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.

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

Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors

PubMed Central

Strowd, Roy E.; Cervenka, Mackenzie C.; Henry, Bobbie J.; Kossoff, Eric H.; Hartman, Adam L.; Blakeley, Jaishri O.

2015-01-01

Dietary glycemic modulation through high-fat, low-carbohydrate diets, which induce a state of systemic ketosis and alter systemic metabolic signaling, have been incorporated into the clinical management of patients with neurological disease for more than a century. Mounting preclinical evidence supports the antitumor, proapoptotic, and antiangiogenic effects of disrupting glycolytic metabolism through dietary intervention. In recent years, interest in incorporating such novel therapeutic strategies in neuro-oncology has increased. To date, 3 published studies incorporating novel dietary therapies in oncology have been reported, including one phase I study in neuro-oncology, and have set the stage for further study in this field. In this article, we review the biochemical pathways, preclinical data, and early clinical translation of dietary interventions that modulate systemic glycolytic metabolism in the management of primary malignant brain tumors. We introduce the modified Atkins diet (MAD), a novel dietary alternative to the classic ketogenic diet, and discuss the critical issues facing future study. PMID:26649186

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.

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

PubMed

Sarker, Marjana Rahman; Franks, Susan F

2018-04-21

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

Management of Leigh syndrome: Current status and new insights.

PubMed

Chen, L; Cui, Y; Jiang, D; Ma, C Y; Tse, H-F; Hwu, W-L; Lian, Q

2018-06-01

Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in pre-clinical studies. In this review, we summarize the genetic basis of LS, current treatment, pre-clinical studies in animal models and the management of other mitochondrial diseases. Future therapeutical strategies and challenges are also discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

PubMed

Koontz, Bridget F; Verhaegen, Frank; De Ruysscher, Dirk

2017-01-01

Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation.

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

PubMed Central

Verhaegen, Frank; De Ruysscher, Dirk

2017-01-01

Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation. PMID:27612010

Pharmacologic therapy for acute pancreatitis

PubMed Central

Kambhampati, Swetha; Park, Walter; Habtezion, Aida

2014-01-01

While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

A window on disease pathogenesis and potential therapeutic strategies: molecular imaging for arthritis

PubMed Central

2011-01-01

Novel molecular imaging techniques are at the forefront of both preclinical and clinical imaging strategies. They have significant potential to offer visualisation and quantification of molecular and cellular changes in health and disease. This will help to shed light on pathobiology and underlying disease processes and provide further information about the mechanisms of action of novel therapeutic strategies. This review explores currently available molecular imaging techniques that are available for preclinical studies with a focus on optical imaging techniques and discusses how current and future advances will enable translation into the clinic for patients with arthritis. PMID:21345267

Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

PubMed

Polyzois, Ioannis; Claffey, Noel; McDonald, Albhe; Hussey, David; Quinn, Frank

2011-05-01

The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson's linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level. © 2011 John Wiley & Sons A/S.

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

PubMed

Sandberg, Kathryn; Umans, Jason G

2015-05-01

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

Psychedelic Drugs in Biomedicine.

PubMed

Kyzar, Evan J; Nichols, Charles D; Gainetdinov, Raul R; Nichols, David E; Kalueff, Allan V

2017-11-01

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

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.

Nanotechnology and nuclear medicine; research and preclinical applications.

PubMed

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

2011-01-01

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

Vets and Videos: Student Learning from Context-Based Assessment in a Pre-Clinical Science Course

ERIC Educational Resources Information Center

Seddon, Jennifer

2008-01-01

To increase the perceived relevance of pre-clinical science courses to undergraduates, a context-based assessment item was introduced to a genetics course that occurs early within a five-year veterinary science programme. The aim was to make a direct link between genetic concepts and the future clinical profession of the students. In the…

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

Tissue engineering of the bladder--reality or myth? A systematic review.

PubMed

Sloff, Marije; Simaioforidis, Vasileios; de Vries, Rob; Oosterwijk, Egbert; Feitz, Wout

2014-10-01

We systematically reviewed preclinical studies in the literature to evaluate the potential of tissue engineering of the bladder. Study outcomes were compared to the available clinical evidence to assess the feasibility of tissue engineering for future clinical use. Preclinical studies of tissue engineering for bladder augmentation were identified through a systematic search of PubMed and Embase™ from January 1, 1980 to January 1, 2014. Primary studies in English were included if bladder reconstruction after partial cystectomy was performed using a tissue engineered biomaterial in any animal species, with cystometric bladder capacity as an outcome measure. Outcomes were compared to clinical studies available at http://www.clinicaltrials.gov and published clinical studies. A total of 28 preclinical studies are included, demonstrating remarkable heterogeneity in study characteristics and design. Studies in which preoperative bladder volumes were compared to postoperative volumes were considered the most clinically relevant (18 studies). Bladder augmentation through tissue engineering resulted in a normal bladder volume in healthy animals, with the influence of a cellular component being negligible. Furthermore, experiments in large animal models (pigs and dogs) approximated the desired bladder volume more accurately than in smaller species. The initial clinical experience was based on seemingly predictive healthy animal models with a promising outcome. Unfortunately these results were not substantiated in all clinical trials, revealing dissimilar outcomes in different clinical/disease backgrounds. Thus, the translational predictability of a model using healthy animals might be questioned. Through this systematic approach we present an unbiased overview of all published preclinical studies investigating the effect of bladder tissue engineering on cystometric bladder capacity. Preclinical research in healthy animals appears to show the feasibility of bladder augmentation by tissue engineering. However, in view of the disappointing clinical results based on healthy animal models new approaches should also be evaluated in preclinical models using dysfunctional/diseased bladders. This endeavor may aid in the development of clinically applicable tissue engineered bladder augmentation with satisfactory long-term outcome. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

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.

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed Central

Shah, Khalid

2016-01-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. PMID:27282399

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

(±)-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.

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.

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

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

PubMed

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

2016-09-21

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

In vivo preclinical verification of a multimodal diffuse reflectance and correlation spectroscopy system for sensing tissue perfusion

NASA Astrophysics Data System (ADS)

Pakela, Julia M.; Lee, Seung Yup; Hedrick, Taylor L.; Vishwanath, Karthik; Helton, Michael C.; Chung, Yooree G.; Kolodziejski, Noah J.; Staples, Christopher J.; McAdams, Daniel R.; Fernandez, Daniel E.; Christian, James F.; O'Reilly, Jameson; Farkas, Dana; Ward, Brent B.; Feinberg, Stephen E.; Mycek, Mary-Ann

2017-02-01

In reconstructive surgery, impeded blood flow in microvascular free flaps due to a compromise in arterial or venous patency secondary to blood clots or vessel spasms can rapidly result in flap failures. Thus, the ability to detect changes in microvascular free flaps is critical. In this paper, we report progress on in vivo pre-clinical testing of a compact, multimodal, fiber-based diffuse correlation and reflectance spectroscopy system designed to quantitatively monitor tissue perfusion in a porcine model's surgically-grafted free flap. We also describe the device's sensitivity to incremental blood flow changes and discuss the prospects for continuous perfusion monitoring in future clinical translational studies.

Tissue concentrations of vitamin K and expression of key enzymes of vitamin K metabolism are influenced by sex and diet but not housing in C57Bl6 mice

USDA-ARS?s Scientific Manuscript database

Background: There has been limited characterization of biological variables that impact vitamin K metabolism. This gap in knowledge can limit the translation of data obtained from preclinical animal studies to future human studies. Objective: The purpose of this study was to determine the effects of...

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

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

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

PubMed

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

2011-03-01

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

Organ-on-a-chip platforms for studying drug delivery systems.

PubMed

Bhise, Nupura S; Ribas, João; Manoharan, Vijayan; Zhang, Yu Shrike; Polini, Alessandro; Massa, Solange; Dokmeci, Mehmet R; Khademhosseini, Ali

2014-09-28

Novel microfluidic tools allow new ways to manufacture and test drug delivery systems. Organ-on-a-chip systems - microscale recapitulations of complex organ functions - promise to improve the drug development pipeline. This review highlights the importance of integrating microfluidic networks with 3D tissue engineered models to create organ-on-a-chip platforms, able to meet the demand of creating robust preclinical screening models. Specific examples are cited to demonstrate the use of these systems for studying the performance of drug delivery vectors and thereby reduce the discrepancies between their performance at preclinical and clinical trials. We also highlight the future directions that need to be pursued by the research community for these proof-of-concept studies to achieve the goal of accelerating clinical translation of drug delivery nanoparticles. Copyright © 2014 Elsevier B.V. All rights reserved.

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

Clinical Research with Transcranial Direct Current Stimulation (tDCS): Challenges and Future Directions

PubMed Central

Brunoni, Andre Russowsky; Nitsche, Michael A.; Bolognini, Nadia; Bikson, Marom; Wagner, Tim; Merabet, Lotfi; Edwards, Dylan J.; Valero-Cabre, Antoni; Rotenberg, Alexander; Pascual-Leone, Alvaro; Ferrucci, Roberta; Priori, Alberto; Boggio, Paulo; Fregni, Felipe

2011-01-01

Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS. PMID:22037126

The neurologic control of arousal and orgasm with specific attention to spinal cord lesions: Integrating preclinical and clinical sciences.

PubMed

Alexander, Marcalee Sipski; Marson, Lesley

2018-01-01

Preclinical research in animal models is important for understanding the neural pathways and pathophysiology underlying changes in sexual function after SCI. In vivo animal models, primarily rodents, have provided valuable information on the central pathways regulating sexual arousal and orgasm; however, further research is required in females and preclinical modeling of SCI that can be better translated to men and women. Translation of the autonomic and somatic regulation of sexual responses from preclinical models through clinical research correlates well with respect to the peripheral-spinal systems involved. However, due to the nature of sexual responses, parallel studies are necessary in animals and humans. Human studies of individuals with SCIs have provided information about the neurologic control of arousal and orgasm. Psychogenic arousal is related to the preservation of sensation at T11-L2 whereas orgasm requires the presence of an intact sacral reflex arc. Studies point to evidence of a spinal pattern generator at L3-5. Because of the exact nature of SCIs, further research using neuroimaging will be beneficial, not only to elucidate the neurological control of sexual responses after SCI, but also in able-bodied individuals. Understanding and ameliorating the effects of SCI on sexual function is important to the well-being and quality of life of individuals with SCIs and their partners, thus future research should focus more on this important topic. Published by Elsevier B.V.

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.

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

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

Assessing HIV/AIDS Knowledge and Stigmatizing Attitudes among Medical Students in Universiti Putra Malaysia.

PubMed

Chew, B H; Cheong, A T

2013-01-01

Medical students are future doctors who are trained to treat all kind of diseases including people living with HIV/AIDS (PLWHA) without prejudice. This study was to determine the factors associated with knowledge on HIV/AIDS and stigma towards PLWHA among medical students. This was a cross sectional study with stratified random sampling conducted in a public university, Malaysia. The participants were preclinical-year (year 1 and year 2) and clinical-year (year 3 and year 4) medical students. Simple randomisation was carried out after stratification of medical students into preclinical and clinical-year. The selfadministered questionnaires were consisted of sociodemographic data, items assessing HIV/AIDS knowledge and items assessing stigmatisation attitudes towards PLWHA. We had 100% response rate of 340 participants. Pre-clinical and clinical year medical students each contributed 170 (50%). Majority was female (64.1%). About two-thirds (60.6%) was Malay, followed by Chinese (31.2%) and Indian (7.1%). Pre-clinical students were significantly more stigmatizing in subscale of "attitudes towards imposed measures" (t=3.917, p<0.001), even with adjustment for previous encounter and ethnicity (B= 1.2, 95% CI 0.48 to 1.83, p=0.001). On the other hand, clinical students were found to be significantly less comfortable in handling HIV/AIDS cases (t=0.039, p=0.039), even after controlled for previous encounter and ethnicity (B=0.6, 95% CI 0.29 to 0.98, p< 0.001). Clinical encounter with PLWHA was associated with higher knowledge in HIV/AIDS. Medical students in preclinical years were having stigmatizing attitude towards imposed measures compared to the clinical years who had more stigmatizing attitude in being less comfortable with PLWHA.

Human Hemato-Lymphoid System Mice: Current Use and Future Potential for Medicine

PubMed Central

Rongvaux, Anthony; Takizawa, Hitoshi; Strowig, Till; Willinger, Tim; Eynon, Elizabeth E.

2014-01-01

To directly study complex human hemato-lymphoid system physiology and respective system-associated diseases in vivo, human-to-mouse xenotransplantation models for human blood and blood-forming cells and organs have been developed over the past three decades. We here review the fundamental requirements and the remarkable progress made over the past few years in improving these systems, the current major achievements reached by use of these models, and the future challenges to more closely model and study human health and disease and to achieve predictive preclinical testing of both prevention measures and potential new therapies. PMID:23330956

Intravital microscopy in the study of the tumor microenvironment: from bench to human application.

PubMed

Gabriel, Emmanuel M; Fisher, Daniel T; Evans, Sharon; Takabe, Kazuaki; Skitzki, Joseph J

2018-04-13

Intravital microscopy (IVM) is a dynamic imaging modality that allows for the real time observation of biologic processes in vivo , including angiogenesis and immune cell interactions. In the setting of preclinical cancer models, IVM has facilitated an understanding of the tumor associated vasculature and the role of effector immune cells in the tumor microenvironment. Novel approaches to apply IVM to human malignancies have thus far focused on cancer diagnosis and tumor vessel characterization, but have the potential to provide advances in the field of personalized medicine by identifying individual patients who may respond to systemically delivered chemotherapeutic drugs or immunotherapeutic agents. In this review, we highlight the role that IVM has had in investigating tumor vasculature and the tumor microenvironment in preclinical studies and discuss its current and future applications to directly observe human tumors.

Training future doctors to be patient-centred: efficacy of a communication skills training (CST) programme in a Malaysian medical institution.

PubMed

Lukman, H; Beevi, Z; Yeap, R

2009-03-01

This study evaluates the efficacy of the preclinical communication skills training (CST) programme at the International Medical University in Malaysia. Efficacy indicators include students' (1) perceived competency (2) attitude (3) conceptual knowledge, and (4) performance with regard to patient-centred communication. A longitudinal study with a before-after design tracked a preclinical cohort's progress on the aforementioned indicators as they advance through the training. Results indicate that following the CST, students perceived themselves to be more competent in interpersonal communication, had more positive attitude towards patient-centred communication, and developed a better conceptual knowledge of doctor-patient communication. In addition, those with good conceptual knowledge tend to demonstrate better communication skills performance at the Objective Structure Clinical Examination 12 months following the initial CST.

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.

Gene and cell therapy for pancreatic cancer.

PubMed

Singh, Hans Martin; Ungerechts, Guy; Tsimberidou, Apostolia M

2015-04-01

The clinical outcomes of patients with pancreatic cancer are poor, and the limited success of classical chemotherapy underscores the need for new, targeted approaches for this disease. The delivery of genetic material to cells allows for a variety of therapeutic concepts. Engineered agents based on synthetic biology are under clinical investigation in various cancers, including pancreatic cancer. This review focuses on Phase I - III clinical trials of gene and cell therapy for pancreatic cancer and on future implications of recent translational research. Trials available in the US National Library of Medicine (www.clinicaltrials.gov) until February 2014 were reviewed and relevant published results of preclinical and clinical studies were retrieved from www.pubmed.gov . In pancreatic cancer, gene and cell therapies are feasible and may have synergistic antitumor activity with standard treatment and/or immunotherapy. Challenges are related to application safety, manufacturing costs, and a new spectrum of adverse events. Further studies are needed to evaluate available agents in carefully designed protocols and combination regimens. Enabling personalized cancer therapy, insights from molecular diagnostic technologies will guide the development and selection of new gene-based drugs. The evolving preclinical and clinical data on gene-based therapies can lay the foundation for future avenues improving patient care in pancreatic cancer.

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.

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

Insights into Atherosclerosis Using Nanotechnology

PubMed Central

Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

2010-01-01

A developing forefront in vascular disease research is the application of nanotechnology, the engineering of devices at the molecular scale, for diagnostic and therapeutic applications in atherosclerosis. Promising research in this field over the past decade has resulted in the preclinical validation of nanoscale devices that target cellular and molecular components of the atherosclerotic plaque, including one of its prominent cell types, the macrophage. Nanoscale contrast agents targeting constituents of plaque biology have been adapted for application in multiple imaging modalities, leading toward more detailed diagnostic readouts, whereas nanoscale drug delivery devices can be tailored for site-specific therapeutic activity. This review highlights recent progress in utilizing nanotechnology for the clinical management of atherosclerosis, drawing upon recent preclinical studies relevant to diagnosis and treatment of the plaque and promising future applications. PMID:20425261

Effect of second-generation antipsychotics on cognition: current issues and future challenges

PubMed Central

Hill, S Kristian; Bishop, Jeffrey R; Palumbo, Donna; Sweeney, John A.

2010-01-01

Generalized cognitive impairments are stable deficits linked to schizophrenia and key factors associated with functional disability in the disorder. Preclinical data suggest that second-generation antipsychotics could potentially reduce cognitive impairments; however, recent large clinical trials indicate only modest cognitive benefits relative to first-generation antipsychotics. This might reflect a limited drug effect in humans, a differential drug effect due to brain alterations associated with schizophrenia, or limited sensitivity of the neuropsychological tests for evaluating cognitive outcomes. New adjunctive procognitive drugs may be needed to achieve robust cognitive and functional improvement. Drug discovery may benefit from greater utilization of translational neurocognitive biomarkers to bridge preclinical and clinical proof-of-concept studies, to optimize assay sensitivity, enhance cost efficiency, and speed progress in drug development. PMID:20021320

Interactions between nicotine and drugs of abuse: A review of preclinical findings

PubMed Central

Kohut, Stephen J.

2017-01-01

Polysubstance abuse is common among substance use disorder patients and nicotine is one of the most commonly co-used substances. Epidemiological and clinical laboratory studies suggest that nicotine, when combined with other drugs of abuse, increases intake of one or both substances. This review focuses on the preclinical literature regarding nicotine’s interaction with alcohol, stimulants (i.e., cocaine, amphetamines), opioids (i.e., morphine, heroin) and Δ9-tetrahydrocannabinol (THC). The current understanding of how these various classes of abused drugs may interact with nicotine on behavioral, physiological, and pharmacological indices that may be important in maintaining co-use of one or both substances in human populations are highlighted. Suggestions as to future areas of research and gaps in knowledge are offered. PMID:27589579

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

PubMed

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

2014-11-01

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

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

PubMed

Opal, Steven M; Dellinger, R Phillip; Vincent, Jean-Louis; Masur, Henry; Angus, Derek C

2014-07-01

The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice

PubMed Central

Gill, Ronald G.; Pagni, Philippe P.; Kupfer, Tinalyn; Wasserfall, Clive H.; Deng, Songyan; Posgai, Amanda; Manenkova, Yulia; Bel Hani, Amira; Straub, Laura; Bernstein, Philip; Atkinson, Mark A.; Herold, Kevan C.; von Herrath, Matthias; Staeva, Teodora; Ehlers, Mario R.; Nepom, Gerald T.

2016-01-01

There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet β-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti–IL-1β monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use. PMID:26718498

NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics

PubMed Central

2014-01-01

In May of 2014, the NIH Director together with the Director of the Office of Research on Women’s Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner. PMID:25780556

In search of antiepileptogenic treatments for post-traumatic epilepsy.

PubMed

Saletti, Patricia G; Ali, Idrish; Casillas-Espinosa, Pablo M; Semple, Bridgette D; Lisgaras, Christos; Moshé, Solomon L; Galanopoulou, Aristea S

2018-06-21

Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments. Copyright © 2018. Published by Elsevier Inc.

Biological augmentation and tissue engineering approaches in meniscus surgery.

PubMed

Moran, Cathal J; Busilacchi, Alberto; Lee, Cassandra A; Athanasiou, Kyriacos A; Verdonk, Peter C

2015-05-01

The purpose of this review was to evaluate the role of biological augmentation and tissue engineering strategies in meniscus surgery. Although clinical (human), preclinical (animal), and in vitro tissue engineering studies are included here, we have placed additional focus on addressing preclinical and clinical studies reported during the 5-year period used in this review in a systematic fashion while also providing a summary review of some important in vitro tissue engineering findings in the field over the past decade. A search was performed on PubMed for original works published from 2009 to March 31, 2014 using the term "meniscus" with all the following terms: "scaffolds," "constructs," "cells," "growth factors," "implant," "tissue engineering," and "regenerative medicine." Inclusion criteria were the following: English-language articles and original clinical, preclinical (in vivo), and in vitro studies of tissue engineering and regenerative medicine application in knee meniscus lesions published from 2009 to March 31, 2014. Three clinical studies and 18 preclinical studies were identified along with 68 tissue engineering in vitro studies. These reports show the increasing promise of biological augmentation and tissue engineering strategies in meniscus surgery. The role of stem cell and growth factor therapy appears to be particularly useful. A review of in vitro tissue engineering studies found a large number of scaffold types to be of promise for meniscus replacement. Limitations include a relatively low number of clinical or preclinical in vivo studies, in addition to the fact there is as yet no report in the literature of a tissue-engineered meniscus construct used clinically. Neither does the literature provide clarity on the optimal meniscus scaffold type or biological augmentation with which meniscus repair or replacement would be best addressed in the future. There is increasing focus on the role of mechanobiology and biomechanical and biochemical cues in this process, however, and it is hoped that this may lead to improvements in this strategy. There appears to be significant potential for biological augmentation and tissue engineering strategies in meniscus surgery to enhance options for repair and replacement. However, there are still relatively few clinical studies being reported in this regard. There is a strong need for improved translational activities and infrastructure to link the large amounts of in vitro and preclinical biological and tissue engineering data to clinical application. Level IV, systematic review of Level I-IV studies. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

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.

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

PubMed

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

2013-02-01

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

Preclinical Whole-body Fluorescence Imaging: Review of Instruments, Methods and Applications

PubMed Central

Leblond, Frederic; Davis, Scott C.; Valdés, Pablo A.; Pogue, Brain W.

2013-01-01

Fluorescence sampling of cellular function is widely used in all aspects of biology, allowing the visualization of cellular and sub-cellular biological processes with spatial resolutions in the range from nanometers up to centimeters. Imaging of fluorescence in vivo has become the most commonly used radiological tool in all pre-clinical work. In the last decade, full-body pre-clinical imaging systems have emerged with a wide range of utilities and niche application areas. The range of fluorescent probes that can be excited in the visible to near-infrared part of the electromagnetic spectrum continues to expand, with the most value for in vivo use being beyond the 630 nm wavelength, because the absorption of light sharply decreases. Whole-body in vivo fluorescence imaging has not yet reached a state of maturity that allows its routine use in the scope of large-scale pre-clinical studies. This is in part due to an incomplete understanding of what the actual fundamental capabilities and limitations of this imaging modality are. However, progress is continuously being made in research laboratories pushing the limits of the approach to consistently improve its performance in terms of spatial resolution, sensitivity and quantification. This paper reviews this imaging technology with a particular emphasis on its potential uses and limitations, the required instrumentation, and the possible imaging geometries and applications. A detailed account of the main commercially available systems is provided as well as some perspective relating to the future of the technology development. Although the vast majority of applications of in vivo small animal imaging are based on epi-illumination planar imaging, the future success of the method relies heavily on the design of novel imaging systems based on state-of-the-art optical technology used in conjunction with high spatial resolution structural modalities such as MRI, CT or ultra-sound. PMID:20031443

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.

Inherited variation in immune response genes in follicular lymphoma and diffuse large B-cell lymphoma.

PubMed

Nielsen, Kaspar Rene; Steffensen, Rudi; Haunstrup, Thure Mors; Bødker, Julie Støve; Dybkær, Karen; Baech, John; Bøgsted, Martin; Johnsen, Hans Erik

2015-01-01

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) both depend on immune-mediated survival and proliferation signals from the tumor microenvironment. Inherited genetic variation influences this complex interaction. A total of 89 studies investigating immune-response genes in DLBCL and FL were critically reviewed. Relatively consistent association exists for variation in the tumor necrosis factor alpha (TNFA) and interleukin-10 loci and DLBCL risk; for DLBCL outcome association with the TNFA locus exists. Variations at chromosome 6p31-32 were associated with FL risk. Importantly, individual risk alleles have been shown to interact with each other. We suggest that the pathogenetic impact of polymorphic genes should include gene-gene interaction analysis and should be validated in preclinical model systems of normal B lymphopoiesis and B-cell malignancies. In the future, large cohort studies of interactions and genome-wide association studies are needed to extend the present findings and explore new risk alleles to be studied in preclinical models.

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

Nebulized anticoagulants in lung injury in critically ill patients—an updated systematic review of preclinical and clinical studies

PubMed Central

Juschten, Jenny; Tuinman, Pieter R.; Juffermans, Nicole P.; Dixon, Barry; Levi, Marcel

2017-01-01

Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition (‘pneumonia’, ‘inhalation trauma’ and ‘ARDS’), the intervention (‘nebulized’, ‘vaporized’, and ‘aerosolized’) and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients [‘heparin’, ‘danaparoid’, ‘activated protein C’ (APC), ‘antithrombin’ (AT) and ‘tissue factor pathway inhibitor’ (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects. PMID:29264361

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

PubMed Central

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

2016-01-01

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

Gene therapy for inherited retinal degenerations: initial successes and future challenges

NASA Astrophysics Data System (ADS)

Gupta, Priya R.; Huckfeldt, Rachel M.

2017-10-01

Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therapeutic strategies have demonstrated efficacy in preclinical studies and entered clinical trials with a common goal of improving visual function for patients affected with these conditions. Gene therapy offers a particularly elegant and precise opportunity to target the causative genetic mutations underlying these monogenic diseases. The present review will provide an overview of gene therapy with particular emphasis on key clinical results to date and challenges for the future.

Knowledge, Attitude, and Practice of Yoga in Medical Students: Assessment of Anthropometry and Lifestyle Factors.

PubMed

Hegde, Shreelaxmi V; Rao, Swathi K; Menezes, Ritesh G; Kotian, Shashidhar M; Shetty, Sowmya

2018-03-29

Medical students often experience significant stress during their undergraduate training. Evidence has shown short-term yoga to be effective in decreasing stress in students. This study aimed to assess knowledge about, attitude toward, and practice of (KAP) yoga among medical students. A secondary objective was to analyze their dietary habits and physical activity. Participants consisted of 224 medical students aged 18-23 years in pre- and paraclinical groups. A closed-ended KAP questionnaire was used to collect data. Anthropometric measurements were taken. Results showed that paraclinical students (70.5%) favorably perceived the health benefits of yoga. Nearly three-fourths of study subjects had previously practiced yoga; greater numbers intended to practice yoga in the future. About 95.5% of the preclinical students who had done yoga had discontinued the practice. Perceived barriers to the practice of yoga were lack of time, insufficient facilities, lack of company, and lack of interest. Consideration of the undergraduates' lifestyle revealed that 50.4% of preclinical students did not exercise, and they routinely consumed more junk food with fewer servings of fresh fruits/salads. Preclinical students exhibited higher BMI and waist circumference compared to paraclinical students. Findings suggest that knowledge of and attitude regarding yoga were good among medical undergraduates.

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

PubMed

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

2016-12-01

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

The state of radiologic teaching practice in preclinical medical education: survey of American medical, osteopathic, and podiatric schools.

PubMed

Rubin, Zachary; Blackham, Kristine

2015-04-01

This study describes the state of preclinical radiology curricula in North American allopathic, osteopathic, and podiatric medical schools. An online survey of teaching methods, radiology topics, and future plans was developed. The Associations of American Medical Colleges, Colleges of Osteopathic Medicine, and Colleges of Podiatric Medicine listing for all US, Canadian, and Puerto Rican schools was used for contact information for directors of anatomy and/or radiology courses. Letters were sent via e-mail to 198 schools, with a link to the anonymous survey. Of 198 schools, 98 completed the survey (48%). Radiology curricula were integrated with other topics (91%), and taught by anatomists (42%) and radiologists (43%). The majority of time was spent on the topic of anatomy correlation (35%). Time spent teaching general radiology topics in the curriculum, such as physics (3%), modality differences (6%), radiation safety (2%), and contrast use (2%) was limited. Most schools had plans to implement an innovative teaching method in the near future (62%). The major challenges included limits on: time in the curriculum (73%); resources (32%); and radiology faculty participation (30%). A total of 82% reported that their curriculum did not model the suggestions made by the Alliance of Medical Student Educators in Radiology. This survey describes the current state of preclinical radiology teaching: curricula were nonstandard, integrated into other courses, and predominantly used for anatomy correlation. Other important contextual principles of the practice of radiology were seldom taught. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders.

PubMed

Nguyen, Linda; Thomas, Kelan L; Lucke-Wold, Brandon P; Cavendish, John Z; Crowe, Molly S; Matsumoto, Rae R

2016-03-01

Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Advances of high intensity focused ultrasound (HIFU) for pancreatic cancer.

PubMed

Xiaoping, Li; Leizhen, Zheng

2013-11-01

High intensity focused ultrasound (HIFU) is a novel therapeutic modality. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumours, including pancreatic cancer. Preliminary studies suggest that HIFU may be useful for the palliative therapy of cancer-related pain in patients with unresectable pancreatic cancer. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges.

Stem cell-based therapies for tumors in the brain: are we there yet?

PubMed

Shah, Khalid

2016-08-01

Advances in understanding adult stem cell biology have facilitated the development of novel cell-based therapies for cancer. Recent developments in conventional therapies (eg, tumor resection techniques, chemotherapy strategies, and radiation therapy) for treating both metastatic and primary tumors in the brain, particularly glioblastoma have not resulted in a marked increase in patient survival. Preclinical studies have shown that multiple stem cell types exhibit inherent tropism and migrate to the sites of malignancy. Recent studies have validated the feasibility potential of using engineered stem cells as therapeutic agents to target and eliminate malignant tumor cells in the brain. This review will discuss the recent progress in the therapeutic potential of stem cells for tumors in the brain and also provide perspectives for future preclinical studies and clinical translation. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

Acoustic Droplet Vaporization in Biology and Medicine

PubMed Central

Pitt, William G.

