competency and expertise before students work on patients, but this phase is devoid of exposure to real patients leading to challenges in teaching-learning. Aim The aim of this study was to explore the challenges faced by students during the process of learning preclinical prosthodontics. Materials and Methods Two Focus Group Discussions (FGDs) were conducted with two different groups of students and one FGD was held with prosthodontics faculty. The FGDs explored the student’s and faculty perceptions on the topics which were difficult for the students to understand and their suggestions on how these topics can be made easier to understand. The discussions were audio taped with prior consent and transcribed. Results The students and the faculty felt that the subject of prosthodontics is vast, difficult to visualize and also difficult to correlate theory with practical aspects. Lack of clinical exposure coupled with use of conventional methods of teaching were identified as reasons for difficulty in understanding the subject. Both students and faculty members suggested that use of simulation, demonstrations, and videos could augment the learning process for the students. Early clinical exposure will help solve many problems encountered during learning and contribute to a better understanding. Conclusion The students and faculty expressed a “need” for early clinical exposure to enhance the learner’s understanding of the preclinical aspects of the subject. The present study highlights the need for change in instruction methods to enhance the learning experiences in preclinical prosthodontics of dental undergraduate students in India. PMID:28969263

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.

An Economic Evaluation of Preclinical Testing Strategies Compared to the Compulsory Scrapie Flock Scheme in the Control of Classical Scrapie

PubMed Central

Hawkins, Neil; Houston, Fiona; Fryer, Helen; Kao, Rowland

2012-01-01

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS. PMID:22412943

An empirically derived composite cognitive test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease.

PubMed

Langbaum, Jessica B; Hendrix, Suzanne B; Ayutyanont, Napatkamon; Chen, Kewei; Fleisher, Adam S; Shah, Raj C; Barnes, Lisa L; Bennett, David A; Tariot, Pierre N; Reiman, Eric M

2014-11-01

There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Cognitive Challenges

MedlinePlus

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Preclinical Mouse Models of Neurofibromatosis

DTIC Science & Technology

2004-10-01

collaborated closely and have shared expertise and reagents extensively. This NF Consortium is a member of the Moue Models of Human Cancer Consortium...of the National Cancer Institute and is participating fully in the activities of the group. The current award will support these collaborative...studies through 2005. 14. SUBJECT TERMS 15. NUMBER OF PAGES Neurofibromatosis, cancer , mouse models 48 16. PRICE CODE 17. SECURITY CLASSIFICATION 78

A Randomized, Double-Blind, Crossover Comparison of MK-0929 and Placebo in the Treatment of Adults with ADHD

ERIC Educational Resources Information Center

Rivkin, Anna; Alexander, Robert C.; Knighton, Jennifer; Hutson, Pete H.; Wang, Xiaojing J.; Snavely, Duane B.; Rosah, Thomas; Watt, Alan P.; Reimherr, Fred W.; Adler, Lenard A.

2012-01-01

Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD. Method: A randomized, double-blind, placebo-controlled, crossover study was conducted…

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.

Implementation of new technologies in U.S. dental school curricula.

PubMed

Brownstein, Sheri A; Murad, Aseel; Hunt, Ronald J

2015-03-01

With dentistry rapidly evolving as new technologies are developed, this study aimed to identify the penetration of emerging dental technologies into the curricula of U.S. dental schools and to explore whether certain school characteristics affected adoption of these technologies. A 19-question survey was sent to the academic deans of all 62 U.S. dental schools. In addition to questions about characteristics of the school, the survey asked respondents to indicate where in their curricula the technology was incorporated: preclinical didactic, preclinical laboratory, clinical didactic, and/or clinical patient experience. Of 62 eligible schools, 33 useable responses were received, for a 52% response rate. The results showed that the greatest overall penetration of dental technologies was in preclinical didactic courses and the lowest was in the preclinical laboratory. Specific technologies implemented in the largest percentage of responding schools were digital radiography and rotary endodontics. The technologies with the lowest penetration were CAD/CAM denture fabrication and hard tissue lasers. These results suggest that the incorporation of technology into dental schools is following that of private practice as the most widely adopted technologies were those with the greatest acceptance and use in private practice. Among the respondents, factors such as class size and age of the school had greater impact on incorporation of technology than funding source and geographic location.

Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives.

PubMed

Hovens, Iris B; Schoemaker, Regien G; van der Zee, Eddy A; Heineman, Erik; Izaks, Gerbrand J; van Leeuwen, Barbara L

2012-10-01

Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. Copyright © 2012 Elsevier Inc. All rights reserved.

Teaching methods and surgical training in North American graduate periodontics programs: exploring the landscape.

PubMed

Ghiabi, Edmond; Taylor, K Lynn

2010-06-01

This project aimed at documenting the surgical training curricula offered by North American graduate periodontics programs. A survey consisting of questions on teaching methods employed and the content of the surgical training program was mailed to directors of all fifty-eight graduate periodontics programs in Canada and the United States. The chi-square test was used to assess whether the residents' clinical experience was significantly (P<0.05) influenced by having a) a structured preclinical program or b) another dental residency program in the institution. Thirty-four programs (59 percent) responded to the survey. Twenty-six programs (76 percent of respondents) reported offering a structured preclinical component. Traditional teaching methods such as slides, live demonstration, DVD/CD, and animal cadavers were the most common teaching methods used, whereas online courses, computer simulation, and various surgical mannequins were least commonly used. The most commonly performed surgical procedures were conventional flaps, periodontal plastic procedures, hard tissue grafts, and implants. Furthermore, residents in programs offering a structured preclinical component performed significantly more procedures (P=0.012) using lasers than those in programs not offering a structured preclinical program. Devising new and innovative teaching methods is a clear avenue for future development in North American graduate periodontics programs.

Breast cancer: the role of angiogenesis and antiangiogenic therapy.

PubMed

Miller, Kathy D; Dul, Carrie L

2004-10-01

Angiogenesis plays a role in breast cancer development. Preclinical and clinical evidence is reviewed. Development of targeted antiangiogenic agents provides new challenges to clinical trial design. Current antiangiogenic therapy with traditional agents and novel agents are classified and reviewed.

Rational development of a protective P. vivax vaccine evaluated with transgenic rodent parasite challenge models

PubMed Central

Salman, Ahmed M.; Montoya-Díaz, Eduardo; West, Heather; Lall, Amar; Atcheson, Erwan; Lopez-Camacho, Cesar; Ramesar, Jai; Bauza, Karolis; Collins, Katharine A.; Brod, Florian; Reis, Fernando; Pappas, Leontios; González-Cerón, Lilia; Janse, Chris J.; Hill, Adrian V. S.; Khan, Shahid M.; Reyes-Sandoval, Arturo

2017-01-01

Development of a protective and broadly-acting vaccine against the most widely distributed human malaria parasite, Plasmodium vivax, will be a major step towards malaria elimination. However, a P. vivax vaccine has remained elusive by the scarcity of pre-clinical models to test protective efficacy and support further clinical trials. In this study, we report the development of a highly protective CSP-based P. vivax vaccine, a virus-like particle (VLP) known as Rv21, able to provide 100% sterile protection against a stringent sporozoite challenge in rodent models to malaria, where IgG2a antibodies were associated with protection in absence of detectable PvCSP-specific T cell responses. Additionally, we generated two novel transgenic rodent P. berghei parasite lines, where the P. berghei csp gene coding sequence has been replaced with either full-length P. vivax VK210 or the allelic VK247 csp that additionally express GFP-Luciferase. Efficacy of Rv21 surpassed viral-vectored vaccination using ChAd63 and MVA. We show for the first time that a chimeric VK210/247 antigen can elicit high level cross-protection against parasites expressing either CSP allele, which provide accessible and affordable models suitable to support the development of P. vivax vaccines candidates. Rv21 is progressing to GMP production and has entered a path towards clinical evaluation. PMID:28417968