2013-01-01

This paper reviews the literature regarding the use of acoustic droplet vaporization (ADV) in clinical applications of imaging, embolic therapy, and therapeutic delivery. ADV is a physical process in which the pressure waves of ultrasound induce a phase transition that causes superheated liquid nanodroplets to form gas bubbles. The bubbles provide ultrasonic imaging contrast and other functions. ADV of perfluoropentane was used extensively in imaging for preclinical trials in the 1990s, but its use declined rapidly with the advent of other imaging agents. In the last decade, ADV was proposed and explored for embolic occlusion therapy, drug delivery, aberration correction, and high intensity focused ultrasound (HIFU) sensitization. Vessel occlusion via ADV has been explored in rodents and dogs and may be approaching clinical use. ADV for drug delivery is still in preclinical stages with initial applications to treat tumors in mice. Other techniques are still in preclinical studies but have potential for clinical use in specialty applications. Overall, ADV has a bright future in clinical application because the small size of nanodroplets greatly reduces the rate of clearance compared to larger contrast agent bubbles and yet provides the advantages of ultrasonographic contrast, acoustic cavitation, and nontoxicity of conventional perfluorocarbon contrast agent bubbles. PMID:24350267

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

PubMed Central

Shavit, Yehuda; Grace, Peter M.; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2011-01-01

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. PMID:21752874

PCR examination of bronchoalveolar lavage samples is a useful tool in pre-clinical diagnosis of ovine pulmonary adenocarcinoma (Jaagsiekte).

PubMed

Voigt, K; Brügmann, M; Huber, K; Dewar, P; Cousens, C; Hall, M; Sharp, J M; Ganter, M

2007-12-01

Ovine pulmonary adenocarcinoma (OPA) is a contagious lung tumour of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The disease is a particular problem in flocks in many parts of the world. The aim of the study was to assess screening methods for individual animals as a prelude to future eradication trials. Results of histological examination were used as the standard to evaluate the relative sensitivity and specificity of an established heminested polymerase chain reaction (PCR) test for JSRV proviral DNA from blood and bronchoalveolar lavage (BAL) samples. PCR results from tissue samples are included as control data. PCR testing of blood samples was found to have an estimated sensitivity of only 10% (95% confidence interval (CI) 3-20) while the sensitivity of the PCR test on BAL samples was 89% (CI 79-96) in comparison to the results of histological examination. We conclude that PCR testing of BAL samples is an effective confirmatory test for sheep with suspected clinical OPA. It is also a useful tool for the pre-clinical identification of individual infected sheep within an infected flock and therefore may prove beneficial in future control or eradication programmes.

Pharmacological imaging as a tool to visualise dopaminergic neurotoxicity.

PubMed

Schrantee, A; Reneman, L

2014-09-01

Dopamine abnormalities underlie a wide variety of psychopathologies, including ADHD and schizophrenia. A new imaging technique, pharmacological magnetic resonance imaging (phMRI), is a promising non-invasive technique to visualize the dopaminergic system in the brain. In this review we explore the clinical potential of phMRI in detecting dopamine dysfunction or neurotoxicity, assess its strengths and weaknesses and identify directions for future research. Preclinically, phMRI is able to detect severe dopaminergic abnormalities quite similar to conventional techniques such as PET and SPECT. phMRI benefits from its high spatial resolution and the possibility to visualize both local and downstream effects of dopaminergic neurotransmission. In addition, it allows for repeated measurements and assessments in vulnerable populations. The major challenge is the complex interpretation of phMRI results. Future studies in patients with dopaminergic abnormalities need to confirm the currently reviewed preclinical findings to validate the technique in a clinical setting. Eventually, based on the current review we expect that phMRI can be of use in a clinical setting involving vulnerable populations (such as children and adolescents) for diagnosis and monitoring treatment efficacy. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Copyright © 2013 Elsevier Ltd. All rights reserved.

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.

X-Ray and near-infrared imaging: similarities, differences and combinations

NASA Astrophysics Data System (ADS)

Pogue, Brian W.

2010-02-01

The integration of x-ray imaging with optical imaging is becoming routine at the pre-clinical level, as both projection and tomography systems are now commercially integrated as packaged systems. Yet, the differences between their capabilities are wide, and there is still perhaps a lack of appreciation about how difference pre-clinical x-ray systems are from clinical x-ray systems. In this survey, the key advantages of each approach, x-ray and optical, are described, and the potential synergies and deficiencies are discussed. In simple terms, the major benefit of optical imaging is in the spectroscopic capabilities, which allow the potential for imaging fluorescent agents in vivo, and the future potential for imaging multiple species at a time with spectral discrimination or spectral fitting of the data. In comparison, multienergy x-ray systems are being realized in clinical use, or automated discrimination of soft versus hard tissues, and the combination of optical imaging with this type of dual-energy x-ray imaging will significantly enhance the capabilities of the hybrid systems. Unfortunately, the power of dual energy imaging is not as possible at the pre-clinical stage, because of the limitations of contrast-resolution and x-ray dose. This is discussed and future human systems outlined.

Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

PubMed Central

de Carvalho, Felipe Gonçalves; de Freitas, Gabriel Rodriguez

2016-01-01

Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field. PMID:27698671

Deriving Therapies for Children with Primary CNS Tumors Using Pharmacokinetic Modeling and Simulation of Cerebral Microdialysis Data

PubMed Central

Jacus, M.O.; Throm, S.L.; Turner, D.C.; Patel, Y.T.; Freeman, B.B.; Morfouace, M.; Boulos, N.; Stewart, C. F.

2014-01-01

The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors. PMID:24269626

Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research.

PubMed

Tse, Maric T; Piantadosi, Patrick T; Floresco, Stan B

2015-06-01

Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model

PubMed Central

Higuchi, Tamami; Yokobori, Takehiko; Naito, Tomoharu; Kakinuma, Chihaya; Hagiwara, Shinji; Nishiyama, Masahiko; Asao, Takayuki

2018-01-01

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. PMID:29435042

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.

Advances in Monitoring Cell-Based Therapies with Magnetic Resonance Imaging: Future Perspectives

PubMed Central

Ngen, Ethel J.; Artemov, Dmitri

2017-01-01

Cell-based therapies are currently being developed for applications in both regenerative medicine and in oncology. Preclinical, translational, and clinical research on cell-based therapies will benefit tremendously from novel imaging approaches that enable the effective monitoring of the delivery, survival, migration, biodistribution, and integration of transplanted cells. Magnetic resonance imaging (MRI) offers several advantages over other imaging modalities for elucidating the fate of transplanted cells both preclinically and clinically. These advantages include the ability to image transplanted cells longitudinally at high spatial resolution without exposure to ionizing radiation, and the possibility to co-register anatomical structures with molecular processes and functional changes. However, since cellular MRI is still in its infancy, it currently faces a number of challenges, which provide avenues for future research and development. In this review, we describe the basic principle of cell-tracking with MRI; explain the different approaches currently used to monitor cell-based therapies; describe currently available MRI contrast generation mechanisms and strategies for monitoring transplanted cells; discuss some of the challenges in tracking transplanted cells; and suggest future research directions. PMID:28106829

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

PubMed

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

2018-05-01

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

The Future of Dental Education.

ERIC Educational Resources Information Center

Simonsen, Richard J.

1994-01-01

The author, a representative of the American Dental Trade Association, identifies major challenges facing dental education in the areas of predoctoral dental education, postdoctoral dental education, and continuing dental education. Ten recommendations address preclinical and clinical courses, licensing examinations, mandatory continuing…

Towards immunotherapy with redirected T cells in a large animal model: Ex vivo activation, expansion, and genetic modification of canine T cells

PubMed Central

Mata, Melinda; Vera, Juan; Gerken, Claudia; Rooney, Cliona M.; Miller, Tasha; Pfent, Catherine; Wang, Lisa L.; Wilson-Robles, Heather M.; Gottschalk, Stephen

2014-01-01

Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising anti-tumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells we targeted HER2-positive OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2-positive canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy prior to conducting studies in humans. PMID:25198528

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

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

PubMed

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

2016-01-01

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

A 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.

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.

Biomimetic three-dimensional tissue models for advanced high-throughput drug screening

PubMed Central

Nam, Ki-Hwan; Smith, Alec S.T.; Lone, Saifullah; Kwon, Sunghoon; Kim, Deok-Ho

2015-01-01

Most current drug screening assays used to identify new drug candidates are 2D cell-based systems, even though such in vitro assays do not adequately recreate the in vivo complexity of 3D tissues. Inadequate representation of the human tissue environment during a preclinical test can result in inaccurate predictions of compound effects on overall tissue functionality. Screening for compound efficacy by focusing on a single pathway or protein target, coupled with difficulties in maintaining long-term 2D monolayers, can serve to exacerbate these issues when utilizing such simplistic model systems for physiological drug screening applications. Numerous studies have shown that cell responses to drugs in 3D culture are improved from those in 2D, with respect to modeling in vivo tissue functionality, which highlights the advantages of using 3D-based models for preclinical drug screens. In this review, we discuss the development of microengineered 3D tissue models which accurately mimic the physiological properties of native tissue samples, and highlight the advantages of using such 3D micro-tissue models over conventional cell-based assays for future drug screening applications. We also discuss biomimetic 3D environments, based-on engineered tissues as potential preclinical models for the development of more predictive drug screening assays for specific disease models. PMID:25385716

Multi-Center Trial of Baclofen for Abstinence Initiation in Severe Cocaine Dependent Individuals

PubMed Central

Kahn, Roberta; Biswas, Kousick; Childress, Anna-Rose; Shoptaw, Steve; Fudala, Paul J.; Gorgon, Liza; Montoya, Ivan; Collins, Joseph; McSherry, Frances; Li, Shou-Hua; Chiang, Nora; Alathari, Husam; Watson, Donnie; Liberto, Joseph; Beresford, Thomas; Stock, Christopher; Wallace, Christopher; Gruber, Valerie; Elkashef, Ahmed

2009-01-01

Background Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABAB receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) versus placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. PMID:19414226

Pathogenesis and Prediction of Future Rheumatoid Arthritis

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-13-1-0408 TITLE: Pathogenesis and Prediction of Future Rheumatoid Arthritis PRINCIPAL INVESTIGATOR: Kevin D. Deane, MD/PhD...SUBTITLE 5a. CONTRACT NUMBER Pathogenesis and Prediction of Rheumatoid Arthritis 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...preclinical period of rheumatoid arthritis (RA) development that is characterized by abnormalities of the immune system prior to the onset of the

Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase?

PubMed

Salem, Raneem O; Al-Mously, Najwa; AlFadil, Sara; Baalash, Amal

2016-01-01

Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). Pre-clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress.

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

PubMed Central

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

2017-01-01

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

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

PubMed

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

2017-06-30

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

Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

PubMed Central

Jonker, Simone J.; Menting, Theo P.; Warlé, Michiel C.; Ritskes-Hoitinga, Merel; Wever, Kimberley E.

2016-01-01

Background Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. Method We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. Results We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. Conclusion High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID:26963819

TH-AB-206-02: Nuclear Medicine Theronostics: Wave of the Future; Pre-Clinical and Clinical Opportunities

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

Delpassand, E.

In the past few decades, the field of nuclear medicine has made long strides with the continued advancement of related sciences and engineering and the availability of diagnostic and therapeutic radionuclides. Leveraging these advancements while combining the advantages of therapeutic and diagnostic radionuclides into one radiopharmaceutical has also created a new subfield “theranostics” in nuclear medicine that has the potential to further propel the field into the future. This session is composed of two talks; one focused on the physics principles of theranostics from properties of beta and alpha emitting radionuclides to dosimetric models and quantification; while the second describesmore » preclinical and clinical applications of theranostics and discusses the challenges and opportunities of bringing them to the clinic. At the end of the session the listener should be able to identify: The different properties of beta and alpha emitting radionuclides Which radionuclides are selected for which nuclear medicine therapies and why How PET can be used to accurately quantify the uptake of tumor targeting molecules How individualized dosimetry can be performed from the management of thyroid cancer to novel radiolabeled antibody therapies Promising pre-clinical radiopharmaceutical pairs in prostate cancer and melanoma. Promising clinical Theranostics in neuroendocrine cancers. Challenges of bringing Theranostics to the clinic. E. Delpassand, RITA Foundation -Houston; SBIR Grant; CEO and share holder of RadioMedix.« less

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

PubMed

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

2013-03-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity.

Cocaine-Induced Neurodevelopmental Deficits and Underlying Mechanisms

PubMed Central

Martin, Melissa M.; Graham, Devon L.; McCarthy, Deirdre M.; Bhide, Pradeep G.; Stanwood, Gregg D.

2017-01-01

Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with mechanistic preclinical studies, to define our current knowledge base and identify gaps for future investigation. PMID:27345015

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

Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.

PubMed

Bernardi, Maria-Pia; Ngan, Samuel Y; Michael, Michael; Lynch, A Craig; Heriot, Alexander G; Ramsay, Robert G; Phillips, Wayne A

2015-12-01

Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy.

PubMed

Toczek, Marta; Zielonka, Daniel; Zukowska, Paulina; Marcinkowski, Jerzy T; Slominska, Ewa; Isalan, Mark; Smolenski, Ryszard T; Mielcarek, Michal

2016-11-01

Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings. Copyright © 2016 Elsevier B.V. All rights reserved.

Metabotropic glutamate receptor 5 as a potential target for smoking cessation.

PubMed

Chiamulera, Cristiano; Marzo, Claudio Marcello; Balfour, David J K

2017-05-01

Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence, they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many "off-target" effects to be used clinically. However, newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

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

From bench to almost bedside: the long road to a licensed Ebola virus vaccine.

PubMed

Wong, Gary; Mendoza, Emelissa J; Plummer, Francis A; Gao, George F; Kobinger, Gary P; Qiu, Xiangguo

2018-02-01

The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered: This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion: Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics.

From bench to almost bedside: The long road to a licensed Ebola virus vaccine

PubMed Central

Wong, Gary; Mendoza, Emelissa J.; Plummer, Francis A.; Gao, George F.; Kobinger, Gary P.; Qiu, Xiangguo

2018-01-01

Introduction The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics. PMID:29148858

Preliminary study for small animal preclinical hadrontherapy facility

NASA Astrophysics Data System (ADS)

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

2017-02-01

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

Dose-dependent Toxicity of Humanized Renilla reniformis GFP (hrGFP) Limits Its Utility as a Reporter Gene in Mouse Muscle

PubMed Central

Wallace, Lindsay M; Moreo, Andrew; Clark, K Reed; Harper, Scott Q

2013-01-01

Gene therapy has historically focused on delivering protein-coding genes to target cells or tissues using a variety of vectors. In recent years, the field has expanded to include gene-silencing strategies involving delivery of noncoding inhibitory RNAs, such as short hairpin RNAs or microRNAs (miRNAs). Often called RNA interference (RNAi) triggers, these small inhibitory RNAs are difficult or impossible to visualize in living cells or tissues. To circumvent this detection problem and ensure efficient delivery in preclinical studies, vectors can be engineered to coexpress a fluorescent reporter gene to serve as a marker of transduction. In this study, we set out to optimize adeno-associated viral (AAV) vectors capable of delivering engineered miRNAs and green fluorescent protein (GFP) reporter genes to skeletal muscle. Although the more broadly utilized enhanced GFP (eGFP) gene derived from the jellyfish, Aequorea victoria was a conventional choice, we were concerned about some previous studies suggesting this protein was myotoxic. We thus opted to test vectors carrying the humanized Renilla reniformis-derived GFP (hrGFP) gene, which has not seen as extensive usage as eGFP but was purported to be a safer and less cytotoxic alternative. Employing AAV6 vector dosages typically used in preclinical gene transfer studies (3×1010 –1 × 1011 particles), we found that hrGFP caused dose-dependent myopathy when delivered to wild-type (wt) mouse muscle, whereas identical titers of AAV6 carrying eGFP were relatively benign. Dose de-escalation at or below 8 × 109 AAV particles effectively reduced or eliminated hrGFP-associated myotoxicity, but also had dampening effects on green fluorescence and miRNA-mediated gene silencing in whole muscles. We conclude that hrGFP is impractical for use as a transduction marker in preclinical, AAV-based RNA interference therapy studies where adult mouse muscle is the target organ. Moreover, our data support that eGFP is superior to hrGFP as a reporter gene in mouse muscle. These results may impact the design of future preclinical gene therapy studies targeting muscles and non-muscle tissues alike. PMID:23591809

Medical Ethics Education: Coming of Age.

ERIC Educational Resources Information Center

Miles, Steven H.; And Others

1989-01-01

A discussion of medical ethics in the medical curriculum reviews its recent history, examines areas of consensus, and describes teaching objectives and methods, course content, and program evaluation at preclinical and clinical levels. Prerequisites for successful institutionalization of medical ethics education are defined, and its future is…

Endothelin therapeutics in cancer: Where are we?

PubMed

Rosanò, Laura; Bagnato, Anna

2016-03-15

In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein β-arrestin 1 (β-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ETAR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional β-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches. Copyright © 2016 the American Physiological Society.

IGF-1: an endogenous link between traumatic brain injury and Alzheimer disease?

PubMed

Zheng, Ping; Tong, Wusong

2017-08-01

There is a growing body of evidence that the insulin-like growth factor-1 (IGF-1) is dynamically involved in the regulation of body homeostasis and glucose regulation. Traumatic brain injury (TBI) is considered to be a risk factor for Alzheimer's disease (AD). As alterations of IGF-1 have been implicated in both TBI and AD and the IGF-1 signaling also mediates the neuronal excitability and synaptic plasticity in both diseases, we propose that IGF-1 may act as the endogenous connection between TBI and AD. Growing evidence suggests that dysfunction of this pathway contributes to the progressive loss of neurons in Alzheimer's disease (AD), one of the most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting IGF-1 signaling with currently available antidiabetics. These studies have shown that exogenous administration of IGF-1 reverses signaling abnormalities and has neuroprotective effects. In the first part of this review, we discuss physiological functions of IGF-1 signaling pathway including its distribution within the brain and its relationship with TBI and AD. In the second part, we undertake a comprehensive overview of IGF-1 signaling in TBI and AD, respectively. We then detail targeted IGF-1 in preclinical models of neurodegeneration and the design of clinical trials that have used anti-diabetics for treating AD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into clinical sessions.

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.

Genetically engineered pigs as models for human disease

PubMed Central

Perleberg, Carolin; Kind, Alexander

2018-01-01

ABSTRACT Genetically modified animals are vital for gaining a proper understanding of disease mechanisms. Mice have long been the mainstay of basic research into a wide variety of diseases but are not always the most suitable means of translating basic knowledge into clinical application. The shortcomings of rodent preclinical studies are widely recognised, and regulatory agencies around the world now require preclinical trial data from nonrodent species. Pigs are well suited to biomedical research, sharing many similarities with humans, including body size, anatomical features, physiology and pathophysiology, and they already play an important role in translational studies. This role is set to increase as advanced genetic techniques simplify the generation of pigs with precisely tailored modifications designed to replicate lesions responsible for human disease. This article provides an overview of the most promising and clinically relevant genetically modified porcine models of human disease for translational biomedical research, including cardiovascular diseases, cancers, diabetes mellitus, Alzheimer's disease, cystic fibrosis and Duchenne muscular dystrophy. We briefly summarise the technologies involved and consider the future impact of recent technical advances. PMID:29419487

Recent technological advances in using mouse models to study ovarian cancer.

PubMed

House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

2014-01-01

Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.

Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer

PubMed Central

House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

2014-01-01

Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC. PMID:24592355

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.

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

PubMed

Pehrson, Caroline; Salanti, Ali; Theander, Thor G; Nielsen, Morten A

2017-06-01

Malaria during pregnancy is a massive health problem in endemic areas. Placental malaria infections caused by Plasmodium falciparum are responsible for up to one million babies being born with a low birth weight every year. Significant efforts have been invested into preventing the condition. Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical vaccine development. However, all papers from these searches were not systematically included. Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy will contribute to endpoint measurements, further it may require extensive follow-up to establish protection. Future second generation vaccines may overcome the inherent challenges in making an effective placental malaria vaccine.

Intramuscular injection of AAV8 in mice and macaques is associated with substantial hepatic targeting and transgene expression.

PubMed

Greig, Jenny A; Peng, Hui; Ohlstein, Jason; Medina-Jaszek, C Angelica; Ahonkhai, Omua; Mentzinger, Anne; Grant, Rebecca L; Roy, Soumitra; Chen, Shu-Jen; Bell, Peter; Tretiakova, Anna P; Wilson, James M

2014-01-01

Intramuscular (IM) administration of adeno-associated viral (AAV) vectors has entered the early stages of clinical development with some success, including the first approved gene therapy product in the West called Glybera. In preparation for broader clinical development of IM AAV vector gene therapy, we conducted detailed pre-clinical studies in mice and macaques evaluating aspects of delivery that could affect performance. We found that following IM administration of AAV8 vectors in mice, a portion of the vector reached the liver and hepatic gene expression contributed significantly to total expression of secreted transgenes. The contribution from liver could be controlled by altering injection volume and by the use of traditional (promoter) and non-traditional (tissue-specific microRNA target sites) expression control elements. Hepatic distribution of vector following IM injection was also noted in rhesus macaques. These pre-clinical data on AAV delivery should inform safe and efficient development of future AAV products.

Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments

NASA Astrophysics Data System (ADS)

Dawidczyk, Charlene; Russell, Luisa; Searson, Peter

2014-08-01

The ability to efficiently deliver a drug or gene to a tumor site is dependent on a wide range of factors including circulation time, interactions with the mononuclear phagocyte system, extravasation from circulation at the tumor site, targeting strategy, release from the delivery vehicle, and uptake in cancer cells. Nanotechnology provides the possibility of creating delivery systems where the design constraints are decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing tumor accumulation, and improving efficacy. The physico-chemical properties of nanoparticle-based delivery platforms introduce additional complexity associated with pharmacokinetics and tumor accumulation. To assess the impact of nanoparticle-based delivery systems, we first review the design strategies and pharmacokinetics of FDA-approved nanomedicines. Next we review nanomedicines under development, summarizing the range of nanoparticle platforms, strategies for targeting, and pharmacokinetics. We show how the lack of uniformity in preclinical trials prevents systematic comparison and hence limits advances in the field.

Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development

PubMed Central

Ribas, João; Sadeghi, Hossein; Manbachi, Amir; Leijten, Jeroen; Brinegar, Katelyn; Zhang, Yu Shrike; Ferreira, Lino

2016-01-01

Abstract Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human in vivo dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system—in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development. PMID:28971113

Smoking and increased Alzheimer’s disease risk: A review of potential mechanisms

PubMed Central

Durazzo, Timothy C.; Mattsson, Niklas; Weiner, Michael W.

2014-01-01

Background Cigarette smoking has been linked with both increased and decreased risk for Alzheimer’s disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. Methods Systematic review of published studies on the association between smoking and increased risk for AD, and preclinical and human literature on the relationships between smoking, nicotine exposure and AD-related neuropathology. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. Results Overall, the literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathophysiology and increased risk for AD. Conclusions A reduction in the incidence of smoking will likely reduce the future prevalence of AD. PMID:24924665

The relationship between learning preferences (styles and approaches) and learning outcomes among pre-clinical undergraduate medical students.

PubMed

Liew, Siaw-Cheok; Sidhu, Jagmohni; Barua, Ankur

2015-03-11

Learning styles and approaches of individual undergraduate medical students vary considerably and as a consequence, their learning needs also differ from one student to another. This study was conducted to identify different learning styles and approaches of pre-clinical, undergraduate medical students and also to determine the relationships of learning preferences with performances in the summative examinations. A cross-sectional study was conducted among randomly selected 419 pre-clinical, undergraduate medical students of the International Medical University (IMU) in Kuala Lumpur. The number of students from Year 2 was 217 while that from Year 3 was 202. The Visual, Auditory, Read/Write, Kinesthetic (VARK) and the Approaches and Study Skills Inventory for Students (ASSIST) questionnaires were used for data collection. This study revealed that 343 students (81.9%) had unimodal learning style, while the remaining 76 (18.1%) used a multimodal learning style. Among the unimodal learners, a majority (30.1%) were of Kinesthetic (K) type. Among the middle and high achievers in summative examinations, a majority had unimodal (Kinaesthetic) learning style (30.5%) and were also strategic/deep learners (79.4%). However, the learning styles and approaches did not contribute significantly towards the learning outcomes in summative examinations. A majority of the students in this study had Unimodal (Kinesthetic) learning style. The learning preferences (styles and approaches) did not contribute significantly to the learning outcomes. Future work to re-assess the viability of these learning preferences (styles and approaches) after the incorporation of teaching-learning instructions tailored specifically to the students will be beneficial to help medical teachers in facilitating students to become more capable learners.

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.

Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review

PubMed Central

Wang, Huiying; Lee, In-Seon; Braun, Christoph; Enck, Paul

2016-01-01

To systematically review the effects of probiotics on central nervous system function in animals and humans, to summarize effective interventions (species of probiotic, dose, duration), and to analyze the possibility of translating preclinical studies. Literature searches were conducted in Pubmed, Medline, Embase, and the Cochrane Library. Only randomized controlled trials were included. In total, 38 studies were included: 25 in animals and 15 in humans (2 studies were conducted in both). Most studies used Bifidobacterium (eg, B. longum, B. breve, and B. infantis) and Lactobacillus (eg, L. helveticus, and L. rhamnosus), with doses between 109 and 1010 colony-forming units for 2 weeks in animals and 4 weeks in humans. These probiotics showed efficacy in improving psychiatric disorder-related behaviors including anxiety, depression, autism spectrum disorder (ASD), obsessive-compulsive disorder, and memory abilities, including spatial and non-spatial memory. Because many of the basic science studies showed some efficacy of probiotics on central nervous system function, this background may guide and promote further preclinical and clinical studies. Translating animal studies to human studies has obvious limitations but also suggests possibilities. Here, we provide several suggestions for the translation of animal studies. More experimental designs with both behavioral and neuroimaging measures in healthy volunteers and patients are needed in the future. PMID:27413138

Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review.

PubMed

Wang, Huiying; Lee, In-Seon; Braun, Christoph; Enck, Paul

2016-10-30

To systematically review the effects of probiotics on central nervous system function in animals and humans, to summarize effective interventions (species of probiotic, dose, duration), and to analyze the possibility of translating preclinical studies. Literature searches were conducted in Pubmed, Medline, Embase, and the Cochrane Library. Only randomized controlled trials were included. In total, 38 studies were included: 25 in animals and 15 in humans (2 studies were conducted in both). Most studies used Bifidobacterium (eg, B. longum , B. breve , and B. infantis ) and Lactobacillus (eg, L. helveticus , and L. rhamnosus ), with doses between 10⁸ and 10¹⁰ colony-forming units for 2 weeks in animals and 4 weeks in humans. These probiotics showed efficacy in improving psychiatric disorder-related behaviors including anxiety, depression, autism spectrum disorder (ASD), obsessive-compulsive disorder, and memory abilities, including spatial and non-spatial memory. Because many of the basic science studies showed some efficacy of probiotics on central nervous system function, this background may guide and promote further preclinical and clinical studies. Translating animal studies to human studies has obvious limitations but also suggests possibilities. Here, we provide several suggestions for the translation of animal studies. More experimental designs with both behavioral and neuroimaging measures in healthy volunteers and patients are needed in the future.

Targeted Nanoparticles for Image-guided Treatment of Triple Negative Breast Cancer: Clinical Significance and Technological Advances

PubMed Central

Miller-Kleinhenz, Jasmine M.; Bozeman, Erica N.

2015-01-01

Effective treatment of triple negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and non-invasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise towards the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug-resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention (EPR) effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor associated endothelial cells, stromal fibroblasts and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as others and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. PMID:25966677

Achondroplasia: pathogenesis and implications for future treatment.

PubMed

Laederich, Melanie B; Horton, William A

2010-08-01

Although the genetic defect underlying achondroplasia has been known for over a decade, no effective therapies to stimulate bone growth have emerged. Here we review the recent literature and summarize the molecular mechanisms underlying disease pathology and examine their potential as therapeutic targets. Currently used preclinical models are discussed in the context of recent advances with a special focus on C-type natriuretic peptide. Research on the mutation in Fibroblast Growth Factor Receptor 3 (FGFR3) that causes achondroplasia suggests that disease results from increased signal transduction from the mutant receptor. Thus, current therapeutic strategies have focused on reducing signals emanating from FGFR3. First-generation therapies directly targeting FGFR3, such as kinase inhibitors and neutralizing antibodies, designed for targeting FGFR3 in cancer, are still in the preclinical phase and have yet to translate into the management of achondroplasia. Counteracting signal transduction pathways downstream of FGFR3 holds promise with the discovery that administration of C-type natriuretic peptide to achondroplastic mice ameliorates their clinical phenotype. However, more research into long-term effectiveness and safety of this strategy is needed. Direct targeting of therapeutic agents to growth plate cartilage may enhance efficacy and minimize side effects of these and future therapies. Current research into the pathogenesis of achondroplasia has expanded our understanding of the mechanisms of FGFR3-induced disease and has increased the number of approaches that we may use to potentially correct it. Further research is needed to validate these approaches in preclinical models of achondroplasia.

Mouse brain magnetic resonance microscopy: Applications in Alzheimer disease.

PubMed

Lin, Lan; Fu, Zhenrong; Xu, Xiaoting; Wu, Shuicai

2015-05-01

Over the past two decades, various Alzheimer's disease (AD) trangenetic mice models harboring genes with mutation known to cause familial AD have been created. Today, high-resolution magnetic resonance microscopy (MRM) technology is being widely used in the study of AD mouse models. It has greatly facilitated and advanced our knowledge of AD. In this review, most of the attention is paid to fundamental of MRM, the construction of standard mouse MRM brain template and atlas, the detection of amyloid plaques, following up on brain atrophy and the future applications of MRM in transgenic AD mice. It is believed that future testing of potential drugs in mouse models with MRM will greatly improve the predictability of drug effect in preclinical trials. © 2015 Wiley Periodicals, Inc.

Cell Therapy in Dermatology

PubMed Central

Petrof, Gabriela; Abdul-Wahab, Alya; McGrath, John A.

2014-01-01

Harnessing the regenerative capacity of keratinocytes and fibroblasts from human skin has created new opportunities to develop cell-based therapies for patients. Cultured cells and bioengineered skin products are being used to treat patients with inherited and acquired skin disorders associated with defective skin, and further clinical trials of new products are in progress. The capacity of extracutaneous sources of cells such as bone marrow is also being investigated for its plasticity in regenerating skin, and new strategies, such as the derivation of inducible pluripotent stem cells, also hold great promise for future cell therapies in dermatology. This article reviews some of the preclinical and clinical studies and future directions relating to cell therapy in dermatology, particularly for inherited skin diseases associated with fragile skin and poor wound healing. PMID:24890834

Mesenchymal stem cells and immunomodulation: current status and future prospects

PubMed Central

Gao, F; Chiu, S M; Motan, D A L; Zhang, Z; Chen, L; Ji, H-L; Tse, H-F; Fu, Q-L; Lian, Q

2016-01-01

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy. PMID:26794657

Isolation and characterisation of mesenchymal stem/stromal cells in the ovine endometrium.

PubMed

Letouzey, Vincent; Tan, Ker Sin; Deane, James A; Ulrich, Daniela; Gurung, Shanti; Ong, Y Rue; Gargett, Caroline E

2015-01-01

Mesenchymal stem/stromal cells (MSC) were recently discovered in the human endometrium. These cells possess key stem cell properties and show promising results in small animal models when used for preclinical tissue engineering studies. A small number of surface markers have been identified that enrich for MSC from bone marrow and human endometrium, including the Sushi Domain-containing 2 (SUSD2; W5C5) and CD271 markers. In preparation for developing a large animal preclinical model for urological and gynecological tissue engineering applications we aimed to identify and characterise MSC in ovine endometrium and determine surface markers to enable their prospective isolation. Ovine endometrium was obtained from hysterectomised ewes following progesterone synchronisation, dissociated into single cell suspensions and tested for MSC surface markers and key stem cell properties. Purified stromal cells were obtained by flow cytometry sorting with CD49f and CD45 to remove epithelial cells and leukocytes respectively, and MSC properties investigated. There was a small population CD271+ stromal cells (4.5 ± 2.3%) in the ovine endometrium. Double labelling with CD271 and CD49f showed that the sorted CD271+CD49f- stromal cell population possessed significantly higher cloning efficiency, serial cloning capacity and a qualitative increased ability to differentiate into 4 mesodermal lineages (adipocytic, smooth muscle, chondrocytic and osteoblastic) than CD271-CD49f- cells. Immunolabelling studies identified an adventitial perivascular location for ovine endometrial CD271+ cells. This is the first study to characterise MSC in the ovine endometrium and identify a surface marker profile identifying their location and enabling their prospective isolation. This knowledge will allow future preclinical studies with a large animal model that is well established for pelvic organ prolapse research.

Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group.

PubMed

Corbett, Dale; Carmichael, S Thomas; Murphy, Timothy H; Jones, Theresa A; Schwab, Martin E; Jolkkonen, Jukka; Clarkson, Andrew N; Dancause, Numa; Weiloch, Tadeusz; Johansen-Berg, Heidi; Nilsson, Michael; McCullough, Louise D; Joy, Mary T

2017-08-01

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

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

PubMed

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

2018-02-01

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

Methodological Rigor in Preclinical Cardiovascular Studies

PubMed Central

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

2017-01-01

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields. PMID:28373349

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

PubMed

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

2017-06-09

Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields. © 2017 The Authors.

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

Evaluation of the appropriateness of the preclinical phase (stage A and stage B) of heart failure Management in Outpatient clinics in Italy rationale and design of the 'VASTISSIMO' study.

PubMed

Mureddu, Gian F; Nistri, Stefano; Faggiano, Pompilio; Fimiani, Biagio; Misuraca, Gianfranco; Maggi, Antonio; Gori, Anna M; Uguccioni, Massimo; Tavazzi, Luigi; Zito, Giovanni B

2016-07-01

Early detection of heart failure, when still preclinical, is fundamental. Therefore, it is important to assess whether preclinical heart failure management by cardiologists is adequate. The VASTISSIMO study ('EValuation of the AppropriateneSs of The preclInical phase (Stage A and Stage B) of heart failure Management in Outpatient clinics in Italy') is a prospective nationwide study aimed to evaluate the appropriateness of diagnosis and management of preclinical heart failure (stages A and B) by cardiologists working in outpatient clinics in Italy. Secondary goals are to verify if an online educational course for cardiologists can improve management of preclinical heart failure, and evaluate how well cardiologists are aware of patients' adherence to medications. The study involves 80 outpatient cardiology clinics distributed throughout Italy, affiliated either to the Hospital Cardiologists Association or to the Regional Association of Outpatient Cardiologists, and is designed with two phases of consecutive outpatient enrolment each lasting 1 month. In phase 1, physicians' awareness of the risk of heart failure and their decision-making process are recorded. Subsequently, half of the cardiologists are randomized to undergo an online educational course aimed to improve preclinical heart failure management through implementation of guideline recommendations. At the end of the course, all cardiologists are evaluated (phase 2) to see whether changes in clinical management have occurred in those who underwent the educational program versus those who did not. Patients' adherence to prescribed medications will be assessed through the Morisky Self-report Questionnaire. This study should provide valuable information about cardiologists' awareness of preclinical heart failure and the appropriateness of clinical practice in outpatient cardiology clinics in Italy.

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

PubMed

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

2013-01-01

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

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…

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.

Systematic approaches to toxicology in the zebrafish.

PubMed

Peterson, Randall T; Macrae, Calum A

2012-01-01

As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.

Vitamins and Melanoma

PubMed Central

Russo, Irene; Caroppo, Francesca; Alaibac, Mauro

2015-01-01

A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. PMID:26213971

Advances in clinical NK cell studies: Donor selection, manufacturing and quality control

PubMed Central

Koehl, U.; Kalberer, C.; Spanholtz, J.; Lee, D. A.; Miller, J. S.; Cooley, S.; Lowdell, M.; Uharek, L.; Klingemann, H.; Curti, A.; Leung, W.; Alici, E.

2016-01-01

ABSTRACT Natural killer (NK) cells are increasingly used in clinical studies in order to treat patients with various malignancies. The following review summarizes platform lectures and 2013–2015 consortium meetings on manufacturing and clinical use of NK cells in Europe and United States. A broad overview of recent pre-clinical and clinical results in NK cell therapies is provided based on unstimulated, cytokine-activated, as well as genetically engineered NK cells using chimeric antigen receptors (CAR). Differences in donor selection, manufacturing and quality control of NK cells for cancer immunotherapies are described and basic recommendations are outlined for harmonization in future NK cell studies. PMID:27141397

[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.

A prospective, randomized controlled preclinical trial to evaluate different formulations of biphasic calcium phosphate in combination with a hydroxyapatite collagen membrane to reconstruct deficient alveolar ridges.

PubMed

Nevins, Myron; Nevins, Marc L; Schupbach, Peter; Kim, Soo-Woo; Lin, Zhao; Kim, David M

2013-04-01

Many patients and clinicians would prefer a synthetic particulate bone replacement graft, but most available alloplastic biomaterials have limited osteogenic potential. An alloplast with increased regenerative capacity would be advantageous for the treatment of localized alveolar ridge defects. This prospective, randomized controlled preclinical trial utilized 6 female foxhounds to analyze the osteogenic impact of different formulations of biphasic calcium phosphate (BCP) in combination with an hydroxyapatite-collagen membrane and their ability to reconstruct deficient alveolar ridges for future implant placement. The grafted sites were allowed to heal 3 months, and then trephine biopsies were obtained to perform light microscopic and histomorphometric analyses. All treated sites healed well with no early membrane exposure or adverse soft tissue responses during the healing period. The grafted sites exhibited greater radiopacity than the surrounding native bone with BCP particles seen as radiopaque granules. The graft particles appeared to be well-integrated and no areas of loose particles were observed. Histologic evaluation demonstrated BCP particles embedded in woven bone with dense connective tissue/marrow space. New bone growth was observed around the graft particles as well as within the structure of the graft particulate. There was intimate contact between the graft particles and newly formed bone, and graft particles were bridged by the newly formed bone in all biopsies from the tested groups. The present study results support the potential of these BCP graft particulates to stimulate new bone formation. Clinical studies are recommended to confirm these preclinical findings.

Understanding Medical Students' Experience with Stress and Its Related Constructs: A Focus Group Study from Singapore.

PubMed

Farquhar, Julia; Lie, Desiree; Chan, Angelique; Ow, Mandy; Vidyarthi, Arpana

2018-02-01

In order to protect medical students from burnout and its untoward psychiatric effects, it is imperative to understand their stress, burnout, coping, and resilience experiences. This study aimed to derive collective definitions from the medical student perspective, to identify common themes of students' experiences, and to distinguish pre-clinical and clinical year students' experiences relating to these four constructs. The authors conducted focus groups of medical students in Singapore across 4 years using a semi-structured question guide. Participants shared their understanding, experiences, and the relationships between stress, burnout, coping, and resilience. Coders independently evaluated construct definitions and derived common themes through an iterative process, and compared transcripts of pre-clinical and clinical year students to determine differences in experience over time. Nine focus groups (54 students, 28 females, mean age 24.3) were conducted. Students identified common definitions for each construct. Nine themes emerged within three domains: (1) relating constructs to personal experience, (2) interrelating stress, burnout, coping, and resilience, and (3) understanding the necessity of stress. Compared to clinical students, pre-clinical students reported theory-based rather than reality-based experiences and exam-induced stress, defined constructs using present rather than future situations, and described constructs as independent rather than interrelated. This sample of medical students in Singapore shares a common understanding of stress, burnout, coping, and resilience, but experiences these uniquely. They perceive a positive role for stress. These findings build upon prior literature, suggesting an interrelationship between stress and its related constructs and adding the novel perspective of students from an Asian country.

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.

Magnetic Resonance Guided Focused Ultrasound Surgery: Part 2 – A Review of Current and Future Applications

PubMed Central

Medel, Ricky; Monteith, Stephen J.; Elias, W. Jeffrey; Eames, Matthew; Snell, John; Sheehan, Jason P.; Wintermark, Max; Jolesz, Ferenc A.; Kassell, Neal F.

2014-01-01

Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) represents a novel combination of technologies that is actively being realized as a non-invasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological utilization. A combined search of Pubmed and Medline was performed to identify the key events and current status of MRgFUS, with a focus on neurological applications. MRgFUS signifies a potentially ideal device for the treatment of neurological diseases. As it is nearly real-time, it allows monitored provision of treatment location and energy deposition, is noninvasive, thereby limiting or eliminating disruption of normal tissue, provides focal delivery of therapeutic agents, enhances radiation delivery, and permits modulation of neural function. Multiple clinical applications are currently in clinical use and many more are under active preclinical investigation. The therapeutic potential of MRgFUS is expanding rapidly. Although clinically in its infancy, preclinical and early phase I clinical trials in neurosurgery suggest a promising future for MRgFUS. Further investigation is necessary to define its true potential and impact. PMID:22791029

Benefits of Case-Based versus Traditional Lecture-Based Instruction in a Preclinical Removable Prosthodontics Course.

PubMed

Samuelson, David B; Divaris, Kimon; De Kok, Ingeborg J

2017-04-01

This study compared the acceptability and relative effectiveness of case-based learning (CBL) versus traditional lecture-based (LB) instruction in a preclinical removable prosthodontics course in the University of North Carolina at Chapel Hill School of Dentistry DDS curriculum. The entire second-year class (N=82) comprised this crossover study's sample. Assessments of baseline comprehension and confidence in removable partial denture (RPD) treatment planning were conducted at the beginning of the course. Near the end of the course, half of the class received CBL and LB instruction in an RPD module in alternating sequence, with students serving as their own control group. Assessments of perceived RPD treatment planning efficacy, comprehension, and instruction method preference were administered directly after students completed the RPD module and six months later. Analyses of variance accounting for period, carryover, and sequence effects were used to determine the relative effects of each approach using a p<0.05 statistical significance threshold. The results showed that the students preferred CBL (81%) over LB instruction (9%), a pattern that remained unchanged after a six-month period. Despite notable period and carryover effects, CBL was also associated with higher gains in RPD treatment planning comprehension (p=0.04) and perceived efficacy (p=0.01) compared to LB instruction. These gains diminished six months after the course-a finding based on a 49% follow-up response rate. Overall, the students overwhelmingly preferred CBL to LB instruction, and the findings suggest small albeit measurable educational benefits associated with CBL. This study's findings support the introduction and further testing of CBL in the preclinical dental curriculum, in anticipation of possible future benefits evident during clinical training.

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.

Clinical skills development in student-run free clinic volunteers: a multi-trait, multi-measure study.

PubMed

Nakamura, Mio; Altshuler, David; Chadwell, Margit; Binienda, Juliann

2014-12-12

At Wayne State University School of Medicine (WSU SOM), the Robert R. Frank Student Run Free Clinic (SRFC) is one place preclinical students can gain clinical experience. There have been no published studies to date measuring the impact of student-run free clinic (SRFC) volunteerism on clinical skills development in preclinical medical students. Surveys were given to first year medical students at WSU SOM at the beginning and end of Year 1 to assess perception of clinical skills, including self-confidence, self-reflection, and professionalism. Scores of the Year 1 Objective Structured Clinical Exam (OSCE) were compared between SRFC volunteers and non-volunteers. There were a total of 206 (68.2%) and 80 (26.5%) survey responses at the beginning and end of Year 1, respectively. Of the 80 students, 31 (38.7%) volunteered at SRFC during Year 1. Statistically significant differences were found between time points in self-confidence (p < 0.001) in both groups. When looking at self-confidence in skills pertaining to SRFC, the difference between groups was statistically significant (p = 0.032) at both time points. A total of 302 students participated in the Year 1 OSCE, 27 (9%) of which were SRFC volunteers. No statistically significant differences were found between groups for mean score (p = 0.888) and established level of rapport (p = 0.394). While this study indicated no significant differences in clinical skills in students who volunteer at the SRFC, it is a first step in attempting to measure clinical skill development outside of the structured medical school setting. The findings lend themselves to development of research designs, clinical surveys, and future studies to measure the impact of clinical volunteer opportunities on clinical skills development in future physicians.

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.

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.

Role of self-efficacy and anxiety among pre-clinically disabled older adults when using compensatory strategies to complete daily tasks

PubMed Central

Higgins, Torrance J.; Janelle, Christopher M.; Naugle, Kelly M.; Knaggs, Jeffrey; Hoover, Brian M.; Marsiske, Michael; Manini, Todd M.

2012-01-01

Classic developmental theory suggests that aging is associated with using compensatory strategies to prolong independence. While compensatory strategies are typically considered positive adaptations, they also signify an early phase in the disablement process — commonly known as pre-clinical disability. To build a better understanding of psychological constructs related to these early signs of disability, we examined the contribution of self-efficacy and state anxiety on using compensatory strategies among pre-clinically disabled older adults. Compensatory strategies were observed during performance of daily activities in 257 pre-clinically disabled older adults (67.6 ± 7.04), and self-efficacy and state anxiety were evaluated prior to performing each task. In univariate models, lower self-efficacy and higher anxiety were associated with more compensation (Spearman correlations: 0.15-0.48, p < 0.05). Multivariate logistic regression indicated that low self-efficacy [Odds Ratio (OR): 1.70; 95% Confidence Interval (CI): 1.40-2.08) and high anxiety (OR: 1.34; 95% CI: 1.10-1.63) were positively associated with using ≥ 6 compensatory strategies – a level signifying substantial compensation. When considered jointly with self-efficacy, the association with anxiety was reversed— higher anxiety demonstrated a lower likelihood of using compensation (OR: 0.70-0.73; 95% CI: 0.50-0.99). The addition of self-efficacy might remove the self-defeating cognitions characterizing anxiety allowing the remaining arousal component to appear beneficial. In conclusion, lower self-efficacy and higher anxiety are associated with using compensation to complete daily tasks among pre-clinically disabled older adults. Such psychological constructs may contribute to the use of compensatory strategies and represent future intervention targets to help reduce early signs of disability. PMID:22770713

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

PubMed

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

2016-01-01

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

Terminal-decline effects for select cognitive tasks after controlling for preclinical dementia.

PubMed

Laukka, Erika J; MacDonald, Stuart W S; Bäckman, Lars

2008-05-01

In a previous study, the authors found no accelerated decline in close proximity to death for a measure of global cognitive functioning, after excluding persons in a preclinical phase of dementia. However, specific cognitive tasks might be more sensitive to terminal-decline effects. The purpose of this study was to explore possible terminal-decline effects for a range of cognitive tasks after controlling for preclinical dementia. Community-based cohort study. The Kungsholmen district of Stockholm. A total of 585 persons (75+ years) were repeatedly assessed over an 11-year period. Level and change in cognitive performance were compared for three groups: persons in close proximity to death, persons in a preclinical phase of dementia, and persons who remained alive and nondemented throughout the study. Tasks assessing primary and episodic memory, verbal ability, and visuospatial skill. Compared with an analysis where all dead subjects were included in the impending-death group, removing the preclinical dementia cases resulted in markedly attenuated mortality-related effects. However, the impending-death group still declined at a faster rate relative to the comparison group on Digit Span-forward, word recognition, and category fluency. Notably, these were tasks for which the comparison group showed no significant decline. A considerable proportion of the terminal-decline effect is accounted for by the impact of preclinical dementia. However, for tasks that are relatively resistant to age-related change, such effects might be detected independently of preclinical dementia.

A technical feasibility study of surfactant-free drug suspensions using octenyl succinate-modified starches.

PubMed

Kuentz, Martin; Egloff, Peter; Röthlisberger, Dieter

2006-05-01

Many new drugs exhibit poor wetting behaviour and low aqueous solubility. This is particularly an issue for preclinical studies like toxicological trials, in which considerably higher doses and volumes are being administered compared to clinical studies. Preclinical vehicles typically contain high levels of surfactants that can exert biological effects. However, the biological inertness of vehicles is pivotal for the application in preclinical studies stressing the need in finding new excipients to solve formulation problems of today's drug discovery. The present study investigated the technical feasibility of surfactant-free suspensions using a new poorly soluble drug as model. It was shown that octenyl succinate-modified starches adequately wetted the drug and homogenous tasteless suspensions were obtained. The polymer xanthan gum was identified as macroscopically compatible gelling agent. Concentration effects of xanthan, drug and different modified starches were studied in a D-optimal design with respect to rheological properties. The suspensions were also tested in an analytical centrifuge using NIR transmission profiles to obtain a measure of sedimentation stability under accelerated conditions. The modified starches exhibited only little influence on the viscosity as well as on the yield point in contrast to the rheological effects of xanthan gum. This gelling agent was the main stabilising excipient as the modified starches hindered to a lesser extent sedimentation. The most stable suspensions displayed convenient flow properties. The viscosity at 100 s(-1) and 25 degrees C was in technically acceptable range of 120-140 mPa s in view of a application via gavage or a syringe in animal studies. The results demonstrated that surfactant-free drug suspensions with excellent technical performance can be obtained using octenyl succinate-modified starches. The vehicles were tasteless and based on the experience of modified starches in the food industry, the vehicles should exhibit good tolerability. The future use of such surfactant-free drug suspensions in toxicological, pharmacokinetic and pharmacodynamic studies will have to determine their advantage in terms of biological inertness.

Dose-dependent Toxicity of Humanized Renilla reniformis GFP (hrGFP) Limits Its Utility as a Reporter Gene in Mouse Muscle.

PubMed

Wallace, Lindsay M; Moreo, Andrew; Clark, K Reed; Harper, Scott Q

2013-04-16

Gene therapy has historically focused on delivering protein-coding genes to target cells or tissues using a variety of vectors. In recent years, the field has expanded to include gene-silencing strategies involving delivery of noncoding inhibitory RNAs, such as short hairpin RNAs or microRNAs (miRNAs). Often called RNA interference (RNAi) triggers, these small inhibitory RNAs are difficult or impossible to visualize in living cells or tissues. To circumvent this detection problem and ensure efficient delivery in preclinical studies, vectors can be engineered to coexpress a fluorescent reporter gene to serve as a marker of transduction. In this study, we set out to optimize adeno-associated viral (AAV) vectors capable of delivering engineered miRNAs and green fluorescent protein (GFP) reporter genes to skeletal muscle. Although the more broadly utilized enhanced GFP (eGFP) gene derived from the jellyfish, Aequorea victoria was a conventional choice, we were concerned about some previous studies suggesting this protein was myotoxic. We thus opted to test vectors carrying the humanized Renilla reniformis-derived GFP (hrGFP) gene, which has not seen as extensive usage as eGFP but was purported to be a safer and less cytotoxic alternative. Employing AAV6 vector dosages typically used in preclinical gene transfer studies (3×10(10) -1 × 10(11) particles), we found that hrGFP caused dose-dependent myopathy when delivered to wild-type (wt) mouse muscle, whereas identical titers of AAV6 carrying eGFP were relatively benign. Dose de-escalation at or below 8 × 10(9) AAV particles effectively reduced or eliminated hrGFP-associated myotoxicity, but also had dampening effects on green fluorescence and miRNA-mediated gene silencing in whole muscles. We conclude that hrGFP is impractical for use as a transduction marker in preclinical, AAV-based RNA interference therapy studies where adult mouse muscle is the target organ. Moreover, our data support that eGFP is superior to hrGFP as a reporter gene in mouse muscle. These results may impact the design of future preclinical gene therapy studies targeting muscles and non-muscle tissues alike.Molecular Therapy - Nucleic Acids (2013) 2, e86; doi:10.1038/mtna.2013.16; published online 16 April 2013.

The study design elements employed by researchers in preclinical animal experiments from two research domains and implications for automation of systematic reviews.

PubMed

O'Connor, Annette M; Totton, Sarah C; Cullen, Jonah N; Ramezani, Mahmood; Kalivarapu, Vijay; Yuan, Chaohui; Gilbert, Stephen B

2018-01-01

Systematic reviews are increasingly using data from preclinical animal experiments in evidence networks. Further, there are ever-increasing efforts to automate aspects of the systematic review process. When assessing systematic bias and unit-of-analysis errors in preclinical experiments, it is critical to understand the study design elements employed by investigators. Such information can also inform prioritization of automation efforts that allow the identification of the most common issues. The aim of this study was to identify the design elements used by investigators in preclinical research in order to inform unique aspects of assessment of bias and error in preclinical research. Using 100 preclinical experiments each related to brain trauma and toxicology, we assessed design elements described by the investigators. We evaluated Methods and Materials sections of reports for descriptions of the following design elements: 1) use of comparison group, 2) unit of allocation of the interventions to study units, 3) arrangement of factors, 4) method of factor allocation to study units, 5) concealment of the factors during allocation and outcome assessment, 6) independence of study units, and 7) nature of factors. Many investigators reported using design elements that suggested the potential for unit-of-analysis errors, i.e., descriptions of repeated measurements of the outcome (94/200) and descriptions of potential for pseudo-replication (99/200). Use of complex factor arrangements was common, with 112 experiments using some form of factorial design (complete, incomplete or split-plot-like). In the toxicology dataset, 20 of the 100 experiments appeared to use a split-plot-like design, although no investigators used this term. The common use of repeated measures and factorial designs means understanding bias and error in preclinical experimental design might require greater expertise than simple parallel designs. Similarly, use of complex factor arrangements creates novel challenges for accurate automation of data extraction and bias and error assessment in preclinical experiments.

Reproducibility2020: Progress and priorities

PubMed Central

Freedman, Leonard P.; Venugopalan, Gautham; Wisman, Rosann

2017-01-01

The preclinical research process is a cycle of idea generation, experimentation, and reporting of results. The biomedical research community relies on the reproducibility of published discoveries to create new lines of research and to translate research findings into therapeutic applications. Since 2012, when scientists from Amgen reported that they were able to reproduce only 6 of 53 “landmark” preclinical studies, the biomedical research community began discussing the scale of the reproducibility problem and developing initiatives to address critical challenges. Global Biological Standards Institute (GBSI) released the “Case for Standards” in 2013, one of the first comprehensive reports to address the rising concern of irreproducible biomedical research. Further attention was drawn to issues that limit scientific self-correction, including reporting and publication bias, underpowered studies, lack of open access to methods and data, and lack of clearly defined standards and guidelines in areas such as reagent validation. To evaluate the progress made towards reproducibility since 2013, GBSI identified and examined initiatives designed to advance quality and reproducibility. Through this process, we identified key roles for funders, journals, researchers and other stakeholders and recommended actions for future progress. This paper describes our findings and conclusions. PMID:28620458

Preclinical drug development.

PubMed

Brodniewicz, Teresa; Grynkiewicz, Grzegorz

2010-01-01

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

Therapeutic Vaccination for HPV Induced Cervical Cancers

PubMed Central

Brinkman, Joeli A.; Hughes, Sarah H.; Stone, Pamela; Caffrey, Angela S.; Muderspach, Laila I.; Roman, Lynda D.; Weber, Jeffrey S.; Kast, W. Martin

2007-01-01

Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence. PMID:17627067

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

PubMed Central

Jevtovic-Todorovic, V.; Absalom, A. R.; Blomgren, K.; Brambrink, A.; Crosby, G.; Culley, D. J.; Fiskum, G.; Giffard, R. G.; Herold, K. F.; Loepke, A. W.; Ma, D.; Orser, B. A.; Planel, E.; Slikker, W.; Soriano, S. G.; Stratmann, G.; Vutskits, L.; Xie, Z.; Hemmings, H. C.

2013-01-01

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. PMID:23722106

Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.

PubMed

Yatuv, Rivka; Robinson, Micah; Dayan, Inbal; Baru, Moshe

2010-02-01

Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases. Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa. The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed. PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy

PubMed Central

Myers, Stephanie M.; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anti-cancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms, and explore the implications for future anticancer drug development against these targets. PMID:26976726

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy.

PubMed

Myers, Stephanie M; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anticancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms and explore the implications for future anticancer drug development against these targets.

Biological Therapies: Effects of Proinflammatory Pathways and their Inhibition on the Myocardium of Rheumatoid Athritis Patients.

PubMed

Obermair, Florian; Pieringer, Herwig

2015-01-01

The elevated risk of heart failure (HF) in rheumatoid arthritis (RA) is considered to be partly caused by the chronic low-grade systemic inflammation. As potent suppressors of inflammation, biologics were expected to influence HF development in RA. Unfortunately, case reports of HF in RA patients and non-RA HF studies have suggested that these drugs may even increase HF rates in RA. With this review we want to provide insight into the molecular mechanisms by which elevated cytokines, immune cell alterations and biologics influence myocardial function in RA patients. Beside preclinical data, clinical studies that assess the influence of biologics on HF development are reviewed. Preclinical studies suggest a bidirectional role of the investigated cytokines (TNF-alpha, IL- 1, IL-6) on myocardial function. Common mechanisms of immune cell alterations in HF and RA have been observed in preclinical studies. High doses of infliximab in non-RA patients with HF were found to be harmful. The vast majority of retrospective studies suggest that TNF-alpha inhibitors do not increase the risk of HF development in RA patients. Nevertheless randomized controlled trials are missing and TNF-alpha inhibitors are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II based on non-RA HF studies. Due to rare adverse events of HF, rituximab is contraindicated in RA patients with HF NYHA IV. Cytokines seem to have a bidirectional influence on HF development in RA. According to the published evidence it is unlikely that TNFalpha inhibitors substantially increase the risk of HF development in an RA population. Nevertheless they are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II. The influence of anakinra, tocilizumab, rituximab and abatacept needs to be investigated in future studies.

Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances.

PubMed

Miller-Kleinhenz, Jasmine M; Bozeman, Erica N; Yang, Lily

2015-01-01

Effective treatment of triple-negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle-based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor-associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in-depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. © 2015 Wiley Periodicals, Inc.

Bone Tissue Engineering Under Xenogeneic-Free Conditions in a Large Animal Model as a Basis for Early Clinical Applicability.

PubMed

Weigand, Annika; Beier, Justus P; Schmid, Rafael; Knorr, Tobias; Kilian, David; Götzl, Rebekka; Gerber, Thomas; Horch, Raymund E; Boos, Anja M

2017-03-01

For decades, researchers have been developing a range of promising strategies in bone tissue engineering with the aim of producing a significant clinical benefit over existing therapies. However, a major problem concerns the traditional use of xenogeneic substances for the expansion of cells, which complicates direct clinical transfer. The study's aim was to establish a totally autologous sheep model as a basis for further preclinical studies and future clinical application. Ovine mesenchymal stromal cells (MSC) were cultivated in different concentrations (0%, 2%, 5%, 10%, and 25%) of either autologous serum (AS) or fetal calf serum (FCS). With an increase of serum concentration, enhanced metabolic activity and proliferation could be observed. There were minor differences between MSC cultivated in AS or FCS, comparing gene and protein expression of osteogenic and stem cell markers, morphology, and osteogenic differentiation. MSC implanted subcutaneously in the sheep model, together with a nanostructured bone substitute, either in stable block or moldable putty form, induced similar vascularization and remodeling of the bone substitute irrespective of cultivation of MSC in AS or FCS and osteogenic differentiation. The bone substitute in block form together with MSC proved particularly advantageous in the induction of ectopic bone formation compared to the cell-free control and putty form. It could be demonstrated that AS is suitable for replacement of FCS for cultivation of ovine MSC for bone tissue engineering purposes. Substantial progress has been made in the development of a strictly xenogeneic-free preclinical animal model to bring future clinical application of bone tissue engineering strategies within reach.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

PubMed Central

Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesús, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; Auladell, Carme; Camins, Antoni

2017-01-01

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered. PMID:29254093

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

PubMed

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

2015-04-01

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

Evaluating the interaction of a tracheobronchial stent in an ovine in-vivo model.

PubMed

McGrath, Donnacha J; Thiebes, Anja Lena; Cornelissen, Christian G; O'Brien, Barry; Jockenhoevel, Stefan; Bruzzi, Mark; McHugh, Peter E

2018-04-01

Tracheobronchial stents are used to restore patency to stenosed airways. However, these devices are associated with many complications such as stent migration, granulation tissue formation, mucous plugging and stent strut fracture. Of these, granulation tissue formation is the complication that most frequently requires costly secondary interventions. In this study a biomechanical lung modelling framework recently developed by the authors to capture the lung in-vivo stress state under physiological loading is employed in conjunction with ovine pre-clinical stenting results and device experimental data to evaluate the effect of stent interaction on granulation tissue formation. Stenting is simulated using a validated model of a prototype covered laser-cut tracheobronchial stent in a semi-specific biomechanical lung model, and physiological loading is performed. Two computational methods are then used to predict possible granulation tissue formation: the standard method which utilises the increase in maximum principal stress change, and a newly proposed method which compares the change in contact pressure over a respiratory cycle. These computational predictions of granulation tissue formation are then compared to pre-clinical stenting observations after a 6-week implantation period. Experimental results of the pre-clinical stent implantation showed signs of granulation tissue formation both proximally and distally, with a greater proximal reaction. The standard method failed to show a correlation with the experimental results. However, the contact change method showed an apparent correlation with granulation tissue formation. These results suggest that this new method could be used as a tool to improve future device designs.

Reproducibility of preclinical animal research improves with heterogeneity of study samples

PubMed Central

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

2018-01-01

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

From Theory to Application: A Study of Knowledge Transfer in Dental Education

ERIC Educational Resources Information Center

Peltz, Ivy D.

2014-01-01

Traditionally, dental education is divided into two phases: pre-clinical and clinical education. The pre-clinical phase of dental education includes the assimilation of theoretical topical knowledge in addition to the completion of simulated exercises. Upon completion of and demonstration of competency in their pre-clinical courses, students begin…

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

Tracking stem cell migration and survival in brain injury: current approaches and future prospects.

PubMed

Darkazalli, Ali; Levenson, Cathy W

2012-10-01

In recent years, stem cell-mediated therapies have gained considerable ground as potential treatments for a wide variety of brain pathologies including traumatic brain injury, stroke and neurodegenerative diseases. Despite extensive preclinical studies, many of these therapies have not been fully translated into viable clinical approaches. This is partly due to our inability to reliably track and monitor transplanted stem cells longitudinally over long periods of time in vivo. In this review, we discuss the predominant histological cell tracing methodologies, such as immunohistochemistry, and fluorescent cellular dyes and proteins, and compare them to emerging cellular imaging technologies. We show that advances in magnetic resonance imaging (MRI) have resulted in opportunities to use this technology to further our understanding of stem cell characteristics and behaviors in vivo. While MRI may not completely replace conventional cell tracking methods in pre-clinical, mechanistic work, it is clear that it has the potential to function as a powerful diagnostic tool for tracking stem cell migration and survival as well as for evaluating the efficacy of stem cell-mediated therapies.

Review of SPECT collimator selection, optimization, and fabrication for clinical and preclinical imaging

PubMed Central

Van Audenhaege, Karen; Van Holen, Roel; Vandenberghe, Stefaan; Vanhove, Christian; Metzler, Scott D.; Moore, Stephen C.

2015-01-01

In single photon emission computed tomography, the choice of the collimator has a major impact on the sensitivity and resolution of the system. Traditional parallel-hole and fan-beam collimators used in clinical practice, for example, have a relatively poor sensitivity and subcentimeter spatial resolution, while in small-animal imaging, pinhole collimators are used to obtain submillimeter resolution and multiple pinholes are often combined to increase sensitivity. This paper reviews methods for production, sensitivity maximization, and task-based optimization of collimation for both clinical and preclinical imaging applications. New opportunities for improved collimation are now arising primarily because of (i) new collimator-production techniques and (ii) detectors with improved intrinsic spatial resolution that have recently become available. These new technologies are expected to impact the design of collimators in the future. The authors also discuss concepts like septal penetration, high-resolution applications, multiplexing, sampling completeness, and adaptive systems, and the authors conclude with an example of an optimization study for a parallel-hole, fan-beam, cone-beam, and multiple-pinhole collimator for different applications. PMID:26233207

Integrating Hyperthermia into Modern Radiation Oncology: What Evidence Is Necessary?

PubMed Central

Peeken, Jan C.; Vaupel, Peter; Combs, Stephanie E.

2017-01-01

Hyperthermia (HT) is one of the hot topics that have been discussed over decades. However, it never made its way into primetime. The basic biological rationale of heat to enhance the effect of radiation, chemotherapeutic agents, and immunotherapy is evident. Preclinical work has confirmed this effect. HT may trigger changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses. Despite the increasing number of solid clinical studies, only few centers have included this adjuvant treatment into their repertoire. Over the years, abundant prospective and randomized clinical data have emerged demonstrating a clear benefit of combined HT and radiotherapy for multiple entities such as superficial breast cancer recurrences, cervix carcinoma, or cancers of the head and neck. Regarding less investigated indications, the existing data are promising and more clinical trials are currently recruiting patients. How do we proceed from here? Preclinical evidence is present. Multiple indications benefit from additional HT in the clinical setting. This article summarizes the present evidence and develops ideas for future research. PMID:28713771

Current status and future perspectives of sonodynamic therapy in glioma treatment.

PubMed

Wang, Xiaobing; Jia, Yali; Wang, Pan; Liu, Quanhon; Zheng, Hairong

2017-07-01

Malignant glioma is one of the most challenging central nervous system diseases to treat, and has high rates of recurrence and mortality. The current therapies include surgery, radiation therapy, and chemotherapy, although these approaches often failed to control tumor progression or improve patient survival. Sonodynamic therapy is a developing cancer treatment that uses ultrasound combined with a sonosensitizer to synergistically kill tumor cells, and has provided impressive results in both in vitro and in vivo studies. The ultrasound waves can penetrate deep tissues and reversibly open the blood-brain barrier to enhance drug delivery to the brain. Thus, sonodynamic therapy has a promising potential in glioma treatment. In this review, we summarize the studies that have confirmed the pre-clinical efficacy of sonodynamic therapy for glioma treatment, and discuss the future directions for this emerging treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Current and Future Clinical Applications of High-Intensity Focused Ultrasound (HIFU) for Pancreatic Cancer.

PubMed

Jang, Hyun Joo; Lee, Jae-Young; Lee, Don-Haeng; Kim, Won-Hong; Hwang, Joo Ha

2010-09-01

High-intensity focused ultrasound (HIFU) is a novel therapeutic modality that permits noninvasive treatment of various benign and malignant solid tumors, including prostatic cancer, uterine fibroids, hepatic tumors, renal tumors, breast cancers, and pancreatic cancers. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumors, including pancreatic cancer. The results of nonrandomized studies of HIFU therapy in patients with pancreatic cancer have suggested that HIFU treatment can effectively alleviate cancer-related pain without any significant complications. This noninvasive method of delivering ultrasound energy into the body has recently been evolving from a method for purely thermal ablation to harnessing the mechanical effects of HIFU to induce a systemic immune response and to enhance targeted drug delivery. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges.

Current and Future Clinical Applications of High-Intensity Focused Ultrasound (HIFU) for Pancreatic Cancer

PubMed Central

Jang, Hyun Joo; Lee, Jae-Young; Lee, Don-Haeng; Kim, Won-Hong

2010-01-01

High-intensity focused ultrasound (HIFU) is a novel therapeutic modality that permits noninvasive treatment of various benign and malignant solid tumors, including prostatic cancer, uterine fibroids, hepatic tumors, renal tumors, breast cancers, and pancreatic cancers. Several preclinical and clinical studies have investigated the safety and efficacy of HIFU for treating solid tumors, including pancreatic cancer. The results of nonrandomized studies of HIFU therapy in patients with pancreatic cancer have suggested that HIFU treatment can effectively alleviate cancer-related pain without any significant complications. This noninvasive method of delivering ultrasound energy into the body has recently been evolving from a method for purely thermal ablation to harnessing the mechanical effects of HIFU to induce a systemic immune response and to enhance targeted drug delivery. This review provides a brief overview of HIFU, describes current clinical applications of HIFU for pancreatic cancer, and discusses future applications and challenges. PMID:21103296

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.

Achieving Biocompatible SABRE: An in vitro Cytotoxicity Study

PubMed Central

Manoharan, Anand; Rayner, Peter J.; Iali, Wissam; Burns, Michael J.; Perry, V. Hugh

2018-01-01

Abstract Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using in vitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion‐exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future in vivo study. PMID:29232489

Regulatory considerations on new adjuvants and delivery systems.

PubMed

Sesardic, D

2006-04-12

New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

[Preclinical and clinical management after mass disaster : Experiences from the train collision in Bad Aibling on 9 February 2016].

PubMed

Regel, G; Bracht, M; Huth, M; Maier, K J; Böcker, W

2016-06-01

Mass casualty incidents (MCI) in this day and age represent a special challenge, which initially require on-site coordination and logistics and then a professional distribution of victims (triage) to surrounding hospitals. Technical, logistical and even specialist errors can impair this flow of events. It therefore seems advisable to make a detailed analysis of every MCI. In this article the railway incident from 9 February 2016 is analyzed taking the preclinical and clinical cirumstances into consideration and conclusions for future management are drawn. As a special entity it could be determined that fixed table units in passenger trains represent a particularly dangerous hazard and in many instances in this analysis led to characteristic abdominal and thoracic injuries.

How Can Gastric Cancer Molecular Profiling Guide Future Therapies?

PubMed

Corso, Simona; Giordano, Silvia

2016-07-01

Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Where VC Fears To Tread

PubMed Central

MULLEN, PATRICK

2007-01-01

In recent years, venture capitalists have been less willing to place bets on pre-clinical technologies. Major drug manufacturers, flush with cash but increasingly bereft of blockbusters, are stepping into the breach. So are established biotech companies. Here’s a look at how the changing sources and timing of investments are helping to shape biotech’s future. PMID:22478674

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

PubMed Central

Kimmelman, Jonathan; Henderson, Valerie C.

2015-01-01

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

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

PubMed Central

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

2017-01-01

Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1 % had lesions resembling proximal MCA or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. Conclusions ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

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

PubMed Central

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

2016-01-01

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

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.

PubMed

Carman, A J; Dacks, P A; Lane, R F; Shineman, D W; Fillit, H M

2014-04-01

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

Effects of Brief Psychoeducational Program on Stigma in Malaysian Pre-clinical Medical Students: A Randomized Controlled Trial.

PubMed

Fernandez, Aaron; Tan, Kit-Aun; Knaak, Stephanie; Chew, Boon How; Ghazali, Sazlina Shariff

2016-12-01

If presented with serious mental illness (SMI), individuals' low help-seeking behaviors and poor adherence to treatment are associated with negative stereotypes and attitudes of healthcare providers. In this study, we examined the effects of a brief psychoeducational program on reducing stigma in pre-clinical medical students. One hundred and two pre-clinical medical students (20-23 years old) were randomly assigned to face-to-face contact + educational lecture (n = 51) condition or video-based contact + educational lecture (n = 51) condition. Measures of pre-clinical medical students' mental illness-related stigma using the Opening Minds Stigma Scale for Health Care Providers (OMS-HC) were administered at pre-, post-treatment, and 1-month follow-up. A 2 (condition: face-to-face contact + educational lecture, video-based contact + educational lecture) by 3 (time: pre-treatment, post-treatment, and 1-month follow-up) mixed model MANOVA was conducted on the Attitudes, Disclosure and Help-Seeking, and Social Distance OMS-HC subscales. Participants' scores on all subscales changed significantly across time, regardless of conditions. To determine how participants' scores changed significantly over time on each subscale, Bonferroni follow-up comparisons were performed to access pairwise differences for the main effect of time. Specifically, pairwise comparisons produced a significant reduction in Social Distance subscale between pre-treatment and post-treatment and between pre-treatment and 1-month follow-up, and a significant increase between post-treatment and 1-month follow-up, regardless of conditions. With respect to the Attitudes and Disclosure and Help-Seeking subscales, pairwise comparisons produced a significant reduction in scores between pre-treatment and post-treatment and a significant increase between post-treatment and 1-month follow-up. Our findings provide additional evidence that educational lecture on mental illness, coupled with either face-to-face contact or video-based contact, is predictive of positive outcomes in anti-stigma programs targeting future healthcare providers.

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

PubMed

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

2016-09-01

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

The 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.

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

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

PubMed

Steward, Oswald; Balice-Gordon, Rita

2014-11-05

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

Assessment of the clinical cardiac drug-drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys.

PubMed

Regan, Christopher P; Morissette, Pierre; Regan, Hillary K; Travis, Jeffery J; Gerenser, Pamela; Wen, Jianzhong; Fitzgerald, Kevin; Gruver, Shaun; DeGeorge, Joseph J; Sannajust, Frederick J

2016-11-01

In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia/bradyarrhythmia in hepatitis C virus (HCV)-infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical in vivo models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug-drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO-dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO-dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK-3682 was completed after AMIO pretreatment. These are the first preclinical in vivo experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential in vivo mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective in vivo cardiac electrophysiological effect, these data enable targeted cellular/molecular mechanistic studies to more precisely identify cell types, receptors, and/or ion channels responsible for the clinical DDI. (Hepatology 2016;64:1430-1441). © 2016 by the American Association for the Study of Liver Diseases.

Natural Killer T Cells in Cancer Immunotherapy

PubMed Central

Nair, Shiny; Dhodapkar, Madhav V.

2017-01-01

Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy. PMID:29018445

Current state and future prospects of immunotherapy for glioma.

PubMed

Kamran, Neha; Alghamri, Mahmoud S; Nunez, Felipe J; Shah, Diana; Asad, Antonela S; Candolfi, Marianela; Altshuler, David; Lowenstein, Pedro R; Castro, Maria G

2018-02-01

There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy.

The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies.

PubMed

Kang, Chang Moo; Babicky, Michele L; Lowy, Andrew M

2014-03-01

Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is overexpressed in the majority of pancreatic cancers. Preclinical studies show that inhibition of RON function decreases pancreatic cancer cell migration, invasion, and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target.

A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

PubMed Central

Mota, Jose Mauricio; Collier, Katharine Ann; Barros Costa, Ricardo Lima; Taxter, Timothy; Kalyan, Aparna; Leite, Caio A.; Chae, Young Kwang; Giles, Francis J.; Carneiro, Benedito A.

2017-01-01

Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future. PMID:29179520

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.

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

A Naturalistic Study of Driving Behavior in Older Adults and Preclinical Alzheimer Disease.

PubMed

Babulal, Ganesh M; Stout, Sarah H; Benzinger, Tammie L S; Ott, Brian R; Carr, David B; Webb, Mollie; Traub, Cindy M; Addison, Aaron; Morris, John C; Warren, David K; Roe, Catherine M

2017-01-01

A clinical consequence of symptomatic Alzheimer's disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with ( n = 10) and without ( n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

Identification of potential or preclinical cognitive impairment and the implications of sophisticated screening with biomarkers and cognitive testing: does it really matter?

PubMed

Gordon, Michael

2013-01-01

The last decade has seen an enormous growth in the interest in the recognition of and intervention in those diagnosed and living with the whole range of cognitive impairment and frank dementia. In the western world, the recognition of the impact on patients, families, health care systems, and societies that dementia poses has led to great efforts to help define the indicators for current and future dementia with the intention to treat those already afflicted even with the primarily symptomatic medications that exist and to recognize those at future risk with the hope of providing counselling to forestall its future development. The idea of "early diagnosis" appears at first glance to be attractive for the purposes of future planning and research studies, but it is not clear what the benefits and risks might be if screening processes define people at risk when beneficial interventions might not yet be determined. The ethical as well as financial implications must be explored and defined before implementation of such screening becomes a normal standard of practice.

Obesity and stroke: Can we translate from rodents to patients?

PubMed Central

Haley, Michael J

2016-01-01

Obesity is a risk factor for stroke and is consequently one of the most common co-morbidities found in patients. There is therefore an identified need to model co-morbidities preclinically to allow better translation from bench to bedside. In preclinical studies, both diet-induced and genetically obese rodents have worse stroke outcome, characterised by increased ischaemic damage and an altered inflammatory response. However, clinical studies have reported an ‘obesity paradox’ in stroke, characterised by reduced mortality and morbidity in obese patients. We discuss the potential reasons why the preclinical and clinical studies may not agree, and review the mechanisms identified in preclinical studies through which obesity may affects stroke outcome. We suggest inflammation plays a central role in this relationship, as obesity features increases in inflammatory mediators such as C-reactive protein and interleukin-6, and chronic inflammation has been linked to worse stroke risk and outcome. PMID:27655337

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

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.

Pluripotent stem cells in translation: a Food and Drug Administration-National Institutes of Health collaboration.

PubMed

Kleitman, Naomi; Rao, Mahendra S; Owens, David F

2013-07-01

Recently, the U.S. Food and Drug Administration (FDA), the U.S. National Institutes of Health, and the stem cell research community have collaborated on a series of workshops that address moving pluripotent stem cell therapies into the clinic. The first two workshops in the series focused on preclinical science, and a third, future workshop will focus on clinical trials. This summary addresses major points from both of the recent preclinically focused meetings. When entering into a therapeutics developmental program based on pluripotent cells, investigators must make decisions at the very early stages that will have major ramifications during later phases of development. Presentations and discussions from both invited participants and FDA staff described the need to characterize and document the quality, variability, and suitability of the cells and commercial reagents used at every translational stage. This requires consideration of future regulatory requirements, ranging from donor eligibility of the original source material to the late-stage manufacturing protocols. Federal, industrial, and academic participants agreed that planning backward is the best way to anticipate what evidence will be needed to justify human testing of novel therapeutics and to eliminate wasted efforts.

Pluripotent Stem Cells in Translation: A Food and Drug Administration-National Institutes of Health Collaboration

PubMed Central

Kleitman, Naomi; Owens, David F.

2013-01-01

Recently, the U.S. Food and Drug Administration (FDA), the U.S. National Institutes of Health, and the stem cell research community have collaborated on a series of workshops that address moving pluripotent stem cell therapies into the clinic. The first two workshops in the series focused on preclinical science, and a third, future workshop will focus on clinical trials. This summary addresses major points from both of the recent preclinically focused meetings. When entering into a therapeutics developmental program based on pluripotent cells, investigators must make decisions at the very early stages that will have major ramifications during later phases of development. Presentations and discussions from both invited participants and FDA staff described the need to characterize and document the quality, variability, and suitability of the cells and commercial reagents used at every translational stage. This requires consideration of future regulatory requirements, ranging from donor eligibility of the original source material to the late-stage manufacturing protocols. Federal, industrial, and academic participants agreed that planning backward is the best way to anticipate what evidence will be needed to justify human testing of novel therapeutics and to eliminate wasted efforts. PMID:23757505

Attitudes towards smoking and tobacco control among pre-clinical medical students in Malaysia.

PubMed

Tee, G H; Hairi, N N; Hairi, F

2012-08-01

Physicians should play a leading role in combatting smoking; information on attitudes of future physicians towards tobacco control measures in a middle-income developing country is limited. Of 310 future physicians surveyed in a medical school in Malaysia, 50% disagreed that it was a doctor's duty to advise smokers to stop smoking; 76.8% agreed that physicians should not smoke before advising others not to smoke; and 75% agreed to the ideas of restricting the sale of cigarettes to minors, making all public places smoke-free and banning advertising of tobacco-related merchandise. Future physicians had positive attitudes towards tobacco regulations but had not grasped their responsibilities in tobacco control measures.

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

PubMed Central

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

2014-01-01

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

Ushering in the study and treatment of preclinical Alzheimer disease.

PubMed

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

2013-07-01

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

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

Preclinical Determinants of Drug Choice under Concurrent Schedules of Drug Self-Administration

PubMed Central

Banks, Matthew L.; Negus, S. Stevens

2012-01-01

Drug self-administration procedures have played a critical role in the experimental analysis of psychoactive compounds, such as cocaine, for over 50 years. While there are numerous permutations of this procedure, this paper will specifically focus on choice procedures using concurrent schedules of intravenous drug self-administration. The aims of this paper are to first highlight the evolution of drug choice procedures and then review the subsequent preclinical body of literature utilizing these choice procedures to understand the environmental, pharmacological, and biological determinants of the reinforcing stimulus effects of drugs. A main rationale for this paper is our proposition that choice schedules are underutilized in investigating the reinforcing effects of drugs in assays of drug self-administration. Moreover, we will conclude with potential future directions and unexplored scientific space for the use of drug choice procedures. PMID:23243420

A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

PubMed

Kerbel, Robert S

2015-01-01

The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy in lung metastases. Developing similar models of metastatic disease but involving mouse tumors grown in syngeneic immunocompetent mice may also prove useful for future translational studies of immune therapy-based treatments.

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

The basics of preclinical drug development for neurodegenerative disease indications.

PubMed

Steinmetz, Karen L; Spack, Edward G

2009-06-12

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

The basics of preclinical drug development for neurodegenerative disease indications

PubMed Central

Steinmetz, Karen L; Spack, Edward G

2009-01-01

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial. PMID:19534731

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

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.

Alzheimer Disease: Scientific Breakthroughs and Translational Challenges.

PubMed

Caselli, Richard J; Beach, Thomas G; Knopman, David S; Graff-Radford, Neill R

2017-06-01

Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E ε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

The Potential of Stem Cells in Treatment of Traumatic Brain Injury.

PubMed

Weston, Nicole M; Sun, Dong

2018-01-25

Traumatic brain injury (TBI) is a global public health concern, with limited treatment options available. Despite improving survival rate after TBI, treatment is lacking for brain functional recovery and structural repair in clinic. Recent studies have suggested that the mature brain harbors neural stem cells which have regenerative capacity following brain insults. Much progress has been made in preclinical TBI model studies in understanding the behaviors, functions, and regulatory mechanisms of neural stem cells in the injured brain. Different strategies targeting these cell population have been assessed in TBI models. In parallel, cell transplantation strategy using a wide range of stem cells has been explored for TBI treatment in pre-clinical studies and some in clinical trials. This review summarized strategies which have been explored to enhance endogenous neural stem cell-mediated regeneration and recent development in cell transplantation studies for post-TBI brain repair. Thus far, neural regeneration through neural stem cells either by modulating endogenous neural stem cells or by stem cell transplantation has attracted much attention. It is highly speculated that targeting neural stem cells could be a potential strategy to repair and regenerate the injured brain. Neuroprotection and neuroregeneration are major aspects for TBI therapeutic development. With technique advancement, it is hoped that stem cell-based therapy targeting neuroregeneration will be able to translate to clinic in not so far future.

Long-acting rilpivirine for HIV prevention.

PubMed

Jackson, Akil; McGowan, Ian

2015-07-01

Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.

ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies.

PubMed

Barnes, Samuel R; Ng, Thomas S C; Santa-Maria, Naomi; Montagne, Axel; Zlokovic, Berislav V; Jacobs, Russell E

2015-06-16

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising technique to characterize pathology and evaluate treatment response. However, analysis of DCE-MRI data is complex and benefits from concurrent analysis of multiple kinetic models and parameters. Few software tools are currently available that specifically focuses on DCE-MRI analysis with multiple kinetic models. Here, we developed ROCKETSHIP, an open-source, flexible and modular software for DCE-MRI analysis. ROCKETSHIP incorporates analyses with multiple kinetic models, including data-driven nested model analysis. ROCKETSHIP was implemented using the MATLAB programming language. Robustness of the software to provide reliable fits using multiple kinetic models is demonstrated using simulated data. Simulations also demonstrate the utility of the data-driven nested model analysis. Applicability of ROCKETSHIP for both preclinical and clinical studies is shown using DCE-MRI studies of the human brain and a murine tumor model. A DCE-MRI software suite was implemented and tested using simulations. Its applicability to both preclinical and clinical datasets is shown. ROCKETSHIP was designed to be easily accessible for the beginner, but flexible enough for changes or additions to be made by the advanced user as well. The availability of a flexible analysis tool will aid future studies using DCE-MRI. A public release of ROCKETSHIP is available at https://github.com/petmri/ROCKETSHIP .

From Molecular Biology to Clinical Trials: Toward Personalized Colorectal Cancer Therapy.

PubMed

Palma, Sabina; Zwenger, Ariel O; Croce, María V; Abba, Martín C; Lacunza, Ezequiel

2016-06-01

During the past years, molecular studies through high-throughput technologies have led to the confirmation of critical alterations in colorectal cancer (CRC) and the discovery of some new ones, including mutations, DNA methylations, and structural chromosomal changes. These genomic alterations might act in concert to dysregulate specific signaling pathways that normally exert their functions on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Targeted therapy against key components of altered signaling pathways has allowed an improvement in CRC treatment. However, a significant percentage of patients with CRC and metastatic CRC will not benefit from these targeted therapies and will be restricted to systemic chemotherapy. Mechanisms of resistance have been associated with specific gene alterations. To fully understand the nature and significance of the genetic and epigenetic defects in CRC that might favor a tumor evading a given therapy, much work remains. Therefore, a dynamic link between basic molecular research and preclinical studies, which ultimately constitute the prelude to standardized therapies, is very important to provide better and more effective treatments against CRC. We present an updated revision of the main molecular features of CRC and their associated therapies currently under study in clinical trials. Moreover, we performed an unsupervised classification of CRC clinical trials with the aim of obtaining an overview of the future perspectives of preclinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

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

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review.

PubMed

Goldberg, Andy; Mitchell, Katrina; Soans, Julian; Kim, Louise; Zaidi, Razi

2017-03-09

The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place.

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

PubMed

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

2010-01-01

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

Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality

PubMed Central

McIntyre, Alan; Harris, Adrian L

2015-01-01

Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. PMID:25700172

The Syk kinase as a therapeutic target in leukemia and lymphoma.

PubMed

Efremov, Dimitar G; Laurenti, Luca

2011-05-01

The B-cell receptor (BCR) delivers antigen-dependent and -independent signals that have been implicated in the pathogenesis of several common B-cell malignancies. Agents that can efficiently block BCR signaling have recently been developed and are currently being evaluated as novel targeted therapies. Among these, agents that inhibit the Syk kinase appear particularly promising in preclinical and early clinical studies. The manuscript provides an overview of recent findings that implicate Syk and the BCR signaling pathway in the pathogenesis of several common lymphoid malignancies. It outlines preclinical and early clinical experiences with the Syk inhibitor fostamatinib disodium (R788) and discusses various options for further clinical development of this compound. Inhibitors of Syk or other components of the BCR signaling pathway are emerging as an exciting novel class of agents for the treatment of common B-cell malignancies. Future efforts should focus on defining the disease entities that are most likely to benefit from these agents, although considerable evidence is already available to pursue such studies in patients with chronic lymphocytic leukemia. Combinations with chemo-immunotherapy, treatment of early-stage disease and consolidation therapy should all be explored and could lead to the development of novel therapeutic approaches with improved efficacy, tolerability and toxicity profiles.

Dietary agents in the prevention of alcohol-induced hepatotoxicty: preclinical observations.

PubMed

Shivashankara, Arnadi Ramachandrayya; Azmidah, Aysha; Haniadka, Raghavendra; Rai, Manoj Ponadka; Arora, Rajesh; Baliga, Manjeshwar Shrinath

2012-02-01

Long term alcohol consumption is one of the important causes for liver failure and death. To complicate the existing problem there are no dependable hepatoprotective drugs and a large number of patients prefer using complementary and alternative medicines for treating and managing hepatic complications. Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed "Let food be thy medicine and medicine be thy food." Exploring the association between diet and health continues even today. Preclinical studies carried out in the recent past have shown that the commonly used dietary agents like Allium sativum (garlic), Camellia sinensis (tea), Curcuma longa (turmeric), Emblica officinalis (Indian gooseberry), Ferula asafoetida (asafoetida), Garcinia cambogia (Malabar tamarind), Glycine max (soyabean), Murraya koenigii (curry leaves), Piper betle (beetle leaf), Prunus armeniaca (apricot), Ocimum gratissimum (wild basil), Theobroma cacao (cocoa), Trigonella foenum-graecum (fenugreek) and Vitis vinifera (grapes) protect against ethanol-induced hepatotoxicity. Mechanistic studies have shown that the beneficial effects of these phytochemicals in preventing the ethanol-induced hepatotoxicity are mediated by the antioxidant, free radical scavenging, anti-inflammatory and anti-fibrotic effects. The present review for the first time collates the hepatoprotective effects of these agents and also emphasizes on aspects that need future research to establish their utility in humans.

Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol.

PubMed

Boggs, Douglas L; Nguyen, Jacques D; Morgenson, Daralyn; Taffe, Michael A; Ranganathan, Mohini

2018-01-01

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are >550 chemical compounds and >100 phytocannabinoids isolated from cannabis, including Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC.

Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation

PubMed Central

Khan, Imran; Arany, Praveen

2015-01-01

Significance: Oral wounds can lead to significant pain and discomfort as well as affect overall general health due to poor diet and inadequate nutrition. Besides many biological and pharmaceutical methods being investigated, there is growing interest in exploring various biophysical devices that utilize electric, magnetic, ultrasound, pressure, and light energy. Recent Advances: Significant insight into mechanisms of these biophysical devices could provide a clear rationale for their clinical use. Preclinical studies are essential precursors in determining physiological mechanisms and elucidation of causal pathways. This will lead to development of safe and effective therapeutic protocols for clinical wound management. Critical Issues: Identification of precise events initiated by biophysical devices, specifically photobiomodulation—the major focus of this review, offers promising avenues in improving oral wound management. The primary phase responses initiated by the interventions that distinctly contribute to the therapeutic response must be clearly delineated from secondary phase responses. The latter events are a consequence of the wound healing process and must not be confused with causal mechanisms. Future Direction: Clinical adoption of these biophysical devices needs robust and efficacious protocols that can be developed by well-designed preclinical and clinical studies. Elucidation of the precise molecular mechanisms of these biophysical approaches could determine optimization of their applications for predictive oral wound care. PMID:26634185

Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology

PubMed Central

Niendorf, Thoralf; Pohlmann, Andreas; Reimann, Henning M.; Waiczies, Helmar; Peper, Eva; Huelnhagen, Till; Seeliger, Erdmann; Schreiber, Adrian; Kettritz, Ralph; Strobel, Klaus; Ku, Min-Chi; Waiczies, Sonia

2015-01-01

Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed. PMID:26617515

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.

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

PubMed

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

1998-01-01

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

Hyperpolarized MRS: New tool to study real-time brain function and metabolism.

PubMed

Mishkovsky, Mor; Comment, Arnaud

2017-07-15

The advent of dissolution dynamic nuclear polarization (DNP) led to the emergence of a new kind of magnetic resonance (MR) measurements providing the opportunity to probe metabolism in vivo in real time. It has been shown that, following the injection of hyperpolarized substrates prepared using dissolution DNP, specific metabolic bioprobes that can be used to differentiate between healthy and pathological tissue in preclinical and clinical studies can be readily detected by MR thanks to the tremendous signal enhancement. The present article aims at reviewing the studies of cerebral function and metabolism based on the use of hyperpolarized MR. The constraints and future opportunities that this technology could offer are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Development of a PET Prostate-Specific Membrane Antigen Imaging Agent: Preclinical Translation for Future Clinical Application

DTIC Science & Technology

2016-10-01

small-molecule peptidomimetic imaging agents labeled with positron emitting fluorine- 18 . These data will enable the filing of an exploratory IND...outcome. 15. SUBJECT TERMS Prostate Cancer, Prostate Specific Membrane Antigen (PSMA), Fluorine- 18 , Molecular Imaging, Radiotracer, Automated...Synthesis, Phosphoramidate, Inhibitor, Peptide Mimic, Peptidomimetic 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a

Pathogenesis and Prediction of Future Rheumatoid Arthritis

DTIC Science & Technology

2014-10-01

characterized by abnormalities of the immune system prior to the onset of the clinically apparent inflammatory joint disease that currently defines RA. The...the clinically apparent inflammatory joint disease that currently defines RA. The primary goal of this project is to investigate this preclinical...environmental exposures such as smoking, periodontal disease were ascertained. Goal 2. Local and governmental IRB approvals, and HRPO approval, were obtained

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.

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

PubMed

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

2018-01-01

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

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

PubMed Central

Ratajczak, Jessica; Gervois, Pascal; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

2018-01-01

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair. PMID:29535784

Clinical perspectives of hybrid proton-fluorine magnetic resonance imaging and spectroscopy.

PubMed

Wolters, Martijn; Mohades, Seyede G; Hackeng, Tilman M; Post, Mark J; Kooi, Marianne E; Backes, Walter H

2013-05-01

The number of applications of fluorine 19 (19F) magnetic resonance (MR) imaging and spectroscopy in biomedical and clinical research is steadily growing. The 100% natural abundance of fluorine and its relatively high sensitivity for MR (83% to that of protons) make it an interesting nucleus for a wide range of MR applications. Fluorinated contrast media have a number of advantages over the conventionally used gadolinium-based or iron-based contrast agents. The absence of an endogenous fluorine background intensity in the human body facilitates reliable quantification of fluorinated contrast medium or drugs. Anatomy can be visualized separately with proton MR imaging, creating the application of hybrid hydrogen 1 (1H)/19F MR imaging. The availability of 2 channels (ie, the 1H and 19F channels) enables dual-targeted molecular imaging. Recently, novel developments have emerged on fluorine-based contrast media in preclinical studies and imaging techniques. The developments in fluorine MR seem promising for clinical applications, with contributions in therapy monitoring, assessment of lung function, angiography, and molecular imaging. This review outlines the translation from recent advances in preclinical MR imaging and spectroscopy to future perspectives of clinical hybrid 1H/19/F MR imaging applications.

Animal Models of Post-Traumatic Stress Disorder and Recent Neurobiological Insights

PubMed Central

Whitaker, Annie M.; Gilpin, Nicholas W.; Edwards, Scott

2014-01-01

Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder characterized by the intrusive re-experiencing of past trauma, avoidant behavior, enhanced fear, and hyperarousal following a traumatic event in vulnerable populations. Preclinical animal models do not replicate the human condition in its entirety, but seek to mimic symptoms or endophenotypes associated with PTSD. Although many models of traumatic stress exist, few adequately capture the complex nature of the disorder and the observed individual variability in susceptibility of humans to develop PTSD. In addition, various types of stressors may produce different molecular neuroadaptations that likely contribute to the various behavioral disruptions produced by each model, although certain consistent neurobiological themes related to PTSD have emerged. For example, animal models report traumatic stress- and trauma reminder-induced alterations in neuronal activity in the amygdala and prefrontal cortex, in agreement with the human PTSD literature. Models have also provided a conceptual framework for the often observed combination of PTSD and co-morbid conditions such as alcohol use disorder (AUD). Future studies will continue to refine preclinical PTSD models in hopes of capitalizing on their potential to deliver new and more efficacious treatments for PTSD and associated psychiatric disorders. PMID:25083568

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.

Human germline gene editing: Recommendations of ESHG and ESHRE.

PubMed

de Wert, Guido; Pennings, Guido; Clarke, Angus; Eichenlaub-Ritter, Ursula; van El, Carla G; Forzano, Francesca; Goddijn, Mariëtte; Heindryckx, Björn; Howard, Heidi C; Radojkovic, Dragica; Rial-Sebbag, Emmanuelle; Tarlatzis, Basil C; Cornel, Martina C

2018-04-01

Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators.

An integrated 2-year clinical skills peer tutoring scheme in a UK-based medical school: perceptions of tutees and peer tutors

PubMed Central

2018-01-01

Background Several benefits of peer tutoring in medical school teaching have been described. However, there is a lack of research on the perceptions of peer tutoring, particularly from tutees who partake in a long-term clinical skills scheme integrated into the medical school curriculum. This study evaluates the opinions of preclinical tutees at the end of a 2-year peer-tutored clinical skills program and peer tutors themselves. Methods A cross-sectional study was conducted in a UK-based medical school that primarily utilizes peer tutoring for clinical skills teaching. A questionnaire was designed to assess the views of preclinical tutees and peer tutors. Likert scales were used to grade responses and comment boxes to collect qualitative data. Results Sixty-five questionnaires were collected (52 tutees, 13 peer tutors). Seventy-nine percent of students felt satisfied with their teaching, and 70% felt adequately prepared for clinical placements. Furthermore, 79% believed that peer tutoring is the most effective method for clinical skills teaching. When compared to faculty teaching, tutees preferred being taught by peer tutors (63%), felt more confident (73%), and were more willing to engage (77%). All peer tutors felt that teaching made them more confident in their Objective Structured Clinical Examination performance, and 91% agreed that being a tutor made them consider pursuing teaching in the future. Thematic analysis of qualitative data identified 3 themes regarding peer tutoring: a more comfortable environment (69%), a more personalized teaching approach (34%), and variation in content taught (14%). Conclusion Preclinical tutees prefer being taught clinical skills by peer tutors compared to faculty, with the peer tutors also benefitting. Studies such as this, looking at long-term schemes, further validate peer tutoring and may encourage more medical schools to adopt this method as an effective way of clinical skills teaching. PMID:29922105

Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects.

PubMed

Kelly, John R; Allen, Andrew P; Temko, Andriy; Hutch, William; Kennedy, Paul J; Farid, Niloufar; Murphy, Eileen; Boylan, Geraldine; Bienenstock, John; Cryan, John F; Clarke, Gerard; Dinan, Timothy G

2017-03-01

Preclinical studies have identified certain probiotics as psychobiotics - live microorganisms with a potential mental health benefit. Lactobacillus rhamnosus (JB-1) has been shown to reduce stress-related behaviour, corticosterone release and alter central expression of GABA receptors in an anxious mouse strain. However, it is unclear if this single putative psychobiotic strain has psychotropic activity in humans. Consequently, we aimed to examine if these promising preclinical findings could be translated to healthy human volunteers. To determine the impact of L. rhamnosus on stress-related behaviours, physiology, inflammatory response, cognitive performance and brain activity patterns in healthy male participants. An 8week, randomized, placebo-controlled, cross-over design was employed. Twenty-nine healthy male volunteers participated. Participants completed self-report stress measures, cognitive assessments and resting electroencephalography (EEG). Plasma IL10, IL1β, IL6, IL8 and TNFα levels and whole blood Toll-like 4 (TLR-4) agonist-induced cytokine release were determined by multiplex ELISA. Salivary cortisol was determined by ELISA and subjective stress measures were assessed before, during and after a socially evaluated cold pressor test (SECPT). There was no overall effect of probiotic treatment on measures of mood, anxiety, stress or sleep quality and no significant effect of probiotic over placebo on subjective stress measures, or the HPA response to the SECPT. Visuospatial memory performance, attention switching, rapid visual information processing, emotion recognition and associated EEG measures did not show improvement over placebo. No significant anti-inflammatory effects were seen as assessed by basal and stimulated cytokine levels. L. rhamnosus was not superior to placebo in modifying stress-related measures, HPA response, inflammation or cognitive performance in healthy male participants. These findings highlight the challenges associated with moving promising preclinical studies, conducted in an anxious mouse strain, to healthy human participants. Future interventional studies investigating the effect of this psychobiotic in populations with stress-related disorders are required. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

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.

The application of antitumor drug-targeting models on liver cancer.

PubMed

Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

2016-06-01

Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

The development of platinum compounds and their possible combination.

PubMed

Pasetto, Lara Maria; D'Andrea, Mario Rosario; Brandes, Alba Ariela; Rossi, Elena; Monfardini, Silvio

2006-10-01

Cisplatin plays a central role in cancer chemotherapy in spite of its toxicity. To circumvent this toxicity and to enhance its therapeutic index a lot of preclinical and clinical studies have been conducted and several thousand analogues have been synthesized. Much more analysis remains to be done, but nowadays, the absence of any definitive, biologically interpretable molecular predictor of activity is consistent with the idea that platinum compounds have multiple intracellular targets and that cells can have multiple mechanisms of resistance. This review analyses a part of these platinum compounds analyzed to date, their mechanism of action, resistance and the future trends in this sector.

The RON Receptor Tyrosine Kinase in Pancreatic Cancer Pathogenesis and Its Potential Implications for Future Targeted Therapies

PubMed Central

Kang, Chang Moo; Babicky, Michele L.; Lowy, Andrew M.

2014-01-01

Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is over-expressed in the majority of pancreatic cancers. Preclinical studies that inhibition of RON function decrease pancreatic cancer cell migration, invasion and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target. PMID:24518495

Patient Derived Xenograft Models: An Emerging Platform for Translational Cancer Research

PubMed Central

Hidalgo, Manuel; Amant, Frederic; Biankin, Andrew V.; Budinská, Eva; Byrne, Annette T.; Caldas, Carlos; Clarke, Robert B.; de Jong, Steven; Jonkers, Jos; Mælandsmo, Gunhild Mari; Roman-Roman, Sergio; Seoane, Joan; Trusolino, Livio; Villanueva, Alberto

2014-01-01

Recently, there has been increasing interest in the development and characterization of patient derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histological and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biological studies, and personalized medicine strategies. This paper summarizes the current state of the art in this field including methodological issues, available collections, practical applications, challenges and shortcoming, and future directions, and introduces a European consortium of PDX models. PMID:25185190

Therapeutic role of rifampicin in Alzheimer's disease.

PubMed

Yulug, Burak; Hanoglu, Lütfü; Ozansoy, Mehmet; Isık, Dogan; Kilic, Ulkan; Kilic, Ertugrul; Schabitz, Wolf Rüdiger

2018-03-01

Rifampicin exerts significant brain protective functions in multiple experimental models. Here we summarize the underlying mechanisms of the neuroprotective and pro-cognitive effects of rifampicin that are mediated by its anti-inflammatory, anti-tau, anti-amyloid, and cholinergic effects. Beyond suggesting that rifampicin shows strong brain protective effects in preclinical models of Alzheimer's disease, we also provide substantial clinical evidence for the neuroprotective and pro-cognitive effects of rifampicin. Future neuroimaging studies combined with clinical assessment scores are the following steps to be taken in this field of research. © 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.

Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects.

PubMed

Di, Shengmeng; Li, Zonghai

2016-04-01

Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed.

Combination of photodynamic therapy and immunomodulation — current status and future trends

PubMed Central

Qiang, Yong-Gang; Yow, Christine M.N.; Huang, Zheng

2008-01-01

Photodynamic therapy (PDT) has been used for the treatment of non-malignant and malignant diseases from head to toe. Over the last decade its clinical application has gained increasing acceptance around the world. Pre-clinical studies demonstrate that, in addition to the direct local cytotoxicity and vascular effects, PDT can induce various host immune responses. Recent clinical data also show that improved clinical outcomes are obtained through the combination of PDT and immunomodulation. This review will summarize and discuss recent progress in developing innovative regimen of PDT combined with immunomodulation for the treatment of both non-malignant and malignant diseases. PMID:18161883

Influence of gut microbiota on neuropsychiatric disorders.

PubMed

Cenit, María Carmen; Sanz, Yolanda; Codoñer-Franch, Pilar

2017-08-14

The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson's disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future.

Influence of gut microbiota on neuropsychiatric disorders

PubMed Central

Cenit, María Carmen; Sanz, Yolanda; Codoñer-Franch, Pilar

2017-01-01

The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson’s disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future. PMID:28852308

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

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

Cardiac tissue engineering: state of the art.

PubMed

Hirt, Marc N; Hansen, Arne; Eschenhagen, Thomas

2014-01-17

The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade. Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing.

Utility of Small Animal Models of Developmental Programming.

PubMed

Reynolds, Clare M; Vickers, Mark H

2018-01-01

Any effective strategy to tackle the global obesity and rising noncommunicable disease epidemic requires an in-depth understanding of the mechanisms that underlie these conditions that manifest as a consequence of complex gene-environment interactions. In this context, it is now well established that alterations in the early life environment, including suboptimal nutrition, can result in an increased risk for a range of metabolic, cardiovascular, and behavioral disorders in later life, a process preferentially termed developmental programming. To date, most of the mechanistic knowledge around the processes underpinning development programming has been derived from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. This review will cover the utility of small animal models in developmental programming, the limitations of such models, and potential future directions that are required to fully maximize information derived from preclinical models in order to effectively translate to clinical use.

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.

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

Implantable Sensors for Regenerative Medicine

PubMed Central

Klosterhoff, Brett S.; Tsang, Melissa; She, Didi; Ong, Keat Ghee; Allen, Mark G.; Willett, Nick J.; Guldberg, Robert E.

2017-01-01

The translation of many tissue engineering/regenerative medicine (TE/RM) therapies that demonstrate promise in vitro are delayed or abandoned due to reduced and inconsistent efficacy when implemented in more complex and clinically relevant preclinical in vivo models. Determining mechanistic reasons for impaired treatment efficacy is challenging after a regenerative therapy is implanted due to technical limitations in longitudinally measuring the progression of key environmental cues in vivo. The ability to acquire real-time measurements of environmental parameters of interest including strain, pressure, pH, temperature, oxygen tension, and specific biomarkers within the regenerative niche in situ would significantly enhance the information available to tissue engineers to monitor and evaluate mechanisms of functional healing or lack thereof. Continued advancements in material and fabrication technologies utilized by microelectromechanical systems (MEMSs) and the unique physical characteristics of passive magnetoelastic sensor platforms have created an opportunity to implant small, flexible, low-power sensors into preclinical in vivo models, and quantitatively measure environmental cues throughout healing. In this perspective article, we discuss the need for longitudinal measurements in TE/RM research, technical progress in MEMS and magnetoelastic approaches to implantable sensors, the potential application of implantable sensors to benefit preclinical TE/RM research, and the future directions of collaborative efforts at the intersection of these two important fields. PMID:27987300

Attitudes of pharmacy and nutrition students towards team-based care after first exposure to interprofessional education in Qatar.

PubMed

Wilby, Kyle John; Al-Abdi, Tamara; Hassan, Abdelmonem; Brown, Marian Amanda; Paravattil, Bridget; Khalifa, Sherief Ibrahim

2015-01-01

Little is known regarding attitudes of healthcare professional students towards team-based care in the Middle East. As modernization of health systems is rapidly occurring across the Gulf Cooperation Council countries, it is important for students to engage in interprofessional education (IPE) activities. The objective of this study was to assess pre-clinical students' attitudes towards interprofessional healthcare teams after completion of their first IPE activity. A previously validated questionnaire was distributed to 25 pharmacy and 17 nutrition students at Qatar University after participation in an IPE event. Questions related to quality of team-based care and physician centricity. Results showed high agreement regarding high quality care provided by teams yet students were unsure of the value of team-based care when considering required time for implementation. Results provide baseline data for future studies to assess student attitudes throughout the professional programs and give valuable insight for future IPE program design in the Middle East.

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

PubMed

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

2013-04-01

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

Mesenchymal stem cells for acute lung injury: Preclinical evidence

PubMed Central

Matthay, Michael A.; Goolaerts, Arnaud; Howard, James P.; Lee, Jae Woo

2013-01-01

Several experimental studies have suggested that mesenchymal stem cells may have value for the treatment of clinical disorders, including myocardial infarction, diabetes, acute renal failure, sepsis, and acute lung injury. In preclinical studies, mesenchymal stem cells have been effective in reducing lung injury from endotoxin, live bacteria, bleomycin, and hyperoxia. In some studies, the cultured medium from mesenchymal stem cells has been as effective as the mesenchymal stem cells themselves. Several paracrine mediators that can mediate the effect of mesenchymal stem cells have been identified, including interleukin-10, interleukin-1ra, keratinocyte growth factor, and prostaglandin E2. Further preclinical studies are needed, as is planning for clinical trials for acute lung injury. PMID:21164399

Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings.

PubMed

Arentz, Susan; Abbott, Jason Anthony; Smith, Caroline Anne; Bensoussan, Alan

2014-12-18

Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions. We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism. A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus-castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism. Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre-clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre-clinical data.

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

ERIC Educational Resources Information Center

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

2016-01-01

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…

Optical Tecnology Developments in Biomedicine: History, Current and Future

PubMed Central

Nioka, Shoko; Chen, Yu

2011-01-01

Biomedical optics is a rapidly emerging field for medical imaging and diagnostics. This paper reviews several biomedical optical technologies that have been developed and translated for either clinical or pre-clinical applications. Specifically, we focus on the following technologies: 1) near-infrared spectroscopy and tomography, 2) optical coherence tomography, 3) fluorescence spectroscopy and imaging, and 4) optical molecular imaging. There representative biomedical applications are also discussed here. PMID:23905030

Pre-Clinical Testing of New Hydroxybutyrate Analogues

DTIC Science & Technology

2012-07-01

representative of any past or future Batches/Lots. The methodology and/or techniques of analysis used to obtailrthese results may or may not be...purpose. For additional information regarding this product and its analysis , please contact your Eastman representative. This material is NOT for human...COMPOSITION INFORMATION ON INGREDIENTS (Typical romposition is given. and it may vaty. A cerlifica /8 of analysis em be provided, if avalabl8.) WeiQht

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery.

PubMed

Petrella, Francesco; Rimoldi, Isabella; Rizzo, Stefania; Spaggiari, Lorenzo

2017-11-23

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

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.

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

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

Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease.

PubMed

Müller, Stephan; Preische, Oliver; Sohrabi, Hamid R; Gräber, Susanne; Jucker, Mathias; Dietzsch, Janko; Ringman, John M; Martins, Ralph N; McDade, Eric; Schofield, Peter R; Ghetti, Bernardino; Rossor, Martin; Graff-Radford, Neill R; Levin, Johannes; Galasko, Douglas; Quaid, Kimberly A; Salloway, Stephen; Xiong, Chengjie; Benzinger, Tammie; Buckles, Virginia; Masters, Colin L; Sperling, Reisa; Bateman, Randall J; Morris, John C; Laske, Christoph

2017-04-27

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

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 checklist is associated with increased quality of reporting preclinical biomedical research: A systematic review

PubMed Central

Olonisakin, Tolani F.; Pribis, John P.; Zupetic, Jill; Yoon, Joo Heung; Holleran, Kyle M.; Jeong, Kwonho; Shaikh, Nader; Rubio, Doris M.; Lee, Janet S.

2017-01-01

Irreproducibility of preclinical biomedical research has gained recent attention. It is suggested that requiring authors to complete a checklist at the time of manuscript submission would improve the quality and transparency of scientific reporting, and ultimately enhance reproducibility. Whether a checklist enhances quality and transparency in reporting preclinical animal studies, however, has not been empirically studied. Here we searched two highly cited life science journals, one that requires a checklist at submission (Nature) and one that does not (Cell), to identify in vivo animal studies. After screening 943 articles, a total of 80 articles were identified in 2013 (pre-checklist) and 2015 (post-checklist), and included for the detailed evaluation of reporting methodological and analytical information. We compared the quality of reporting preclinical animal studies between the two journals, accounting for differences between journals and changes over time in reporting. We find that reporting of randomization, blinding, and sample-size estimation significantly improved when comparing Nature to Cell from 2013 to 2015, likely due to implementation of a checklist. Specifically, improvement in reporting of the three methodological information was at least three times greater when a mandatory checklist was implemented than when it was not. Reporting the sex of animals and the number of independent experiments performed also improved from 2013 to 2015, likely from factors not related to a checklist. Our study demonstrates that completing a checklist at manuscript submission is associated with improved reporting of key methodological information in preclinical animal studies. PMID:28902887

Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

PubMed

Mrena, S; Savola, K; Kulmala, P; Reijonen, H; Ilonen, J; Akerblom, H K; Knip, M

2003-06-01

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.

Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota

PubMed Central

van den Hoogen, Ward J.; Laman, Jon D.; ’t Hart, Bert A.

2017-01-01

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research. PMID:28928747

Achieving Biocompatible SABRE: An in vitro Cytotoxicity Study.

PubMed

Manoharan, Anand; Rayner, Peter J; Iali, Wissam; Burns, Michael J; Perry, V Hugh; Duckett, Simon B

2018-02-20

Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using in vitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion-exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future in vivo study. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research

PubMed Central

Desmet, Eline; Ramadhas, Anesh; Lambert, Jo

2017-01-01

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis skin or the disease pathology. This work provides a complete overview of the different available in vitro psoriasis models and suggests improvements for future models. Moreover, a focus was given to psoriatic skin equivalent models, as they offer several advantages over the other models, including commercial availability and validity. The potential and reported applicability of these models in psoriasis pre-clinical research is extensively discussed. As such, this work offers a guide to researchers in their choice of pre-clinical psoriasis model depending on their type of research question. PMID:28585891

In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research.

PubMed

Desmet, Eline; Ramadhas, Anesh; Lambert, Jo; Van Gele, Mireille

2017-06-01

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis skin or the disease pathology. This work provides a complete overview of the different available in vitro psoriasis models and suggests improvements for future models. Moreover, a focus was given to psoriatic skin equivalent models, as they offer several advantages over the other models, including commercial availability and validity. The potential and reported applicability of these models in psoriasis pre-clinical research is extensively discussed. As such, this work offers a guide to researchers in their choice of pre-clinical psoriasis model depending on their type of research question.

Glutamate-mediated excitotoxicity in schizophrenia: A review

PubMed Central

Plitman, Eric; Nakajima, Shinichiro; de la Fuente-Sandoval, Camilo; Gerretsen, Philip; Chakravarty, M. Mallar; Kobylianskii, Jane; Chung, Jun Ku; Caravaggio, Fernando; Iwata, Yusuke; Remington, Gary; Graff-Guerrero, Ariel

2015-01-01

Findings from neuroimaging studies in patients with schizophrenia suggest widespread structural changes although the mechanisms through which these changes occur are currently unknown. Glutamatergic activity appears to be increased in the early phases of schizophrenia and may contribute to these structural alterations through an excitotoxic effect. The primary aim of this review was to describe the possible role of glutamate-mediated excitotoxicity in explaining the presence of neuroanatomical changes within schizophrenia. A Medline® literature search was conducted, identifying English language studies on the topic of glutamate-mediated excitotoxicity in schizophrenia, using the terms “schizophreni*” and “glutam*” and ((“MRS” or “MRI” or “magnetic resonance”) or (“computed tomography” or “CT”)). Studies concomitantly investigating glutamatergic activity and brain structure in patients with schizophrenia were included. Results are discussed in the context of findings from preclinical studies. Seven studies were identified that met the inclusion criteria. These studies provide inconclusive support for the role of glutamate-mediated excitotoxicity in the occurrence of structural changes within schizophrenia, with the caveat that there is a paucity of human studies investigating this topic. Preclinical data suggest that an excitotoxic effect may occur as a result of a paradoxical increase in glutamatergic activity following N-methyl-D-aspartate receptor hypofunction. Based on animal literature, glutamate-mediated excitotoxicity may account for certain structural changes present in schizophrenia, but additional human studies are required to substantiate these findings. Future studies should adopt a longitudinal design and employ magnetic resonance imaging techniques to investigate whether an association between glutamatergic activity and structural changes exists in patients with schizophrenia. PMID:25159198

Spatial resolution properties of digital autoradiography systems for pre-clinical alpha particle imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Tanguay, Jesse; Benard, Francois; Celler, Anna; Ruth, Thomas; Schaffer, Paul

2017-03-01

Attaching alpha-emitting radionuclides to cancer-targeting agents increases the anti-tumor effects of targeted cancer therapies. The success of alpha therapy for treating bone metastases has increased interest in using targeted alpha therapy (TAT) to treat a broad spectrum of metastatic cancers. Estimating radiation doses to targeted tumors, including small (<250 μm) clusters of cancer cells, and to non-targeted tissues is critical in the pre-clinical development of TATs. However, accurate quantification of heterogeneous distributions of alpha-emitters in small metastases is not possible with existing pre-clinical in-vivo imaging systems. Ex-vivo digital autoradiography using a scintillator in combination with an image intensifier and a charged coupled device (CCD) has gained interest for pre-clinical ex-vivo alpha particle imaging. We present a simulation-based analysis of the fundamental spatial resolution limits of digital autoradiography systems. Spatial resolution was quantified in terms of the modulation transfer function (MTF) and Wagner's equivalent aperture. We modeled systems operating in either particle-counting (PC) or energy-integrating (EI) mode using a cascaded systems approach that accounts for: 1) the stopping power of alpha particles; 2) the distance alpha particles travel within the scintillator; 3) optical blur, and; 4) binning in detector elements. We applied our analysis to imaging of astatine-211 using an LYSO scintillator with thickness ranging from 10 μm to 20 μm. Our analysis demonstrates that when these systems are operated in particle-counting mode with a centroid-calculation algorithm, the effective apertures of 35 μm can be achieved, which suggests that digital autoradiography may enable quantifying the uptake of alpha emitters in tumors consisting of a few cancer cells. Future work will investigate the image noise and energy-resolution properties of digital autoradiography systems.

An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma.

PubMed

Lamhamedi-Cherradi, Salah-Eddine; Menegaz, Brian A; Ramamoorthy, Vandhana; Aiyer, Ramani A; Maywald, Rebecca L; Buford, Adrianna S; Doolittle, Dannette K; Culotta, Kirk S; O'Dorisio, James E; Ludwig, Joseph A

2015-07-01

Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. ©2015 American Association for Cancer Research.

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.

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.

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.

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.

Understanding disease processes in multiple sclerosis through magnetic resonance imaging studies in animal models

PubMed Central

Nathoo, Nabeela; Yong, V. Wee; Dunn, Jeff F.

2014-01-01

There are exciting new advances in multiple sclerosis (MS) resulting in a growing understanding of both the complexity of the disorder and the relative involvement of grey matter, white matter and inflammation. Increasing need for preclinical imaging is anticipated, as animal models provide insights into the pathophysiology of the disease. Magnetic resonance (MR) is the key imaging tool used to diagnose and to monitor disease progression in MS, and thus will be a cornerstone for future research. Although gadolinium-enhancing and T2 lesions on MRI have been useful for detecting MS pathology, they are not correlative of disability. Therefore, new MRI methods are needed. Such methods require validation in animal models. The increasing necessity for MRI of animal models makes it critical and timely to understand what research has been conducted in this area and what potential there is for use of MRI in preclinical models of MS. Here, we provide a review of MRI and magnetic resonance spectroscopy (MRS) studies that have been carried out in animal models of MS that focus on pathology. We compare the MRI phenotypes of animals and patients and provide advice on how best to use animal MR studies to increase our understanding of the linkages between MR and pathology in patients. This review describes how MRI studies of animal models have been, and will continue to be, used in the ongoing effort to understand MS. PMID:24936425

Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students

ERIC Educational Resources Information Center

Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut

2014-01-01

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.…

The Impact of Interactive, Computerized Educational Modules on Preclinical Medical Education

ERIC Educational Resources Information Center

Bryner, Benjamin S.; Saddawi-Konefka, Daniel; Gest, Thomas R.

2008-01-01

Interactive computerized modules have been linked to improved retention of material in clinical medicine. This study examined the effects of a new series of interactive learning modules for preclinical medical education, specifically in the areas of quiz performance, perceived difficulty of concepts, study time, and perceived stress level. We…

[Biological markers in epidemiology: concepts, applications, perspectives (part I)].

PubMed

Hoffmann, W; Latza, U; Ahrens, W; Greiser, K H; Kroke, A; Nieters, A; Schulze, M B; Steiner, M; Terschüren, C; Wjst, M

2002-02-01

The inclusion of biomarkers in epidemiological research provides new possibilities for exposure assessment and the study of early structural or functional changes and pre-clinical stages of diseases. At the same time issues of validity, reliability, and quality control as well as logistics require special attention. Usually epidemiological studies become more expensive with regard to time and cost. Interdisciplinary collaboration between epidemiology, basic research, and laboratory research is crucial. A prerequisite for this collaboration are agreements on definitions, methods and procedures. The definition of "biomarker" and a description of previous uses of biomarkers in epidemiological studies are presented in the first part of this paper. The second part addresses genetic markers and markers of individual sensitivity and susceptibility. We will end with a discussion about the possible future of biomarkers in epidemiology.

Cardiovascular photodynamic therapy: state of the art

NASA Astrophysics Data System (ADS)

Woodburn, Kathryn W.; Rockson, Stanley G.

2000-05-01

Photodynamic therapy (PDT) has been used traditionally for oncologic and ophthalmic indications. In addition, the enormous potential for the use of PDT agents in cardiovascular diseases is currently being translated into reality. Preclinical studies with various photosensitizers have demonstrated reduction in atheromatous plaque and prevention of intimal hyperplasia. With recent advances in light-based vascular devices and laser diode technology, the clinical use of cardiovascular photodynamic therapy is even more likely. Two photosensitizers, 5-aminolevulinic acid (ALA) and AntrinR (motexafin lutetium) Injection, are under clinical evaluation with many other agents in preclinical testing. Here, preclinical studies are reviewed and the clinical viability of cardiovascular photodynamic therapy is discussed.

A statistical analysis of murine incisional and excisional acute wound models.

PubMed

Ansell, David M; Campbell, Laura; Thomason, Helen A; Brass, Andrew; Hardman, Matthew J

2014-01-01

Mice represent the most commonly used species for preclinical in vivo research. While incisional and excisional acute murine wound models are both frequently employed, there is little agreement on which model is optimum. Moreover, current lack of standardization of wounding procedure, analysis time point(s), method of assessment, and the use of individual wounds vs. individual animals as replicates makes it difficult to compare across studies. Here we have profiled secondary intention healing of incisional and excisional wounds within the same animal, assessing multiple parameters to determine the optimal methodology for future studies. We report that histology provides the least variable assessment of healing. Furthermore, histology alone (not planimetry) is able to detect accelerated healing in a castrated mouse model. Perhaps most importantly, we find virtually no correlation between wounds within the same animal, suggesting that use of wound (not animal) biological replicates is perfectly acceptable. Overall, these findings should guide and refine future studies, increasing the likelihood of detecting novel phenotypes while reducing the numbers of animals required for experimentation. © 2014 by the Wound Healing Society.

A statistical analysis of murine incisional and excisional acute wound models

PubMed Central

Ansell, David M; Campbell, Laura; Thomason, Helen A; Brass, Andrew; Hardman, Matthew J

2014-01-01

Mice represent the most commonly used species for preclinical in vivo research. While incisional and excisional acute murine wound models are both frequently employed, there is little agreement on which model is optimum. Moreover, current lack of standardization of wounding procedure, analysis time point(s), method of assessment, and the use of individual wounds vs. individual animals as replicates makes it difficult to compare across studies. Here we have profiled secondary intention healing of incisional and excisional wounds within the same animal, assessing multiple parameters to determine the optimal methodology for future studies. We report that histology provides the least variable assessment of healing. Furthermore, histology alone (not planimetry) is able to detect accelerated healing in a castrated mouse model. Perhaps most importantly, we find virtually no correlation between wounds within the same animal, suggesting that use of wound (not animal) biological replicates is perfectly acceptable. Overall, these findings should guide and refine future studies, increasing the likelihood of detecting novel phenotypes while reducing the numbers of animals required for experimentation. PMID:24635179

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis.

PubMed

Nielsen, Suzanne; Sabioni, Pamela; Trigo, Jose M; Ware, Mark A; Betz-Stablein, Brigid D; Murnion, Bridin; Lintzeris, Nicholas; Khor, Kok Eng; Farrell, Michael; Smith, Andrew; Le Foll, Bernard

2017-08-01

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus.

PubMed

Jenkinson, Claire; Elliott, Victoria L; Evans, Anthony; Oldfield, Lucy; Jenkins, Rosalind E; O'Brien, Darragh P; Apostolidou, Sophia; Gentry-Maharaj, Aleksandra; Fourkala, Evangelia-O; Jacobs, Ian J; Menon, Usha; Cox, Trevor; Campbell, Fiona; Pereira, Stephen P; Tuveson, David A; Park, B Kevin; Greenhalf, William; Sutton, Robert; Timms, John F; Neoptolemos, John P; Costello, Eithne

2016-04-01

Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n= 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n= 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n= 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively;P< 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P< 0.05) and patients with benign biliary obstruction (P< 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P< 0.05) and at clinical diagnosis (P< 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P< 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P= 0.01). Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies. ©2015 American Association for Cancer Research.

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.

PubMed

de Leon, Mony J; Pirraglia, Elizabeth; Osorio, Ricardo S; Glodzik, Lidia; Saint-Louis, Les; Kim, Hee-Jin; Fortea, Juan; Fossati, Silvia; Laska, Eugene; Siegel, Carole; Butler, Tracy; Li, Yi; Rusinek, Henry; Zetterberg, Henrik; Blennow, Kaj

2018-01-01

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Systems 1 and 2 thinking processes and cognitive reflection testing in medical students

PubMed Central

Tay, Shu Wen; Ryan, Paul; Ryan, C Anthony

2016-01-01

Background Diagnostic decision-making is made through a combination of Systems 1 (intuition or pattern-recognition) and Systems 2 (analytic) thinking. The purpose of this study was to use the Cognitive Reflection Test (CRT) to evaluate and compare the level of Systems 1 and 2 thinking among medical students in pre-clinical and clinical programs. Methods The CRT is a three-question test designed to measure the ability of respondents to activate metacognitive processes and switch to System 2 (analytic) thinking where System 1 (intuitive) thinking would lead them astray. Each CRT question has a correct analytical (System 2) answer and an incorrect intuitive (System 1) answer. A group of medical students in Years 2 & 3 (pre-clinical) and Years 4 (in clinical practice) of a 5-year medical degree were studied. Results Ten percent (13/128) of students had the intuitive answers to the three questions (suggesting they generally relied on System 1 thinking) while almost half (44%) answered all three correctly (indicating full analytical, System 2 thinking). Only 3–13% had incorrect answers (i.e. that were neither the analytical nor the intuitive responses). Non-native English speaking students (n = 11) had a lower mean number of correct answers compared to native English speakers (n = 117: 1.0 s 2.12 respectfully: p < 0.01). As students progressed through questions 1 to 3, the percentage of correct System 2 answers increased and the percentage of intuitive answers decreased in both the pre-clinical and clinical students. Conclusions Up to half of the medical students demonstrated full or partial reliance on System 1 (intuitive) thinking in response to these analytical questions. While their CRT performance has no claims to make as to their future expertise as clinicians, the test may be used in helping students to understand the importance of awareness and regulation of their thinking processes in clinical practice. PMID:28344696

Systems 1 and 2 thinking processes and cognitive reflection testing in medical students.

PubMed

Tay, Shu Wen; Ryan, Paul; Ryan, C Anthony

2016-10-01

Diagnostic decision-making is made through a combination of Systems 1 (intuition or pattern-recognition) and Systems 2 (analytic) thinking. The purpose of this study was to use the Cognitive Reflection Test (CRT) to evaluate and compare the level of Systems 1 and 2 thinking among medical students in pre-clinical and clinical programs. The CRT is a three-question test designed to measure the ability of respondents to activate metacognitive processes and switch to System 2 (analytic) thinking where System 1 (intuitive) thinking would lead them astray. Each CRT question has a correct analytical (System 2) answer and an incorrect intuitive (System 1) answer. A group of medical students in Years 2 & 3 (pre-clinical) and Years 4 (in clinical practice) of a 5-year medical degree were studied. Ten percent (13/128) of students had the intuitive answers to the three questions (suggesting they generally relied on System 1 thinking) while almost half (44%) answered all three correctly (indicating full analytical, System 2 thinking). Only 3-13% had incorrect answers (i.e. that were neither the analytical nor the intuitive responses). Non-native English speaking students (n = 11) had a lower mean number of correct answers compared to native English speakers (n = 117: 1.0 s 2.12 respectfully: p < 0.01). As students progressed through questions 1 to 3, the percentage of correct System 2 answers increased and the percentage of intuitive answers decreased in both the pre-clinical and clinical students. Up to half of the medical students demonstrated full or partial reliance on System 1 (intuitive) thinking in response to these analytical questions. While their CRT performance has no claims to make as to their future expertise as clinicians, the test may be used in helping students to understand the importance of awareness and regulation of their thinking processes in clinical practice.

Characterization of nasal potential difference in cftr knockout and F508del-CFTR mice.

PubMed

Saussereau, Emilie Lyne; Roussel, Delphine; Diallo, Siradiou; Debarbieux, Laurent; Edelman, Aleksander; Sermet-Gaudelus, Isabelle

2013-01-01

Treatments designed to correct cystic fibrosis transmembrane conductance regulator (CFTR) defects must first be evaluated in preclinical experiments in the mouse model of cystic fibrosis (CF). Mice nasal mucosa mimics the bioelectric defect seen in humans. The use of nasal potential difference (V(TE)) to assess ionic transport is a powerful test evaluating the restoration of CFTR function. Nasal V(TE) in CF mice must be well characterized for correct interpretation. We performed V(TE) measurements in large-scale studies of two mouse models of CF--B6;129 cftr knockout and FVB F508del-CFTR--and their respective wild-type (WT) littermates. We assessed the repeatability of the test for cftr knockout mice and defined cutoff points distinguishing between WT and F508del-CFTR mice. We determined the typical V(TE) values for CF and WT mice and demonstrated the existence of residual CFTR activity in F508del-CFTR mice. We characterized intra-animal variability in B6;129 mice and defined the cutoff points for F508del-CFTR chloride secretion rescue. Hyperpolarization of more than -2.15 mV after perfusion with a low-concentration Cl(-) solution was considered to indicate a normal response. These data will make it possible to interpret changes in nasal V(TE) in mouse models of CF, in future preclinical studies.

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

PubMed Central

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

2011-01-01

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

Noninvasive vaccination against infectious diseases.

PubMed

Zheng, Zhichao; Diaz-Arévalo, Diana; Guan, Hongbing; Zeng, Mingtao

2018-04-06

The development of a successful vaccine, which should elicit a combination of humoral and cellular responses to control or prevent infections, is the first step in protecting against infectious diseases. A vaccine may protect against bacterial, fungal, parasitic, or viral infections in animal models, but to be effective in humans there are some issues that should be considered, such as the adjuvant, the route of vaccination, and the antigen-carrier system. While almost all licensed vaccines are injected such that inoculation is by far the most commonly used method, injection has several potential disadvantages, including pain, cross contamination, needlestick injury, under- or overdosing, and increased cost. It is also problematic for patients from rural areas of developing countries, who must travel to a hospital for vaccine administration. Noninvasive immunizations, including oral, intranasal, and transcutaneous administration of vaccines, can reduce or eliminate pain, reduce the cost of vaccinations, and increase their safety. Several preclinical and clinical studies as well as experience with licensed vaccines have demonstrated that noninvasive vaccine immunization activates cellular and humoral immunity, which protect against pathogen infections. Here we review the development of noninvasive immunization with vaccines based on live attenuated virus, recombinant adenovirus, inactivated virus, viral subunits, virus-like particles, DNA, RNA, and antigen expression in rice in preclinical and clinical studies. We predict that noninvasive vaccine administration will be more widely applied in the clinic in the near future.

Pancreatic islet isolation variables in non-human primates (rhesus macaques).

PubMed

Andrades, P; Asiedu, C K; Gansuvd, B; Inusah, S; Goodwin, K J; Deckard, L A; Jargal, U; Thomas, J M

2008-07-01

Non-human primates (NHPs) are important preclinical models for pancreatic islet transplantation (PIT) because of their close phylogenetic and immunological relationship with humans. However, low availability of NHP tissue, long learning curves and prohibitive expenses constrain the consistency of isolated NHP islets for PIT studies. To advance preclinical studies, we attempted to identify key variables that consistently influence the quantity and quality of NHP islets. Seventy-two consecutive pancreatic islet isolations from rhesus macaques were reviewed retrospectively. A scaled down, semi-automated islet isolation method was used, and monkeys with streptozotocin-induced diabetes, weighing 3-7 kg, served as recipients for allotransplantation. We analysed the effects of 22 independent variables grouped as donor factors, surgical factors and isolation technique factors. Islet yields, success of isolation and transplantation results were used as quantitative and qualitative outcomes. In the multivariate analysis, variables that significantly affected islet yield were the type of monkey, pancreas preservation, enzyme lot and volume of enzyme delivered. The variables associated with successful isolation were the enzyme lot and volume delivered. The transplant result was correlated with pancreas preservation, enzyme lot, endotoxin levels and COBE collection method. Islet quantity and quality are highly variable between isolations. The data reviewed suggest that future NHP isolations should use bilayer preservation, infuse more than 80 ml of Liberase into the pancreas, collect non-fractioned tissue from the COBE, and strictly monitor for infection.

C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease.

PubMed

Abushouk, Abdelrahman Ibrahim; Negida, Ahmed; Elshenawy, Rasha Abdelsalam; Zein, Hossam; Hammad, Ali M; Menshawy, Ahmed; Mohamed, Wael M Y

2018-04-26

Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

What anatomy is clinically useful and when should we be teaching it?

PubMed

Leveritt, Simon; McKnight, Gerard; Edwards, Kimberley; Pratten, Margaret; Merrick, Deborah

2016-10-01

Anatomy teaching, once thought of as being the cornerstone of medical education, has undergone much change in the recent years. There is now growing concern for falling standards in medical graduates' anatomical knowledge, coupled with a reduction in teaching time and appropriately qualified teaching staff. With limited contact hours available to teach this important discipline, it is essential to consider what anatomy is taught within the medical curriculum to ensure it is fit for clinical practice. The views of medical students, junior doctors, and consultants were obtained from the University of Nottingham and the Trent Deanery in Nottingham, United Kingdom, to establish what core anatomical knowledge they feel medical students should study and assimilate during preclinical training. All participants felt strongly that medical students should be adept at interpreting modern diagnostic images before entering their clinical placement or specialty. Respondents proposed more teaching emphasis should be placed on specific anatomical areas (including lymphatic drainage and dermatome innervation) and illustrated other areas where less detailed teaching was appropriate. Recommendations from our study highlight a need for greater clinical emphasis in anatomy teaching during preclinical years. To successfully achieve this, it is essential that clinicians become integrally involved in the design and delivery of future medical undergraduate anatomy courses. Anat Sci Educ 9: 468-475. © 2016 American Association of Anatomists. © 2016 American Association of Anatomists.

Vaccines for Drug Abuse

PubMed Central

Shen, Xiaoyun; Orson, Frank M.; Kosten, Thomas R.

2012-01-01

Current medications for drug abuse have had only limited success. Anti-addiction vaccines to elicit antibodies that block the pharmacological effects of drugs have great potential for treating drug abuse. We review the status for two vaccines that are undergoing clinical trials (cocaine and nicotine) and two that are still in pre-clinical development (methamphetamine and heroin). We also outline the challenges and ethical concerns for anti-addiction vaccine development and their use as future therapeutics. PMID:22130115

The therapeutic potential of plant-derived vaccines and antibodies.

PubMed

Rodgers, P B; Hamilton, W D; Adair, J R

1999-03-01

The production of recombinant proteins in plants is reviewed with a particular focus on plant-derived vaccines and antibodies for human healthcare. Issues relating to foreign gene expression, such as protein yield, localisation and glycosylation are also considered. Emphasis is placed on reporting progress with preclinical and clinical evaluation of plant-derived vaccines and antibodies. An assessment is made of the likely future direction of research and development in this area.

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours

PubMed Central

2012-01-01

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-β receptor II allowing TFF-β signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances. PMID:22587874

Synthetic immunology: modulating the human immune system.

PubMed

Geering, Barbara; Fussenegger, Martin

2015-02-01

Humans have manipulated the immune system to dampen or boost the immune response for thousands of years. As our understanding of fundamental immunology and biotechnological methodology accumulates, we can capitalize on this combined knowledge to engineer biological devices with the aim of rationally manipulating the immune response. We address therapeutic approaches based on the principles of synthetic immunology that either ameliorate disorders of the immune system by interfering with the immune response, or improve diverse pathogenic conditions by exploiting immune cell effector functions. We specifically highlight synthetic proteins investigated in preclinical and clinical trials, summarize studies that have used engineered immune cells, and finish with a discussion of possible future therapeutic concepts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action

PubMed Central

Alam, Md Nur; Almoyad, Muhammad

2018-01-01

Polyphenols have been reported to have wide spectrum of biological activities including major impact on initiation, promotion, and progression of cancer by modulating different signalling pathways. Colorectal cancer is the second most major cause of mortality and morbidity among females and the third among males. The objective of this review is to describe the activity of a variety of polyphenols in colorectal cancer in clinical trials, preclinical studies, and primary research. The molecular mechanisms of major polyphenols related to their beneficial effects on colorectal cancer are also addressed. Synthetic modifications and other future directions towards exploiting of natural polyphenols against colorectal cancer are discussed in the last section. PMID:29568751

Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives

PubMed Central

Femminella, Grazia Daniela; Bencivenga, Leonardo; Petraglia, Laura; Visaggi, Lucia; Gioia, Lucia; Grieco, Fabrizio Vincenzo; de Lucia, Claudio; Komici, Klara; Edison, Paul

2017-01-01

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD. PMID:28656154

Targeted genetic and viral therapy for advanced head and neck cancers.

PubMed

Huang, Pin-I; Chang, Ju-Fang; Kirn, David H; Liu, Ta-Chiang

2009-06-01

Head and neck cancers usually present with advanced disease and novel therapies are urgently needed. Genetic therapy aims at restoring malfunctioned tumor suppressor gene(s) or introducing proapoptotic genes. Oncolytic virotherapeutics induce multiple cycles of cancer-specific virus replication, followed by oncolysis, virus spreading and infection of adjacent cancer cells. Oncolytic viruses can also be armed to express therapeutic transgene(s). Recent advances in preclinical and clinical studies are revealing the potential of both therapeutic classes for advanced head and neck cancers, including the approval of two products (Gendicine and H101) by a governmental agency. This review summarizes the available clinical data to date and discusses the challenges and future directions.

Progress in Developing Virus-like Particle Influenza Vaccines

PubMed Central

Quan, Fu-Shi; Lee, Young-Tae; Kim, Ki-Hye; Kim, Min-Chul; Kang, Sang-Moo

2016-01-01

Summary Recombinant vaccines based on virus-like particles (VLPs) or nanoparticles have been successful in their safety and efficacy in preclinical and clinical studies. The technology of expressing enveloped VLP vaccines has combined with molecular engineering of proteins in membrane-anchor and immunogenic forms mimicking the native conformation of surface proteins on the enveloped viruses. This review summarizes recent developments in influenza VLP vaccines against seasonal, pandemic, and avian influenza viruses from the perspective of use in humans. The immunogenicity and efficacies of influenza VLP vaccine in the homologous and cross-protection were reviewed. Discussions include limitations of current influenza vaccination strategies and future directions to confer broadly cross protective new influenza vaccines as well as vaccination. PMID:27058302

Transcutaneous measurement of glomerular filtration rate in conscious laboratory animals: state of the art and future perspectives

NASA Astrophysics Data System (ADS)

Friedemann, Jochen; Schock-Kusch, Daniel; Shulhevich, Yury

2017-02-01

Transcutaneous measurement of Glomerular Filtration Rate (tGFR) is now frequently used in preclinical in vivo animal studies. tGFR allows consecutive measurements on the same animal, including multiple measurements on a daily basis. A description of the measurement device and its many applications, along with examples from the recent literature will be given. We will highlight the fields of interest in which the system is used and give an overview about its performance versus endogenous and other exogenous methods of GFR measurement. A special focus will be put on the precision of tGFR compared to standard measurements employed in the research setting.

Adenovirus-vectored Ebola vaccines.

PubMed

Gilbert, Sarah C

2015-01-01

The 2014 outbreak of Ebola virus disease in West Africa has highlighted the need for the availability of effective vaccines against outbreak pathogens that are suitable for use in frontline workers who risk their own health in the course of caring for those with the disease, and also for members of the community in the affected area. Along with effective contact tracing and quarantine, use of a vaccine as soon as an outbreak is identified could greatly facilitate rapid control and prevent the outbreak from spreading. This review describes the progress that has been made in producing and testing adenovirus-based Ebola vaccines in both pre-clinical and clinical studies, and considers the likely future use of these vaccines.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements

PubMed Central

Sprouse, Alyssa A.

2016-01-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug–botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug–botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug–botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. PMID:26438626

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

PubMed

Sprouse, Alyssa A; van Breemen, Richard B

2016-02-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test

PubMed Central

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing. PMID:25010690

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

PubMed

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

2018-04-20

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

Insights from Preclinical Choice Models on Treating Drug Addiction

PubMed Central

Banks, Matthew L.; Negus, S. Stevens

2016-01-01

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

Characterization of novel preclinical dose distributions for micro irradiator

NASA Astrophysics Data System (ADS)

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

2017-05-01

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

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies.

PubMed

Barazzetti, Gaia; Hurst, Samia A; Mauron, Alexandre

2016-08-01

: As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine. ©AlphaMed Press.

Cannabinoids and Epilepsy.

PubMed

Rosenberg, Evan C; Tsien, Richard W; Whalley, Benjamin J; Devinsky, Orrin

2015-10-01

Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

Teaching an engine-driven preparation technique to undergraduates: initial observations.

PubMed

Hänni, S; Schönenberger, K; Peters, O A; Barbakow, F

2003-07-01

This paper describes the initial experiences following the introduction of a rotary engine-driven preparation technique into the undergraduate endodontic programme at the Zurich University Dental Centre. Forty third-year students practised the ProFile.04 (PF.04) technique between January and July 2001 in a preclinical course. Between November 2001 and February 2002, 20 of these students (Group A) root-treated 51 teeth in their clinical course using either PF.04, the balanced force technique (BFT) or a combination of both. The second group of 20 students (Group B) similarly treated another 36 randomly selected teeth between April and July 2002. Types of teeth treated by the students and the canal preparation techniques were recorded. The students also completed a short questionnaire, evaluating their opinions of the new course. Of the 87 teeth endodontically treated during the clinical course, 34, 14 and 39 were shaped using PF.04 alone, a combination of PF.04 and BFT and BFT alone, respectively. No rotary instruments were fractured during the 1-year clinical course, although some instruments were fractured during the preclinical laboratory course. Overall, the students rated the rotary technique as positive. A rotary technique was successfully introduced into an undergraduate endodontic programme (this will be continued in the foreseeable future). However, the continuity between the preclinical and the clinical courses was poor as a result of the constraints of the general teaching programme.

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.

Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease.

PubMed

Mo, Christina; Hannan, Anthony J; Renoir, Thibault

2015-05-01

Unlike many other neurodegenerative diseases with established gene-environment interactions, Huntington's disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identifying environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mechanisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfactory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, however further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity. Copyright © 2015. Published by Elsevier Ltd.

Genomics, proteomics, MEMS and SAIF: which role for diagnostic imaging?

PubMed

Grassi, R; Lagalla, R; Rotondo, A

2008-09-01

In these three words--genomics, proteomics and nanotechnologies--is the future of medicine of the third millennium, which will be characterised by more careful attention to disease prevention, diagnosis and treatment. Molecular imaging appears to satisfy this requirement. It is emerging as a new science that brings together molecular biology and in vivo imaging and represents the key for the application of personalized medicine. Micro-PET (positron emission tomography), micro-SPECT (single photon emission computed tomography), micro-CT (computed tomography), micro-MR (magnetic resonance), micro-US (ultrasound) and optical imaging are all molecular imaging techniques, several of which are applied only in preclinical settings on animal models. Others, however, are applied routinely in both clinical and preclinical setting. Research on small animals allows investigation of the genesis and development of diseases, as well as drug efficacy and the development of personalized therapies, through the study of biological processes that precede the expression of common symptoms of a pathology. Advances in molecular imaging were made possible only by collaboration among scientists in the fields of radiology, chemistry, molecular and cell biology, physics, mathematics, pharmacology, gene therapy and oncology. Although until now researchers have traditionally limited their interactions, it is only by increasing these connections that the current gaps in terminology, methods and approaches that inhibit scientific progress can be eliminated.

Imaging of bacteria: is there any hope for the future based on past experience?

PubMed

Ebenhan, Thomas; Lazzeri, Elena; Gheysens, Olivier

2017-11-21

Infectious diseases remain a major health problem and cause of death worldwide. It is expected that the socio-economic impact will further intensify due to escalating resistance to antibiotics, an ageing population and an increase in the number of patients under immunosuppressive therapy and implanted medical devices. Even though radiolabeled probes and leukocytes are routinely used in clinical practice, it might still be difficult to distinguish sterile inflammation from inflammation caused by bacteria. Moreover, the majority of these probes are based on the attraction of leukocytes which may be hampered in neutropenic patients. Novel approaches that can be implemented in clinical practice and allow for swift diagnosis of infection by targeting the microorganism directly, are posing an attractive strategy. Here we review the current strategies to directly image bacteria using radionuclides and we provide an overview of the preclinical efforts to develop and validate new approaches. Indeed, significant progress has been made in the past years, but very few radiopharmaceuticals (that were promising in preclinical studies) have made it into clinical practice. We will discuss the challenges that remain to select good candidates for imaging agents targeting bacteria. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Current status of endovascular catheter robotics.

PubMed

Lumsden, Alan B; Bismuth, Jean

2018-06-01

In this review, we will detail the evolution of endovascular therapy as the basis for the development of catheter-based robotics. In parallel, we will outline the evolution of robotics in the surgical space and how the convergence of technology and the entrepreneurs who push this evolution have led to the development of endovascular robots. The current state-of-the-art and future directions and potential are summarized for the reader. Information in this review has been drawn primarily from our personal clinical and preclinical experience in use of catheter robotics, coupled with some ground-breaking work reported from a few other major centers who have embraced the technology's capabilities and opportunities. Several case studies demonstrating the unique capabilities of a precisely controlled catheter are presented. Most of the preclinical work was performed in the advanced imaging and navigation laboratory. In this unique facility, the interface of advanced imaging techniques and robotic guidance is being explored. Although this procedure employs a very high-tech approach to navigation inside the endovascular space, we have conveyed the kind of opportunities that this technology affords to integrate 3D imaging and 3D control. Further, we present the opportunity of semi-autonomous motion of these devices to a target. For the interventionist, enhanced precision can be achieved in a nearly radiation-free environment.

Treating autoimmune disorders with venom-derived peptides.

PubMed

Shen, Bingzheng; Cao, Zhijian; Li, Wenxin; Sabatier, Jean-Marc; Wu, Yingliang

2017-09-01

The effective treatment of autoimmune diseases remains a challenge. Voltage-gated potassium Kv1.3 channels, which are expressed in lymphocytes, are a new therapeutic target for treating autoimmune disease. Consequently, Kv1.3 channel-inhibiting venom-derived peptides are a prospective resource for new drug discovery and clinical application. Area covered: Preclinical and clinical studies have produced a wealth of information on Kv1.3 channel-inhibiting venom-derived peptides, especially from venomous scorpions and sea anemones. This review highlights the advances in screening and design of these peptides with diverse structures and potencies. It focuses on representative strategies for improving peptide selectivity and discusses the preclinical research on those venom-derived peptides as well as their clinical developmental status. Expert opinion: Encouraging results indicate that peptides isolated from the venom of venomous animals are a large resource for discovering immunomodulators that act on Kv1.3 channels. Since the structural diversity of venom-derived peptides determines the variety of their pharmacological activities, the design and optimization of venom-peptides for improved Kv1.3 channel-specificity has been advanced through some representative strategies, such as peptide chemical modification, amino acid residue truncation and binding interface modulation. These advances should further accelerate research, development and the future clinical application of venom-derived peptides selectively targeting Kv1.3 channels.

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.

Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder.

PubMed

Banks, Matthew L

2017-04-01

Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation toward abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., money and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self-administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder. © 2016 New York Academy of Sciences.

Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder

PubMed Central

Banks, Matthew L.

2016-01-01

Substance use disorders are diagnosed as a manifestation of inappropriate behavioral allocation towards abused drugs and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., work and social relationships). Substance use disorder treatment goals include not only decreasing drug-maintained behavior but also promoting behavioral reallocation toward these socially adaptive alternative reinforcers. Preclinical drug self-administration procedures that offer concurrent access to both drug and nondrug reinforcers provide a translationally relevant dependent measure of behavioral allocation that may be useful for candidate medication evaluation. In contrast to other abused drugs, such as heroin or cocaine, preclinical methamphetamine versus food choice procedures have been a more recent development. We hypothesize that preclinical to clinical translatability would be improved by the evaluation of repeated pharmacological treatment effects on methamphetamine self-administration under a methamphetamine versus food choice procedure. In support of this hypothesis, a literature review suggests strong concordance between preclinical pharmacological treatment effects on methamphetamine versus food choice in nonhuman primates and clinical medication treatment effects on methamphetamine self-administration in human laboratory studies or methamphetamine abuse metrics in clinical trials. In conclusion, this literature suggests preclinical methamphetamine versus food choice procedures may be useful in developing innovative pharmacotherapies for methamphetamine use disorder. PMID:27936284

Considering sex as a biological variable in preclinical research.

PubMed

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

2017-01-01

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

Increasing efficiency of preclinical research by group sequential designs

PubMed Central

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

2017-01-01

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

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.

Concise Review: Apoptotic Cell-Based Therapies-Rationale, Preclinical Results and Future Clinical Developments.

PubMed

Saas, Philippe; Daguindau, Etienne; Perruche, Sylvain

2016-06-01

The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473. © 2016 AlphaMed Press.

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

The Reversal of Direct Oral Anticoagulants in Animal Models

PubMed Central

Honickel, Markus; Akman, Necib; Grottke, Oliver

2017-01-01

ABSTRACT Several direct oral anticoagulants (DOACs), including direct thrombin and factor Xa inhibitors, have been approved as alternatives to vitamin K antagonist anticoagulants. As with any anticoagulant, DOAC use carries a risk of bleeding. In patients with major bleeding or needing urgent surgery, reversal of DOAC anticoagulation may be required, presenting a clinical challenge. The optimal strategy for DOAC reversal is being refined, and may include use of hemostatic agents such as prothrombin complex concentrates (PCCs; a source of concentrated clotting factors), or DOAC-specific antidotes (which bind their target DOAC to abrogate its activity). Though promising, most specific antidotes are still in development. Preclinical animal research is the key to establishing the efficacy and safety of potential reversal agents. Here, we summarize published preclinical animal studies on reversal of DOAC anticoagulation. These studies (n = 26) were identified via a PubMed search, and used rodent, rabbit, pig, and non-human primate models. The larger of these animals have the advantages of similar blood volume/hemodynamics to humans, and can be used to model polytrauma. We find that in addition to varied species being used, there is variability in the models and assays used between studies; we suggest that blood loss (bleeding volume) is the most clinically relevant measure of DOAC anticoagulation-related bleeding and its reversal. The studies covered indicate that both PCCs and specific reversal agents have the potential to be used as part of a clinical strategy for DOAC reversal. For the future, we advocate the development and use of standardized, clinically, and pharmacologically relevant animal models to study novel DOAC reversal strategies. PMID:28471371

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.

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.

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.

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

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…

Immunotherapy for liver tumors: present status and future prospects

PubMed Central

Matar, Pablo; Alaniz, Laura; Rozados, Viviana; Aquino, Jorge B; Malvicini, Mariana; Atorrasagasti, Catalina; Gidekel, Manuel; Silva, Marcelo; Scharovsky, O Graciela; Mazzolini, Guillermo

2009-01-01

Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field. PMID:19272130

Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date.

PubMed

Hart, Sarah J; Visootsak, Jeannie; Tamburri, Paul; Phuong, Patrick; Baumer, Nicole; Hernandez, Maria-Clemencia; Skotko, Brian G; Ochoa-Lubinoff, Cesar; Liogier D'Ardhuy, Xavier; Kishnani, Priya S; Spiridigliozzi, Gail A

2017-11-01

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome. © 2017 Wiley Periodicals, Inc.

Validation of a Simulation Model of Intrinsic Lutetium-176 Activity in LSO-Based Preclinical PET Systems

NASA Astrophysics Data System (ADS)

McIntosh, Bryan

The LSO scintillator crystal commonly used in PET scanners contains a low level of intrinsic radioactivity due to a small amount of Lu-176. This is not usually a concern in routine scanning but can become an issue in small animal imaging, especially when imaging low tracer activity levels. Previously there had been no systematic validation of simulations of this activity; this thesis discusses the validation of a GATE model of intrinsic Lu-176 against results from a bench-top pair of detectors and a Siemens Inveon preclinical PET system. The simulation results matched those from the bench-top system very well, but did not agree as well with results from the complete Inveon system due to a drop-off in system sensitivity at low energies that was not modelled. With this validation the model can now be used with confidence to predict the effects of Lu-176 activity in future PET systems.

Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease.

PubMed

Eyles, Darryl W; Burne, Thomas H J; McGrath, John J

2013-01-01

Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer's disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

A new method for teaching physical examination to junior medical students.

PubMed

Sayma, Meelad; Williams, Hywel Rhys

2016-01-01

Teaching effective physical examination is a key component in the education of medical students. Preclinical medical students often have insufficient clinical knowledge to apply to physical examination recall, which may hinder their learning when taught through certain understanding-based models. This pilot project aimed to develop a method to teach physical examination to preclinical medical students using "core clinical cases", overcoming the need for "rote" learning. This project was developed utilizing three cycles of planning, action, and reflection. Thematic analysis of feedback was used to improve this model, and ensure it met student expectations. A model core clinical case developed in this project is described, with gout as the basis for a "foot and ankle" examination. Key limitations and difficulties encountered on implementation of this pilot are discussed for future users, including the difficulty encountered in "content overload". This approach aims to teach junior medical students physical examination through understanding, using a simulated patient environment. Robust research is now required to demonstrate efficacy and repeatability in the physical examination of other systems.

Recent Advances in Preclinical Developments Using Adenovirus Hybrid Vectors.

PubMed

Ehrke-Schulz, Eric; Zhang, Wenli; Gao, Jian; Ehrhardt, Anja

2017-10-01

Adenovirus (Ad)-based vectors are efficient gene-transfer vehicles to deliver foreign DNA into living organisms, offering large cargo capacity and low immunogenicity and genotoxicity. As Ad shows low integration rates of their genomes into host chromosomes, vector-derived gene expression decreases due to continuous cell cycling in regenerating tissues and dividing cell populations. To overcome this hurdle, adenoviral delivery can be combined with mechanisms leading to maintenance of therapeutic DNA and long-term effects of the desired treatment. Several hybrid Ad vectors (AdV) exploiting various strategies for long-term treatment have been developed and characterized. This review summarizes recent developments of preclinical approaches using hybrid AdVs utilizing either the Sleeping Beauty transposase system for somatic integration into host chromosomes or designer nucleases, including transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease for permanent gene editing. Further options on how to optimize these vectors further are discussed, which may lead to future clinical applications of these versatile gene-therapy tools.

Mouse Models of Breast Cancer: Platforms for Discovering Precision Imaging Diagnostics and Future Cancer Medicine.

PubMed

Manning, H Charles; Buck, Jason R; Cook, Rebecca S

2016-02-01

Representing an enormous health care and socioeconomic challenge, breast cancer is the second most common cancer in the world and the second most common cause of cancer-related death. Although many of the challenges associated with preventing, treating, and ultimately curing breast cancer are addressable in the laboratory, successful translation of groundbreaking research to clinical populations remains an important barrier. Particularly when compared with research on other types of solid tumors, breast cancer research is hampered by a lack of tractable in vivo model systems that accurately recapitulate the relevant clinical features of the disease. A primary objective of this article was to provide a generalizable overview of the types of in vivo model systems, with an emphasis primarily on murine models, that are widely deployed in preclinical breast cancer research. Major opportunities to advance precision cancer medicine facilitated by molecular imaging of preclinical breast cancer models are discussed. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Resveratrol in metabolic health: an overview of the current evidence and perspectives.

PubMed

Poulsen, Morten Møller; Jørgensen, Jens Otto Lunde; Jessen, Niels; Richelsen, Bjørn; Pedersen, Steen Bønløkke

2013-07-01

In the search for novel preventive and therapeutic modalities in the management of metabolic diseases and obesity, resveratrol has attracted great attention over the past decades. Preclinical trials suggest that resveratrol mimics the metabolic effects of calorie restriction (CR) via activation of silent mating type information regulation 2 homolog 1 (SIRT1). In experimental animals, this potential translates into prevention or improvement of glucose metabolism, anti-inflammation, cancer, and nonalcoholic fatty liver disease. Moreover, and in accordance with CR, supplementation with resveratrol promotes longevity in several primitive species and protects against diet-induced metabolic abnormalities in rodents. Despite the substantial preclinical evidence, human clinical data are very scarce, and even though the compound is widely distributed as an over-the-counter human nutritional supplement, its therapeutic rationale has not been well characterized. In this review, we provide a brief overview of the field and discuss the future scientific directions of resveratrol research. © 2013 New York Academy of Sciences.

Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies.

PubMed

Dos Santos, Rafael G; Hallak, Jaime E C

2017-01-01

Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.

Targeting Androgen Receptor in Breast Cancer: Enzalutamide as a Novel Breast Cancer Therapeutic

DTIC Science & Technology

2015-09-01

preclinical work. Clinical Aim 3: To determine if changes in molecular determinants between pre-treatment biopsies and tissue at time of disease ...D’Amato NC, Elias A, Richer JK. Androgen receptor biology in triple negative breast cancer: a case for AR+ and quadruple negative disease subtypes...cancer and can we target it? 14th Annual International Congress on the Future of Breast Cancer. PER. Huntington Beach, CA 7/17/15. Inventions

Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives.

PubMed

Huang, Yi-Zhou; Xie, Hui-Qi; Silini, Antonietta; Parolini, Ornella; Zhang, Yi; Deng, Li; Huang, Yong-Can

2017-10-01

Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed.

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

PubMed Central

Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

2013-01-01

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

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.

Insights from Preclinical Choice Models on Treating Drug Addiction.

PubMed

Banks, Matthew L; Negus, S Stevens

2017-02-01

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

IMPACT OF OBESITY ON DEVELOPMENT AND PROGRESSION OF MAMMARY TUMORS IN PRECLINICAL MODELS OF BREAST CANCER

PubMed Central

Cleary, Margot P.

2013-01-01

Overweight and/or obesity are known risk factors for postmenopausal breast cancer. More recently increased body weight has also been associated with poor prognosis for both pre- and postmenopausal breast cancer. This relationship has primarily been identified through epidemiological studies. Additional information from in vitro studies has also been produced in attempts to delineate mechanisms of action for the association of obesity and body weight and breast cancer. This approach has identified potential growth factors such as insulin, leptin, estrogen and IGF-I which are reported to be modulated by body weight changes. However, in vitro studies are limited in scope and frequently use non-physiological concentrations of growth factors, while long follow-up is needed for human studies. Preclinical animal models provide an intermediary approach to investigate the impact of body weight and potential growth factors on mammary/breast tumor development and progression. Here results of a number of studies addressing this issue are presented. In the majority of the studies either genetically-obese or diet-induced obese rodent models have been used to investigate spontaneous, transgenic and carcinogen-induced mammary tumor development. To study tumor progression the major focus has been allograft studies in mice with either genetic or dietary-induced obesity. In general, obesity has been demonstrated to shorten mammary tumor latency and to impact tumor pathology. However, in rodents with defects in leptin and other growth factors the impact of obesity is not as straightforward. Future studies using more physiologically relevant obesity models and clearly distinguishing diet composition from body weight effects will be important in continuing to understand the factors associated with body weight’s impact on the mammary/breast cancer development and progression. PMID:24122258

Optical clearing of vaginal tissues in cadavers

NASA Astrophysics Data System (ADS)

Chang, Chun-Hung; Hardy, Luke A.; Peters, Michael G.; Bastawros, Dina A.; Myers, Erinn M.; Kennelly, Michael J.; Fried, Nathaniel M.

2018-02-01

A nonsurgical laser procedure is being developed for treatment of female stress urinary incontinence (SUI). Previous studies in porcine vaginal tissues, ex vivo, as well as computer simulations, showed the feasibility of using near-infrared laser energy delivered through a transvaginal contact cooling probe to thermally remodel endopelvic fascia, while preserving the vaginal wall from thermal damage. This study explores optical properties of vaginal tissue in cadavers as an intermediate step towards future pre-clinical and clinical studies. Optical clearing of tissue using glycerol resulted in a 15-17% increase in optical transmission after 11 min at room temperature (and a calculated 32.5% increase at body temperature). Subsurface thermal lesions were created using power of 4.6 - 6.4 W, 5.2-mm spot, and 30 s irradiation time, resulting in partial preservation of vaginal wall to 0.8 - 1.1 mm depth.

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.

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

[Interdisciplinary longitudinal curriculum "Medical Psychology, Psychotherapy and Psychosomatics." Experiences from the preclinical segment].

PubMed

Schüppel, R; Bayer, A; Hrabal, V; Hölzer, M; Allert, G; Tiedemann, G; Hochkirchen, B; Stephanos, S; Kächele, H; Zenz, H

1998-05-01

The departments of Medical Psychology, Psychosomatics and Psychotherapy developed an interdisciplinary longitudinal curriculum in order to coach medical students for the whole length of their medical education. Experiences from the first four undergraduate semesters are reported. 46 students (33 females, 13 males), mean age 22.3 +/- 2.6 years, attended 60 hours of interdisciplinary group sessions. Frequent motives to join the course were interest in psychosocial disciplines and relevant previous experience. The students expected to benefit from this project in their study, their future practice as a physician, and in their personal development. Important educational goals that could be attained were the adoption of a patient-centred view in medicine as well as strengthening of the students' critical capacities and sensitivity. The students especially appreciated the possibility of group discussions and the opportunity to participate actively in the course. Based on a critical review of the evaluation, the possibility of a transfer of our model is considered and perspectives for the future are developed.

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

PubMed Central

Kaux, Jean-François; Drion, Pierre; Croisier, Jean-Louis; Crielaard, Jean-Michel

2015-01-01

Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon’s healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed. PMID:26195890

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

Magnetic resonance imaging with hyperpolarized agents: methods and applications

NASA Astrophysics Data System (ADS)

Adamson, Erin B.; Ludwig, Kai D.; Mummy, David G.; Fain, Sean B.

2017-07-01

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

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

PubMed

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

2010-02-01

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

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.

Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

PubMed

Martin, Frederic D C; Benjamin, Amanda; MacLean, Ruth; Hollinshead, David M; Landqvist, Claire

2017-12-01

In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Radiochemistry, pre-clinical studies and first clinical investigation of 90Y-labeled hydroxyapatite (HA) particles prepared utilizing 90Y produced by (n,γ) route.

PubMed

Vimalnath, K V; Chakraborty, Sudipta; Rajeswari, A; Sarma, H D; Nuwad, Jitendra; Pandey, Usha; Kamaleshwaran, K; Shinto, Ajit; Dash, Ashutosh

2015-05-01

The scope of using no carrier added (NCA) (90)Y [T(1/2) = 64.1 h, Eβ(max) = 2.28 MeV] obtained from (90)Sr/(90)Y generator in radiation synovectomy (RSV) is widely accepted. In the present study, the prospect of using (90)Y produced by (n,γ) route in a medium flux research reactor for use in RSV was explored. Yttrium-90 was produced by thermal neutron irradiation of Y(2)O(3) target at a neutron flux of ~1×10(14) n/cm(2).s for 14 d. The influence of various experimental parameters were systematically investigated and optimized to arrive at the most favorable conditions for the formulation of (90)Y labeled hydroxyapatite (HA) using HA particles of 1-10 μm size range. An optimized kit formulation strategy was developed for convenient one-step compounding of (90)Y-HA, which is easily adaptable at hospital radiopharmacy. The pre-clinical biological evaluation of (90)Y-HA particles was studied by carrying out biodistribution and bioluminiscence imaging studies in Wistar rats. The first clinical investigation using the radiolabeled preparation was performed on a patient suffering from chronic arthritis in knee joint by administering 185 MBq (90)Y-HA formulated at the hospital radiopharmacy deploying the proposed strategy. Yttrium-90 was produced with a specific activity of 851 ± 111 MBq/mg and radionuclidic purity of 99.95 ± 0.02%. (90)Y-labeled HA particles (185 ± 10 MBq doses) were formulated in high radiochemical purity (>99%) and excellent in vitro stability. The preparation showed promising results in pre-clinical studies carried out in Wistar rats. The preliminary results of the first clinical investigation of (90)Y-HA preparation in a patient with rheumatoid arthritis in knee joints demonstrated the effectiveness of the formulation prepared using (90)Y produced via (n,γ) route in the management of the disease. The studies revealed that effective utilization of (90)Y produced via (n,γ) route in a medium flux research reactor coupled with the developed strategy of using HA kits for convenient formulation of (90)Y-HA at the hospital radiopharmacy can contribute to sustainable growth in the clinical utilization of (90)Y in RSV in the foreseeable future. Copyright © 2015 Elsevier Inc. All rights reserved.

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

Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity.

PubMed

Sanders, R D; Ma, D; Brooks, P; Maze, M

2008-11-01

Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.

The Burn Wound Microenvironment

PubMed Central

Rose, Lloyd F.; Chan, Rodney K.

2016-01-01

Significance: While the survival rate of the severely burned patient has improved significantly, relatively little progress has been made in treatment or prevention of burn-induced long-term sequelae, such as contraction and fibrosis. Recent Advances: Our knowledge of the molecular pathways involved in burn wounds has increased dramatically, and technological advances now allow large-scale genomic studies, providing a global view of wound healing processes. Critical Issues: Translating findings from a large number of in vitro and preclinical animal studies into clinical practice represents a gap in our understanding, and the failures of a number of clinical trials suggest that targeting single pathways or cytokines may not be the best approach. Significant opportunities for improvement exist. Future Directions: Study of the underlying molecular influences of burn wound healing progression will undoubtedly continue as an active research focus. Increasing our knowledge of these processes will identify additional therapeutic targets, supporting informed clinical studies that translate into clinical relevance and practice. PMID:26989577

Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain: an update.

PubMed

Monfett, Michael; Harrison, Julian; Boachie-Adjei, Kwadwo; Lutz, Gregory

2016-06-01

The aim of this article is to provide an overview of clinical and translational research on intradiscal platelet-rich plasma (PRP) as a minimally invasive treatment for discogenic low back pain. A literature review of in vitro, in vivo, and clinical studies was performed. There is strong in vitro evidence that supports the use of intradiscal PRP for discogenic low back pain. There are also promising findings in select preclinical animal studies. A clinical study of 29 participants who underwent intradiscal PRP injections for discogenic low back pain found statistically and clinically significant improvements in pain and function through two years of follow-up. Intradiscal PRP is a safe and a possibly effective treatment for discogenic low back pain. Future studies are warranted to determine the best candidates for this treatment, what the optimal injectate is and what relationships exist between patient-reported outcomes and radiological findings.

Excessive Labeling Technique Provides a Highly Sensitive Fluorescent Probe for Real-time Monitoring of Biodegradation of Biopolymer Pharmaceuticals in vivo.

PubMed

Terekhov, S S; Smirnov, I V; Shamborant, O G; Zenkova, M A; Chernolovskaya, E L; Gladkikh, D V; Murashev, A N; Dyachenko, I A; Knorre, V D; Belogurov, A A; Ponomarenko, N A; Deyev, S M; Vlasov, V V; Gabibov, A G

2014-10-01

Recombinant proteins represent a large sector of the biopharma market. Determination of the main elimination pathways raises the opportunities to significantly increase their half-lives in vivo. However, evaluation of biodegradation of pharmaceutical biopolymers performed in the course of pre-clinical studies is frequently complicated. Noninvasive pharmacokinetic and biodistribution studies in living organism are possible using proteins conjugated with near-infrared dyes. In the present study we designed a highly efficient probe based on fluorescent dye self-quenching for monitoring of in vivo biodegradation of recombinant human butyrylcholinesterase. The maximum enhancement of integral fluorescence in response to degradation of an intravenously administered enzyme was observed 6 h after injection. Importantly, excessive butyrylcholinesterase labeling with fluorescent dye results in significant changes in the pharmacokinetic properties of the obtained conjugate. This fact must be taken into consideration during future pharmacokinetic studies using in vivo bioimaging.

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.

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

PubMed

Baylis, Francoise; McLeod, Marcus

2017-01-01

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

Trends in Handheld Computing Among Medical Students

PubMed Central

Grasso, Michael A.; Yen, M. Jim; Mintz, Matthew L.

2005-01-01

The purpose of this study was to identify trends in the utilization and acceptance of handheld computers (personal digital assistants) among medical students during preclinical and clinical training. These results can be used to identify differences between preclinical and clinical users, differences between current use and idealized use, and perceived limitations of these devices. PMID:16779255

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

PubMed Central

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

2013-01-01

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

Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy.

PubMed Central

Sugar, A M; Goldani, L Z; Picard, M

1991-01-01

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds. PMID:1759836

Pharmacological potentials of betalains.

PubMed

Kaur, Ginpreet; Thawkar, Baban; Dubey, Shivangi; Jadhav, Priyanka

2018-06-06

Betalains are water soluble plant pigments in plants of the order Caryophyllales, which are widely used as colorants. Several preclinical studies reported that betanin reveals antioxidants, anti-inflammatory, hepatoprotective, anticancer, anti-diabetes, anti-lipid emic, antimicrobial activity, radio protective and anti-proliferative activity. They are isolated from sources such as red beetroot, amaranth, prickly pear, red pitahaya, etc. Betalains are divided into two groups based on the colour and confer either the betacyanins (purple reddish) or betaxanthins (yellowish orange). Betalain is one of the promising nutraceuticals which can provide beneficial effects for prevention and cure of various diseases. The purpose of this review is to focus on nutraceutical facts of betalains by focusing on the ongoing treatment using betalains and to address its future nutraceuticals implications.

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 a PET Prostate-Specific Membrane Antigen Imaging Agent: Preclinical Translation for Future Clinical Application

DTIC Science & Technology

2017-10-01

94103 REPORT DATE : October 2017 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland...display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE...Annual 3. DATES COVERED 30 Sep 2016 - 29 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Development of a PET Prostate-Specific Membrane Antigen

A Gram Stain Hands-On Workshop Enhances First Year Medical Students' Technique Competency in Comprehension and Memorization.

PubMed

Delfiner, Matthew S; Martinez, Luis R; Pavia, Charles S

2016-01-01

Laboratory diagnostic tests have an essential role in patient care, and the increasing number of medical and health professions schools focusing on teaching laboratory medicine to pre-clinical students reflects this importance. However, data validating the pedagogical methods that best influence students' comprehension and interpretation of diagnostic tests have not been well described. The Gram stain is a simple yet significant and frequently used diagnostic test in the clinical setting that helps classify bacteria into two major groups, Gram positive and negative, based on their cell wall structure. We used this technique to assess which educational strategies may improve students' learning and competency in medical diagnostic techniques. Hence, in this randomized controlled study, we compared the effectiveness of several educational strategies (e.g. workshop, discussion, or lecture) in first year medical students' competency in comprehension and interpretation of the Gram stain procedure. We demonstrated that a hands-on practical workshop significantly enhances students' competency in memorization and overall comprehension of the technique. Interestingly, most students irrespective of their cohort showed difficulty in answering Gram stain-related analytical questions, suggesting that more emphasis should be allocated by the instructors to clearly explain the interpretation of the diagnostic test results to students in medical and health professional schools. This proof of principle study highlights the need of practical experiences on laboratory medical techniques during pre-clinical training to facilitate future medical doctors' and healthcare professionals' basic understanding and competency in diagnostic testing for better patient care.

Estrogens and Coronary Artery Disease: New Clinical Perspectives.

PubMed

Meyer, M R; Barton, M

2016-01-01

In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the "classical" receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development. © 2016 Elsevier Inc. All rights reserved.

CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

PubMed

Kosovec, Juliann E; Zaidi, Ali H; Omstead, Ashten N; Matsui, Daisuke; Biedka, Mark J; Cox, Erin J; Campbell, Patrick T; Biederman, Robert W W; Kelly, Ronan J; Jobe, Blair A

2017-11-21

Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

Antibody-linked drug shrinks various types of tumors in preclinical study | Center for Cancer Research

Cancer.gov

A preclinical study by Center for Cancer Research investigators and colleagues shows that a drug guided by an attached target-seeking antibody can recognize cells infiltrating tumors, the tumor stroma, and cause various types of tumors to shrink, and in many cases, disappear. Their findings suggest that when stromal cells take up the ADC, they cleave the drug from the antibody

Choice Impulsivity: Definitions, Measurement Issues, and Clinical Implications

PubMed Central

Hamilton, Kristen R.; Mitchell, Marci R.; Wing, Victoria C.; Balodis, Iris M.; Bickel, Warren K.; Fillmore, Mark; Lane, Scott D.; Lejuez, C. W.; Littlefield, Andrew K.; Luijten, Maartje; Mathias, Charles W.; Mitchell, Suzanne H.; Napier, T. Celeste; Reynolds, Brady; Schütz, Christian G.; Setlow, Barry; Sher, Kenneth J.; Swann, Alan C.; Tedford, Stephanie E.; White, Melanie J.; Winstanley, Catharine A.; Yi, Richard; Potenza, Marc N.; Moeller, F. Gerard

2015-01-01

Background Impulsivity critically relates to many psychiatric disorders. Given the multi-faceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. Method The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Results Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. Conclusions The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures. PMID:25867841

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

Use of dynamic images in radiology education: Movies of CT and MRI in the anatomy classroom.

PubMed

Jang, Hye Won; Oh, Chang-Seok; Choe, Yeon Hyeon; Jang, Dong Su

2018-04-19

Radiology education is a key component in many preclinical anatomy courses. However, the reported effectiveness of radiology education within such anatomy classrooms has varied. This study was conducted to determine if a novel educational method using dynamic images of movies of computed tomography (CT) and magnetic resonance imaging (MRI) was effective in radiology education during a preclinical anatomy course, aided by clay modeling, specific hand gestures (digit anatomy), and reports from dissection findings uploaded to the anatomy course website (digital reports). Feedback surveys using a five-point Likert scale were administered to better clarify students' opinions regarding their understanding of CT and MRI of anatomical structures, as well as to determine if such preclinical radiology education was helpful in their clinical studies. After completion of the anatomy course taught with dynamic images of CT and MRI, most students demonstrated an adequate understanding of basic CT and MR images. Additionally, students in later clinical years generally believed that their study of radiologic images during the preclinical anatomy course was helpful for their clinical studies and clerkship rotations. Moreover, student scores on imaging anatomy examinations demonstrated meaningful improvements in performance after using dynamic images from movies of CT and MRI. Anat Sci Educ. © 2018 American Association of Anatomists. © 2018 American Association of Anatomists.

Comparison of computer-assisted instruction (CAI) versus traditional textbook methods for training in abdominal examination (Japanese experience).

PubMed

Qayumi, A K; Kurihara, Y; Imai, M; Pachev, G; Seo, H; Hoshino, Y; Cheifetz, R; Matsuura, K; Momoi, M; Saleem, M; Lara-Guerra, H; Miki, Y; Kariya, Y

2004-10-01

This study aimed to compare the effects of computer-assisted, text-based and computer-and-text learning conditions on the performances of 3 groups of medical students in the pre-clinical years of their programme, taking into account their academic achievement to date. A fourth group of students served as a control (no-study) group. Participants were recruited from the pre-clinical years of the training programmes in 2 medical schools in Japan, Jichi Medical School near Tokyo and Kochi Medical School near Osaka. Participants were randomly assigned to 4 learning conditions and tested before and after the study on their knowledge of and skill in performing an abdominal examination, in a multiple-choice test and an objective structured clinical examination (OSCE), respectively. Information about performance in the programme was collected from school records and students were classified as average, good or excellent. Student and faculty evaluations of their experience in the study were explored by means of a short evaluation survey. Compared to the control group, all 3 study groups exhibited significant gains in performance on knowledge and performance measures. For the knowledge measure, the gains of the computer-assisted and computer-assisted plus text-based learning groups were significantly greater than the gains of the text-based learning group. The performances of the 3 groups did not differ on the OSCE measure. Analyses of gains by performance level revealed that high achieving students' learning was independent of study method. Lower achieving students performed better after using computer-based learning methods. The results suggest that computer-assisted learning methods will be of greater help to students who do not find the traditional methods effective. Explorations of the factors behind this are a matter for future research.

Stem Cell Therapies for Knee Cartilage Repair: The Current Status of Preclinical and Clinical Studies

PubMed Central

Anderson, John A.; Little, Dianne; Toth, Alison P.; Moorman, Claude T.; Tucker, Bradford S.; Ciccotti, Michael G.; Guilak, Farshid

2014-01-01

Background Articular cartilage damage of the knee is common, causing significant morbidity worldwide. Many adult tissues contain cells that are able to differentiate into multiple cell types, including chondrocytes. These stem cells have gained significant attention over the past decade and may become frontline management for cartilage defects in the very near future. Purpose The role of stem cells in the treatment of knee osteochondral defects was reviewed. Recent animal and clinical studies were reviewed to determine the benefits and potential outcomes of using stem cells for cartilage defects. Study Design Literature review. Methods A PubMed search was undertaken. The key phrase “stem cells and knee” was used. The search included reviews and original articles over an unlimited time period. From this search, articles outlining animal and clinical trials were selected. A search of current clinical trials in progress was performed on the clinicaltrials.gov website, and “stem cells and knee” was used as the search phrase. Results Stem cells have been used in many recent in vitro and animal studies. A number of cell-based approaches for cartilage repair have progressed from preclinical animal studies into clinical trials. Conclusion The use of stem cells for the treatment of cartilage defects is increasing in animal and clinical studies. Methods of delivery of stem cells to the knee’s cartilage vary from direct injection to implantation with scaffolds. While these approaches are highly promising, there is currently limited evidence of a direct clinical benefit, and further research is required to assess the overall outcome of stem cell therapies for knee cartilage repair. PMID:24220016

Learning styles and academic achievement among undergraduate medical students in Thailand.

PubMed

Jiraporncharoen, Wichuda; Angkurawaranon, Chaisiri; Chockjamsai, Manoch; Deesomchok, Athavudh; Euathrongchit, Juntima

2015-01-01

This study aimed to explore the associations between learning styles and high academic achievement and to ascertain whether the factors associated with high academic achievement differed between preclinical and clinical students. A survey was conducted among undergraduate medical students in Chiang Mai University, Thailand. The Index of Learning Styles questionnaire was used to assess each student's learning style across four domains. High academic achievement was defined as a grade point average of at least 3.0. Of the 1,248 eligible medical students, 1,014 (81.3%) participated. Learning styles differed between the preclinical and clinical students in the active/reflective domain. A sequential learning style was associated with high academic achievement in both preclinical and clinical students. A reflective learning style was only associated with high academic achievement among preclinical students. The association between learning styles and academic achievement may have differed between preclinical and clinical students due to different learning content and teaching methods. Students should be encouraged to be flexible in their own learning styles in order to engage successfully with various and changing teaching methods across the curriculum. Instructors should be also encouraged to provide a variety of teaching materials and resources to suit different learning styles.

Stress, Burnout and Coping Strategies in Preclinical Medical Students.

PubMed

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

2016-02-01

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

Stress, Burnout and Coping Strategies in Preclinical Medical Students

PubMed Central

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

2016-01-01

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

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

Future directions in bladder cancer immunotherapy: towards adaptive immunity

PubMed Central

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

Future directions in bladder cancer immunotherapy: towards adaptive immunity.

PubMed

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

Future Prospects for the Total Artificial Heart.

PubMed

Sunagawa, Gengo; Horvath, David J; Karimov, Jamshid H; Moazami, Nader; Fukamachi, Kiyotaka

2016-01-01

A total artificial heart (TAH) is the sole remaining option for patients with biventricular failure who cannot be rescued by left ventricular assist devices (LVADs) alone. However, the pulsatile TAH in clinical use today has limitations: large pump size, unknown durability, required complex anticoagulation regimen, and association with significant postsurgical complications. That pump is noisy; its large pneumatic driving lines traverse the body, with bulky external components for its drivers. Continuous-flow pumps, which caused a paradigm shift in the LVAD field, have already contributed to the rapidly evolving development of TAHs. Novel continuous-flow TAHs are only in preclinical testing or developmental stages. We here review the current state of TAHs, with recommended requirements for the TAH of the future.

CRISPR-mediated Ophthalmic Genome Surgery.

PubMed

Cho, Galaxy Y; Abdulla, Yazeed; Sengillo, Jesse D; Justus, Sally; Schaefer, Kellie A; Bassuk, Alexander G; Tsang, Stephen H; Mahajan, Vinit B

2017-09-01

Clustered regularly interspaced short palindromic repeats (CRISPR) is a genome engineering system with great potential for clinical applications due to its versatility and programmability. This review highlights the development and use of CRISPR-mediated ophthalmic genome surgery in recent years. Diverse CRISPR techniques are in development to target a wide array of ophthalmic conditions, including inherited and acquired conditions. Preclinical disease modeling and recent successes in gene editing suggest potential efficacy of CRISPR as a therapeutic for inherited conditions. In particular, the treatment of Leber congenital amaurosis with CRISPR-mediated genome surgery is expected to reach clinical trials in the near future. Treatment options for inherited retinal dystrophies are currently limited. CRISPR-mediated genome surgery methods may be able to address this unmet need in the future.

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

PubMed

Kim, Soonih

2014-01-01

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

Health behaviors, care needs and attitudes towards self-prescription: a cross-sectional survey among Dutch medical students.

PubMed

Van der Veer, Tjeerd; Frings-Dresen, Monique H W; Sluiter, Judith K

2011-01-01

There is a growing awareness of the potent ways in which the wellbeing of physicians impacts the health of their patients. The purpose of this study was to investigate the health behaviors, care needs and attitudes towards self-prescription of Dutch medical students, and any differences between junior preclinical and senior clinically active students. All students (n = 2695) of a major Dutch medical school were invited for an online survey. Physical activity, eating habits, alcohol consumption, smoking, Body Mass Index, substance use and amount of sleep per night were inquired, as well as their need for different forms of care and their attitude towards self-prescription. Data of 902 students were used. Physical activity levels (90% sufficient) and smoking prevalence (94% non-smokers) were satisfying. Healthy eating habits (51% insufficient) and alcohol consumption (46% excessive) were worrying. Body Mass Indexes were acceptable (20% unhealthy). We found no significant differences in health behaviors between preclinical and clinically active students. Care needs were significantly lower among clinically active students. (p<0.05) Student acceptance of self-prescription was significantly higher among clinically active students. (p<0.001) Unhealthy behaviors are prevalent among medical students, but are no more prevalent during the clinical study phase. The need for specific forms of care appears lower with study progression. This could be worrying as the acceptance of self-care and self-prescription is higher among senior clinical students. Medical faculties need to address students' unhealthy behaviors and meet their care needs for the benefit of both the future physicians as well as their patients.

The role of gangliosides in brain development and the potential benefits of perinatal supplementation.

PubMed

Ryan, Jennifer M; Rice, Gregory E; Mitchell, Murray D

2013-11-01

The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research. © 2013.

Virtual reality, augmented reality, and robotics applied to digestive operative procedures: from in vivo animal preclinical studies to clinical use

NASA Astrophysics Data System (ADS)

Soler, Luc; Marescaux, Jacques

2006-04-01

Technological innovations of the 20 th century provided medicine and surgery with new tools, among which virtual reality and robotics belong to the most revolutionary ones. Our work aims at setting up new techniques for detection, 3D delineation and 4D time follow-up of small abdominal lesions from standard mecial images (CT scsan, MRI). It also aims at developing innovative systems making tumor resection or treatment easier with the use of augmented reality and robotized systems, increasing gesture precision. It also permits a realtime great distance connection between practitioners so they can share a same 3D reconstructed patient and interact on a same patient, virtually before the intervention and for real during the surgical procedure thanks to a telesurgical robot. In preclinical studies, our first results obtained from a micro-CT scanner show that these technologies provide an efficient and precise 3D modeling of anatomical and pathological structures of rats and mice. In clinical studies, our first results show the possibility to improve the therapeutic choice thanks to a better detection and and representation of the patient before performing the surgical gesture. They also show the efficiency of augmented reality that provides virtual transparency of the patient in real time during the operative procedure. In the near future, through the exploitation of these systems, surgeons will program and check on the virtual patient clone an optimal procedure without errors, which will be replayed on the real patient by the robot under surgeon control. This medical dream is today about to become reality.

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.

Early clinical applications for imaging at microscopic detail: microfocus computed tomography (micro-CT).

PubMed

Hutchinson, J Ciaran; Shelmerdine, Susan C; Simcock, Ian C; Sebire, Neil J; Arthurs, Owen J

2017-07-01

Microfocus CT (micro-CT) has traditionally been used in industry and preclinical studies, although it may find new applicability in the routine clinical setting. It can provide high-resolution three-dimensional digital imaging data sets to the same level of detail as microscopic examination without the need for tissue dissection. Micro-CT is already enabling non-invasive detailed internal assessment of various tissue specimens, particularly in breast imaging and early gestational fetal autopsy, not previously possible from more conventional modalities such as MRI or CT. In this review, we discuss the technical aspects behind micro-CT image acquisition, how early work with small animal studies have informed our knowledge of human disease and the imaging performed so far on human tissue specimens. We conclude with potential future clinical applications of this novel and emerging technique.

VARK Learning Preferences and Mobile Anatomy Software Application Use in Pre-Clinical Chiropractic Students

ERIC Educational Resources Information Center

Meyer, Amanda J.; Stomski, Norman J.; Innes, Stanley I.; Armson, Anthony J.

2016-01-01

Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists…

Comparative Analysis of Nursing Students' Perspectives toward Avatar Learning Modality: Gain Pre-Clinical Experience via Self-Paced Cognitive Tool

ERIC Educational Resources Information Center

Commendador, Kathleen; Chi, Robert

2013-01-01

This study was undertaken to better understand the nature of nursing students' perspectives toward simulative learning modality for gaining pre-clinical experience via self-paced cognitive tool--Avatar. Findings indicates that participants engaged in synchronous Avatar learning environment had higher levels of appreciation toward Avatar learning…

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

Efficacy of Alteplase® in a mouse model of acute ischemic stroke: a retrospective pooled analysis

PubMed Central

Orset, Cyrille; Haelewyn, Benoit; Allan, Stuart M.; Ansar, Saema; Campos, Francesco; Cho, Tae Hee; Durand, Anne; El Amki, Mohamad; Fatar, Marc; Garcia-Yébenes, Isaac; Gauberti, Maxime; Grudzenski, Saskia; Lizasoain, Ignacio; Lo, Eng; Macrez, Richard; Margaill, Isabelle; Maysami, Samaneh; Meairs, Stephen; Nighoghossian, Norbert; Orbe, Josune; Paramo, Jose Antonio; Parienti, Jean-Jacques; Rothwell, Nancy J.; Rubio, Marina; Waeber, Christian; Young, Alan R.

2016-01-01

Background and purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Conclusion Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial. PMID:27032444

The role of flower pollen extract in managing patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials.

PubMed

Cai, Tommaso; Verze, Paolo; La Rocca, Roberto; Anceschi, Umberto; De Nunzio, Cosimo; Mirone, Vincenzo

2017-04-21

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still a challenge to manage for all physicians. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic efficacy of flower pollen extract would be helpful for physicians who are considering a phytotherapeutic approach to treating patients with CP/CPPS. A comprehensive search of the PubMed and Embase databases up to June 2016 was performed. This comprehensive analysis included both pre-clinical and clinical trials on the role of flower pollen extract in CP/CPPS patients. Moreover, a meta-analysis of available randomized controlled trials (RCTs) was performed. The NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and Quality of Life related questionnaires (QoL) were the most commonly used tools to evaluate the therapeutic efficacy of pollen extract. Pre-clinical studies demonstrated the anti-inflammatory and anti-proliferative role of pollen extract. 6 clinical, non-controlled studies including 206 patients, and 4 RCTs including 384 patients were conducted. The mean response rate in non-controlled studies was 83.6% (62.2%-96.0%). The meta-analysis revealed that flower pollen extract could significantly improve patients' quality of life [OR 0.52 (0.34-.0.81); p = 0.02]. No significant adverse events were reported. Most of these studies presented encouraging results in terms of variations in NIH-CPSI and QoL scores. These studies suggest that the use of flower pollen extract for the management of CP/CPPS patients is beneficial. Future publications of robust evidence from additional RCTs and longer-term follow-up would provide more support encouraging the use of flower pollen extracts for CP/CPPS patients.

Statins in Asthma: Potential Beneficial Effects and Limitations

PubMed Central

Bhattacharjee, Dipanjan

2015-01-01

Asthma's sustenance as a global pandemic, across centuries, can be attributed to the lack of an understanding of its workings and the inability of the existing treatment modalities to provide a long lasting cure without major adverse effects. The discovery of statins boosted by a better comprehension of the pathophysiology of asthma in the past few decades has opened up a potentially alternative line of treatment that promises to be a big boon for the asthmatics globally. However, the initial excellent results from the preclinical and animal studies have not borne the results in clinical trials that the scientific world was hoping for. In light of this, this review analyzes the ways by which statins could benefit in asthma via their pleiotropic anti-inflammatory properties and explain some of the queries raised in the previous studies and provide recommendations for future studies in this field. PMID:26618001

The challenge of developing a herpes simplex virus 2 vaccine

PubMed Central

Dropulic, Lesia K; Cohen, Jeffrey I

2013-01-01

HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies. PMID:23252387

Targeting the DNA damage response in oncology: past, present and future perspectives.

PubMed

Basu, Bristi; Yap, Timothy A; Molife, L Rhoda; de Bono, Johann S

2012-05-01

The success of poly(ADP-ribose) polymerase inhibition in BRCA1 or BRCA2 deficient tumors as an anticancer strategy provided proof-of-concept for a synthetic lethality approach in oncology. There is therefore now active interest in expanding this approach to include other agents targeting the DNA damage response (DDR). We review lessons learnt from the development of inhibitors against DNA damage response mechanisms and envision the future of DNA repair inhibition in oncology. Preclinical synthetic lethality screens may potentially identify the best combinations of DNA-damaging drugs with inhibitors of DNA repair and the DDR or two agents acting within the DDR. Efforts are currently being made to establish robust and cost-effective assays that may be implemented within appropriate time-scales in parallel with future clinical studies. Detection of relevant mutations in a high-throughput manner, such as with next-generation sequencing for genes implicated in homologous recombination, including BRCA1, BRCA2, and ataxia telangiectasia mutated is anticipated. Novel approaches targeting the DDR are currently being evaluated and inhibitors of ATM, RAD51 and DNA-dependent protein kinase are now in early drug discovery and development. There remains great enthusiasm in oncology practice for pursuing the strategy of synthetic lethality. The future development of antitumor agents targeting the DDR should include detailed correlative biomarker work within early phase clinical studies wherever possible, with clear attempts to identify doses at which robust target modulation is observed.

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

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

PubMed Central

Walther, Sebastian; Halpern, Michael

2010-01-01

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

Preclinical Testing of a Translocator Protein Ligand for the Treatment of Amyotrophic Lateral Sclerosis

DTIC Science & Technology

2017-03-01

Accessed October 26, 2015]. Barneoud, P. et al., 1997. Quantitative motor assessment in FALS mice: a longitudinal study . Neuroreport, 8, pp.2861–2865...cell study , we found that PK acts directly on motor neurons to prevent their death, not via the astrocytes. Then, we evidenced that PK protects not...in TSPO content may protect motor neurons against ALS. Second, in our preclinical study in ALS mice, we have determined that the best route to

Impact of Age and Polytherapy on Fingolimod Induced Bradycardia: a Preclinical Study.

PubMed

Ritter, Christian; Svačina, Martin K R; Bobylev, Ilja; Joshi, Abhijeet; Schneider, Toni; Lehmann, Helmar C

2017-03-01

Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.

Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways

PubMed Central

Evans, Christopher M.; Fingerlin, Tasha E.; Schwarz, Marvin I.; Lynch, David; Kurche, Jonathan; Warg, Laura; Yang, Ivana V.; Schwartz, David A.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF. PMID:27630174

Use of multimodality imaging and artificial intelligence for diagnosis and prognosis of early stages of Alzheimer's disease.

PubMed

Liu, Xiaonan; Chen, Kewei; Wu, Teresa; Weidman, David; Lure, Fleming; Li, Jing

2018-04-01

Alzheimer's disease (AD) is a major neurodegenerative disease and the most common cause of dementia. Currently, no treatment exists to slow down or stop the progression of AD. There is converging belief that disease-modifying treatments should focus on early stages of the disease, that is, the mild cognitive impairment (MCI) and preclinical stages. Making a diagnosis of AD and offering a prognosis (likelihood of converting to AD) at these early stages are challenging tasks but possible with the help of multimodality imaging, such as magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG)-positron emission topography (PET), amyloid-PET, and recently introduced tau-PET, which provides different but complementary information. This article is a focused review of existing research in the recent decade that used statistical machine learning and artificial intelligence methods to perform quantitative analysis of multimodality image data for diagnosis and prognosis of AD at the MCI or preclinical stages. We review the existing work in 3 subareas: diagnosis, prognosis, and methods for handling modality-wise missing data-a commonly encountered problem when using multimodality imaging for prediction or classification. Factors contributing to missing data include lack of imaging equipment, cost, difficulty of obtaining patient consent, and patient drop-off (in longitudinal studies). Finally, we summarize our major findings and provide some recommendations for potential future research directions. Copyright © 2018 Elsevier Inc. All rights reserved.

Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities

PubMed Central

Moloney, Rachel D.; O’Mahony, Siobhain M.; Dinan, Timothy G.; Cryan, John F.

2015-01-01

Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent. PMID:25762939

Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review.

PubMed

Wang, Yuchen; Newman, Maureen R; Benoit, Danielle S W

2018-06-01

Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical studies has shown promise, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed

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

2011-09-15

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

Design of a Type-1 Diabetes Vaccine Candidate Using Edible Plants Expressing a Major Autoantigen

PubMed Central

Bertini, Edoardo; Merlin, Matilde; Gecchele, Elisa; Puggia, Andrea; Brozzetti, Annalisa; Commisso, Mauro; Falorni, Alberto; Bini, Vittorio; Klymyuk, Victor; Pezzotti, Mario; Avesani, Linda

2018-01-01

Type-1 diabetes (T1D) is a metabolic disease involving the autoimmune destruction of insulin-producing pancreatic beta cells. It is often diagnosed by the detection of autoantibodies, typically those recognizing insulin itself or the 65-kDa isoform of glutamic acid decarboxylase (GAD65). Oral insulin can be used to induce systemic immunological tolerance and thus prevent or delay the onset of T1D, suggesting that combination treatments with other autoantigens such as GAD65 could be even more successful. GAD65 has induced oral tolerance and prevented T1D in preclinical studies but it is difficult to produce in sufficient quantities for clinical testing. Here we combined edible plant systems, namely spinach (Spinacia oleracea cv Industra) and red beet (Beta vulgaris cv Moulin Rouge), with the magnICON® expression system to develop a safe, cost-effective and environmentally sustainable platform for the large-scale production of GAD65. The superior red beet platform was extensively characterized in terms of recombinant protein yields and bioequivalence to wild-type plants, and the product was tested for its ability to resist simulated gastric digestion. Our results indicate that red beet plants are suitable for the production of a candidate oral vaccine based on GAD65 for the future preclinical and clinical testing of T1D immunotherapy approaches. PMID:29765386

Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma

PubMed Central

Zolkind, Paul; Przybylski, Dariusz; Marjanovic, Nemanja; Nguyen, Lan; Lin, Tianxiang; Johanns, Tanner; Alexandrov, Anton; Zhou, Liye; Allen, Clint T.; Miceli, Alexander P.; Schreiber, Robert D.; Artyomov, Maxim; Dunn, Gavin P.; Uppaluri, Ravindra

2018-01-01

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics. PMID:29423108

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.

Heterologous Prime-Boost HIV-1 Vaccination Regimens in Pre-Clinical and Clinical Trials

PubMed Central

Brown, Scott A.; Surman, Sherri L.; Sealy, Robert; Jones, Bart G.; Slobod, Karen S.; Branum, Kristen; Lockey, Timothy D.; Howlett, Nanna; Freiden, Pamela; Flynn, Patricia; Hurwitz, Julia L.

2010-01-01

Currently, there are more than 30 million people infected with HIV-1 and thousands more are infected each day. Vaccination is the single most effective mechanism for prevention of viral disease, and after more than 25 years of research, one vaccine has shown somewhat encouraging results in an advanced clinical efficacy trial. A modified intent-to-treat analysis of trial results showed that infection was approximately 30% lower in the vaccine group compared to the placebo group. The vaccine was administered using a heterologous prime-boost regimen in which both target antigens and delivery vehicles were changed during the course of inoculations. Here we examine the complexity of heterologous prime-boost immunizations. We show that the use of different delivery vehicles in prime and boost inoculations can help to avert the inhibitory effects caused by vector-specific immune responses. We also show that the introduction of new antigens into boost inoculations can be advantageous, demonstrating that the effect of ‘original antigenic sin’ is not absolute. Pre-clinical and clinical studies are reviewed, including our own work with a three-vector vaccination regimen using recombinant DNA, virus (Sendai virus or vaccinia virus) and protein. Promising preliminary results suggest that the heterologous prime-boost strategy may possibly provide a foundation for the future prevention of HIV-1 infections in humans. PMID:20407589

Is adiponectin a marker of preclinical atherosclerosis in kidney transplantation?

PubMed

Cañas, Laura; Bayés, Beatriz; Granada, Maria L; Ibernon, Meritxell; Porrini, Esteban; Benítez, Rosa; Díaz, Juan M; Lauzurica, Ricardo; Moreso, Francesc; Torres, Armando; Lampreabe, Ildefonso; Serra, Assumpta; Romero, Ramon

2012-01-01

The aim of this study was to analyze the relationship between pre-transplant adiponectin (pre-ADP), abnormalities in glucose homeostasis (AGH) at three months post-transplantation, and preclinical atherosclerosis in non-diabetic patients prior to kidney transplantation (KT). We carried out a multicenter study in 157 non-diabetic KT patients (66.5% men; age: 50±13 yr). Pre-ADP levels were analyzed using radioimmunoassay. Carotid ultrasound was performed to determine carotid intima-media thickness (c-IMT). Oral glucose tolerance test was carried out to classify patients according ADA criteria. Of the patients, 52.8% had AGH. Median pre-ADP was 19.5 (14-27) μg/mL. An inverse correlation was found between ADP and HOMA index (r=-0.432; p<0.001). Median c-IMT was 0.6 (0.48-0.71) mm. Significant inverse correlation existed between ADP and c-IMT on both sides (p<0.05). Patients with c-IMT >0.6 mm had more AGH (p=0.012) and lower ADP levels (p=0.02). We performed a logistic regression analysis using preclinical atherosclerosis (c-IMT ≥0.6 mm) as dependent variable and sex, age, BMI, ADP, AGH, and HOMA index as independent variables of altered c-IMT. Age, pre-ADP, and AGH were independent risk factors for elevated c-IMT. Patients with AGH have a greater presence of preclinical atherosclerosis. ADP has an inverse relationship with AGH and is an independent marker of preclinical atherosclerosis. © 2011 John Wiley & Sons A/S.

DNA nanomaterials for preclinical imaging and drug delivery.

PubMed

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

2016-10-10

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

Near-infrared fluorescence image-guidance in plastic surgery: A systematic review.

PubMed

Cornelissen, Anouk J M; van Mulken, Tom J M; Graupner, Caitlin; Qiu, Shan S; Keuter, Xavier H A; van der Hulst, René R W J; Schols, Rutger M

2018-01-01

Near-infrared fluorescence (NIRF) imaging technique, after administration of contrast agents with fluorescent characteristics in the near-infrared (700-900 nm) range, is considered to possess great potential for the future of plastic surgery, given its capacity for perioperative, real-time anatomical guidance and identification. This study aimed to provide a comprehensive literature review concerning current and potential future applications of NIRF imaging in plastic surgery, thereby guiding future research. A systematic literature search was performed in databases of Cochrane Library CENTRAL, MEDLINE, and EMBASE (last search Oct 2017) regarding NIRF imaging in plastic surgery. Identified articles were screened and checked for eligibility by two authors independently. Forty-eight selected studies included 1166 animal/human subjects in total. NIRF imaging was described for a variety of (pre)clinical applications in plastic surgery. Thirty-two articles used NIRF angiography, i.e., vascular imaging after intravenous dye administration. Ten articles reported on NIRF lymphography after subcutaneous dye administration. Although currently most applied, general protocols for dosage and timing of dye administration for NIRF angiography and lymphography are still lacking. Three articles applied NIRF to detect nerve injury, and another three studies described other novel applications in plastic surgery. Future standard implementation of novel intraoperative optical techniques, such as NIRF imaging, could significantly contribute to perioperative anatomy guidance and facilitate critical decision-making in plastic surgical procedures. Further investigation (i.e., large multicenter randomized controlled trials) is mandatory to establish the true value of this innovative surgical imaging technique in standard clinical practice and to aid in forming consensus on protocols for general use.Level of Evidence: Not ratable.

Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status.

PubMed

Haedersdal, Merete; Erlendsson, Andrés M; Paasch, Uwe; Anderson, R Rox

2016-05-01

Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice. We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy. We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence. All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long-lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas. Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The failure to detect drug-induced sensory loss in standard preclinical studies.

PubMed

Gauvin, David V; Abernathy, Matthew M; Tapp, Rachel L; Yoder, Joshua D; Dalton, Jill A; Baird, Theodore J

2015-01-01

Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

Preclinical students’ experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia

PubMed Central

2012-01-01

Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419

A quantitative analysis of statistical power identifies obesity endpoints for improved in vivo preclinical study design

PubMed Central

Selimkhanov, Jangir; Thompson, W. Clayton; Guo, Juen; Hall, Kevin D.; Musante, Cynthia J.

2017-01-01

The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design. PMID:28392555

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

PubMed

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

2013-09-01

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

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

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

'Muscle-sparing' statins: preclinical profiles and future clinical use.

PubMed

Pfefferkorn, Jeffrey A

2009-03-01

Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

Insights into cerebellar development and medulloblastoma.

PubMed

Bihannic, Laure; Ayrault, Olivier

2016-01-01

Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Iron overload cardiomyopathy: from diagnosis to management.

PubMed

Díez-López, Carles; Comín-Colet, Josep; González-Costello, José

2018-05-01

Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.

Identification and preclinical testing of novel antiepileptic compounds.

PubMed

Meldrum, B S

1997-01-01

Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.

A report from the European Society of Cardiology Congress 2013 (August 31-September 4, 2013 - Amsterdam, the Netherlands).

PubMed

Rabasseda, X

2013-09-01

Many are the diseases that can affect the heart and the vessels, most of which were discussed during the European Society of Cardiology Congress 2013 in Amsterdam. With an attendance of almost 30,000 delegates buzzing the halls of the RAI convention center, Amsterdam was the capital of cardiologic science this summer, and a big challenge for any attendee trying to get the most out of all the oral and poster sessions missing the minimum of new science being presented. Thomson Reuters Cortellis™ supplements the information for any scientist who missed an important session, with a particular focus on new investigational drugs, many of them still in preclinical research, which will certainly impact how cardiovascular disorders are treated in a foreseeable future. Clinical and preclinical research advance to bring novel therapeutic targets, new drugs and new insight into patient characteristics requiring particular treatment approaches. This report is a sample of the new science discussed during the 5 days of meetings. Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.

Translational science: past, present, and future.

PubMed

Curry, Stephen H

2008-02-01

The concept of translational science is at least 15 years old. However, in its most recent incarnation, it represents the identification of a funding category designed to encourage academic participation in a critical stage of the drug discovery and product development process. It is hoped that this will make the process both shorter and more efficient. In this review, the author first considers the historical development of the pharmaceutical R&D process. The place of translational science in the process, the scientific techniques involved, and aspects of the business environment necessary for its success are then considered. Translational science does not displace preclinical development. Both concepts are relevant to the paramount importance of successfully and expeditiously bridging the gap between preclinical science and clinical testing, "from bench to bedside." Translational science is particularly likely to stimulate biomarker research in the universities and related business community and will probably give a modest boost to early clinical testing and commercialization of discoveries within the academic setting. Whether there will be a consequent improvement in the quality and efficiency of the overall process remains to be seen.

A new method for teaching physical examination to junior medical students

PubMed Central

Sayma, Meelad; Williams, Hywel Rhys

2016-01-01

Introduction Teaching effective physical examination is a key component in the education of medical students. Preclinical medical students often have insufficient clinical knowledge to apply to physical examination recall, which may hinder their learning when taught through certain understanding-based models. This pilot project aimed to develop a method to teach physical examination to preclinical medical students using “core clinical cases”, overcoming the need for “rote” learning. Methods This project was developed utilizing three cycles of planning, action, and reflection. Thematic analysis of feedback was used to improve this model, and ensure it met student expectations. Results and discussion A model core clinical case developed in this project is described, with gout as the basis for a “foot and ankle” examination. Key limitations and difficulties encountered on implementation of this pilot are discussed for future users, including the difficulty encountered in “content overload”. Conclusion This approach aims to teach junior medical students physical examination through understanding, using a simulated patient environment. Robust research is now required to demonstrate efficacy and repeatability in the physical examination of other systems. PMID:26937208

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.

The Challenge of Targeting Notch in Hematologic Malignancies

PubMed Central

Hernandez Tejada, Fiorela N.; Galvez Silva, Jorge R.; Zweidler-McKay, Patrick A.

2014-01-01

Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor. Targeting Notch signaling in T-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future. PMID:24959528

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

PubMed

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

2018-05-01

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

Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity.

PubMed

Abushouk, Abdelrahman Ibrahim; Ismail, Ammar; Salem, Amr Muhammad Abdo; Afifi, Ahmed M; Abdel-Daim, Mohamed M

2017-06-01

Doxorubicin (DOX) is an anthracycline antibiotic, which is effectively used in the treatment of different malignancies, such as leukemias and lymphomas. Its most serious side effect is dose-dependent cardiotoxicity, which occurs through inducing oxidative stress apoptosis. Due to the myelosuppressive effect of dexrazoxane, a commonly-used drug to alleviate DOX-induced cardiotoxicity, researchers investigated the potential of phytochemicals for prophylaxis and treatment of this condition. Phytochemicals are plant chemicals that have protective or disease preventive properties. Preclinical trials have shown antioxidant properties for several plant extracts, such as those of Aerva lanata, Aronia melanocarpa, Astragalus polysaccharide, and Bombyx mori plants. Other plant extracts showed an ability to inhibit apoptosis, such as those of Astragalus polysaccharide, Azadirachta indica, Bombyx mori, and Allium stavium plants. Unlike synthetic agents, phytochemicals do not impair the clinical activity of DOX and they are particularly safe for long-term use. In this review, we summarized the results of preclinical trials that investigated the cardioprotective effects of phytochemicals against DOX-induced cardiotoxicity. Future human trials are required to translate these cardioprotective mechanisms into practical clinical implications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

First impressions: what are preclinical medical students in the US and Canada learning about sexual and reproductive health?

PubMed

Steinauer, Jody; LaRochelle, Flynn; Rowh, Marta; Backus, Lois; Sandahl, Yarrow; Foster, Angel

2009-07-01

This study evaluates the inclusion of sexual and reproductive health (SRH) topics in preclinical US and Canadian medical education. Between 2002 and 2005, we sent surveys to the student coordinators of active Medical Students for Choice chapters at 122 US and Canadian medical schools. Students reported on the preclinical curricular inclusion of 50 specific SRH topics in the broad categories of pregnancy, contraception, infertility, elective abortion, ethical and social issues, and other topics. We received 77 completed surveys, for an overall response rate of 63%. Coverage of pregnancy physiology and STIs/HIV was uniformly high. In contrast, inclusion of contraceptive methods and elective abortion procedures greatly varied by subtopic and geographic region. Thirty-three percent of respondents reported no coverage of elective abortion-related topics. Inclusion of contraception and elective abortion in preclinical medical school courses varies widely. As critical components of women's lives and health, we recommend that medical schools work to integrate comprehensive family planning content into their standard curricula.

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.

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

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.

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.

Update on apelin peptides as putative targets for cardiovascular drug discovery.

PubMed

Charles, Christopher J

2011-06-01

The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms. This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure. More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.

Evolution of ischemic damage and behavioural deficit over 6 months after MCAo in the rat: Selecting the optimal outcomes and statistical power for multi-centre preclinical trials

PubMed Central

Churilov, Leonid; Sidon, T. Kate; Aleksoska, Elena; Cox, Susan F.; Macleod, Malcolm R.; Howells, David W.

2017-01-01

Key disparities between the timing and methods of assessment in animal stroke studies and clinical trial may be part of the reason for the failure to translate promising findings. This study investigates the development of ischemic damage after thread occlusion MCAo in the rat, using histological and behavioural outcomes. Using the adhesive removal test we investigate the longevity of behavioural deficit after ischemic stroke in rats, and examine the practicality of using such measures as the primary outcome for future studies. Ischemic stroke was induced in 132 Spontaneously Hypertensive Rats which were assessed for behavioural and histological deficits at 1, 3, 7, 14, 21, 28 days, 12 and 24 weeks (n>11 per timepoint). The basic behavioural score confirmed induction of stroke, with deficits specific to stroke animals. Within 7 days, these deficits resolved in 50% of animals. The adhesive removal test revealed contralateral neglect for up to 6 months following stroke. Sample size calculations to facilitate the use of this test as the primary experimental outcome resulted in cohort sizes much larger than are the norm for experimental studies. Histological damage progressed from a necrotic infarct to a hypercellular area that cleared to leave a fluid filled cavity. Whilst absolute volume of damage changed over time, when corrected for changes in hemispheric volume, an equivalent area of damage was lost at all timepoints. Using behavioural measures at chronic timepoints presents significant challenges to the basic science community in terms of the large number of animals required and the practicalities associated with this. Multicentre preclinical randomised controlled trials as advocated by the MultiPART consortium may be the only practical way to deal with this issue. PMID:28182727

Update on the chemopreventive effects of ginger and its phytochemicals.

PubMed

Baliga, Manjeshwar Shrinath; Haniadka, Raghavendra; Pereira, Manisha Maria; D'Souza, Jason Jerome; Pallaty, Princy Louis; Bhat, Harshith P; Popuri, Sandhya

2011-07-01

The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger, is one of the most widely used spice and condiment. It is also an integral part of many traditional medicines and has been extensively used in Chinese, Ayurvedic, Tibb-Unani, Srilankan, Arabic, and African traditional medicines, since antiquity, for many unrelated human ailments including common colds, fever, sore throats, vomiting, motion sickness, gastrointestinal complications, indigestion, constipation, arthritis, rheumatism, sprains, muscular aches, pains, cramps, hypertension, dementia, fever, infectious diseases, and helminthiasis. The putative active compounds are nonvolatile pungent principles, namely gingerols, shogaols, paradols, and zingerone. These compounds are some of the extensively studied phytochemicals and account for the antioxidant, anti-inflammatory, antiemetic, and gastroprotective activities. A number of preclinical investigations with a wide variety of assay systems and carcinogens have shown that ginger and its compounds possess chemopreventive and antineoplastic effects. A number of mechanisms have been observed to be involved in the chemopreventive effects of ginger. The cancer preventive activities of ginger are supposed to be mainly due to free radical scavenging, antioxidant pathways, alteration of gene expressions, and induction of apoptosis, all of which contribute towards decrease in tumor initiation, promotion, and progression. This review provides concise information from preclinical studies with both cell culture models and relevant animal studies by focusing on the mechanisms responsible for the chemopreventive action. The conclusion describes directions for future research to establish its activity and utility as a human cancer preventive and therapeutic drug. The above-mentioned mechanisms of ginger seem to be promising for cancer prevention; however, further clinical studies are warranted to assess the efficacy and safety of ginger.

Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm.

PubMed

Bujarski, Spencer; Jentsch, J David; Roche, Daniel J O; Ramchandani, Vijay A; Miotto, Karen; Ray, Lara A

2018-05-08

The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.

The Hamburg Selection Procedure for Dental Students – Introduction of the HAM-Nat as subject-specific test for study aptitude

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2013-01-01

Introduction: The present study examines the question whether the selection of dental students should be based solely on average school-leaving grades (GPA) or whether it could be improved by using a subject-specific aptitude test. Methods: The HAM-Nat Natural Sciences Test was piloted with freshmen during their first study week in 2006 and 2007. In 2009 and 2010 it was used in the dental student selection process. The sample size in the regression models varies between 32 and 55 students. Results: Used as a supplement to the German GPA, the HAM-Nat test explained up to 12% of the variance in preclinical examination performance. We confirmed the prognostic validity of GPA reported in earlier studies in some, but not all of the individual preclinical examination results. Conclusion: The HAM-Nat test is a reliable selection tool for dental students. Use of the HAM-Nat yielded a significant improvement in prediction of preclinical academic success in dentistry. PMID:24282449

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.

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.

Peer-assisted learning: filling the gaps in basic science education for preclinical medical students.

PubMed

Sammaraiee, Yezen; Mistry, Ravi D; Lim, Julian; Wittner, Liora; Deepak, Shantal; Lim, Gareth

2016-09-01

In contrast to peer-assisted learning (PAL) in clinical training, there is scant literature on the efficacy of PAL during basic medical sciences teaching for preclinical students. A group of senior medical students aimed to design and deliver clinically oriented small-group tutorials after every module in the preclinical curriculum at a United Kingdom medical school. Twenty tutorials were delivered by senior students throughout the year to first- and second-year students. A baseline questionnaire was delivered to inform the development of the program followed by an end-point questionnaire the next year (n = 122). Quizzes were administered before and after five separate tutorials to assess changes in mean student scores. Additionally, each tutorial was evaluated via a questionnaire for participants (n = 949). All five posttutorial quizzes showed a significant improvement in mean student score (P < 0.05). Questionnaires showed students found the program to be relevant and useful for revision purposes and appreciated how tutorials contextualized basic science to clinical medicine. Students appreciated the interactive nature of the sessions and found receiving personalized feedback about their learning and consolidating information with someone familiar with the material to be useful. With the inclusion of the program, students felt there were now an adequate number of tutorials during the year. In conclusion, this study shows that senior medical students can design and deliver a program that adds value to the mostly lecture-based formal preclinical curriculum. We hope that our study can prompt further work to explore the effect of PAL on the teaching of basic sciences during preclinical studies. Copyright © 2016 The American Physiological Society.

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.

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.

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

PubMed

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

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p < 0.001), psychological health (r = 0.29, p < 0.001), social relations (r = 0.11, p = 0.03) and environment (r = 0.23, p < 0.001). Male student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

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

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.

How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school

PubMed Central

Świerszcz, Jolanta; Stalmach-Przygoda, Agata; Kuźma, Marcin; Jabłoński, Konrad; Cegielny, Tomasz; Skrzypek, Agnieszka; Wieczorek-Surdacka, Ewa; Kruszelnicka, Olga; Chmura, Kaja; Chyrchel, Bernadeta; Surdacki, Andrzej; Nowakowski, Michał

2017-01-01

Objective As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. Design Analysis of routinely collected data. Setting One Polish medical school. Participants Complete OSCE records for 462 second-year students and 445 third-year students. Outcome measures OSCE scores by matriculation year. Results In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third-year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second-year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG — tasks which had not been included in the second-year preclinical training. Conclusion Our results suggest the importance of preclinical training in a CS laboratory to improve students’ competence in physical examination at the completion of introductory clinical clerkships during the first clinical year. PMID:28864488