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Sample records for abuse preclinical models

  1. Preclinical models in radiation oncology

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

  2. The role of setting for ketamine abuse: clinical and preclinical evidence.

    De Luca, Maria Teresa; Meringolo, Maria; Spagnolo, Primavera Alessandra; Badiani, Aldo

    2012-01-01

    Drug abuse is often seen as a unitary phenomenon, partly as a result of the discovery over the past three decades of shared mechanisms of action for addictive substances. Yet the pattern of drug taking is often very different from drug to drug. This is particularly evident in the case of 'club drugs', such as ketamine. Although the number of ketamine abusers is relatively small in the general population, it is quite substantial in some settings. In particular, ketamine abuse is almost exclusively limited to clubs and large music parties, which suggests a major role of context in modulating the reward effects of this drug. This review focuses on recent preclinical and clinical findings, including previously unpublished data, that provide evidence that, even under controlled conditions, ketamine reward is a function of the setting of drug taking. PMID:23159868

  3. GEMMs as preclinical models for testing pancreatic cancer therapies

    Aarthi Gopinathan; Morton, Jennifer P.; Jodrell, Duncan I.; Owen J. Sansom

    2015-01-01

    ABSTRACT Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the fi...

  4. Kinetic modeling in pre-clinical positron emission tomography

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

    2014-07-01

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

  5. Adolescent Victims of Abuse: A Treatment Model.

    Anderson-Merchant, Darlene

    This paper presents a theory and model for treating adolescent victims of physical and sexual abuse and neglect. The theory examines issues related to abuse or neglect and the effect that an abusive history has on adolescent development. Specific issues noted are depression, anger, low self-esteem, self-shame, lack of trust, a sense of…

  6. The role of setting for ketamine abuse: clinical and preclinical evidence

    De Luca, Maria Teresa; MERINGOLO, MARIA; Spagnolo, Primavera Alessandra; Badiani, Aldo

    2012-01-01

    Drug abuse is often seen as a unitary phenomenon, partly as a result of the discovery over the past three decades of shared mechanisms of action for addictive substances. Yet the pattern of drug taking is often very different from drug to drug. This is particularly evident in the case of 'club drugs', such as ketamine. Although the number of ketamine abusers is relatively small in the general population, it is quite substantial in some settings. In particular, ketamine abuse is almost exclusi...

  7. GEMMs as preclinical models for testing pancreatic cancer therapies.

    Gopinathan, Aarthi; Morton, Jennifer P; Jodrell, Duncan I; Sansom, Owen J

    2015-10-01

    Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer. PMID:26438692

  8. GEMMs as preclinical models for testing pancreatic cancer therapies

    Aarthi Gopinathan

    2015-10-01

    Full Text Available Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs, the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.

  9. Modeling mania in preclinical settings: A comprehensive review.

    Sharma, Ajaykumar N; Fries, Gabriel R; Galvez, Juan F; Valvassori, Samira S; Soares, Jair C; Carvalho, André F; Quevedo, Joao

    2016-04-01

    The current pathophysiological understanding of mechanisms leading to onset and progression of bipolar manic episodes remains limited. At the same time, available animal models for mania have limited face, construct, and predictive validities. Additionally, these models fail to encompass recent pathophysiological frameworks of bipolar disorder (BD), e.g. neuroprogression. Therefore, there is a need to search for novel preclinical models for mania that could comprehensively address these limitations. Herein we review the history, validity, and caveats of currently available animal models for mania. We also review new genetic models for mania, namely knockout mice for genes involved in neurotransmission, synapse formation, and intracellular signaling pathways. Furthermore, we review recent trends in preclinical models for mania that may aid in the comprehension of mechanisms underlying the neuroprogressive and recurring nature of BD. In conclusion, the validity of animal models for mania remains limited. Nevertheless, novel (e.g. genetic) animal models as well as adaptation of existing paradigms hold promise. PMID:26545487

  10. History of Preclinical Models of Intracerebral Hemorrhage

    Ma, Qingyi; Khatibi, Nikan; Chen, Hank; Tang, Jiping; Zhang, John H.

    2011-01-01

    In order to understand a disease process, effective modeling is required that can assist scientists in understanding the pathophysiological processes that take place. Intracerebral hemorrhage (ICH), a devastating disease representing 15% of all stroke cases, is just one example of how scientists have developed models that can effectively mimic human clinical scenarios. Currently there are three models of hematoma injections that are being used to induce an ICH in subjects. They include the mi...

  11. History of preclinical models of intracerebral hemorrhage.

    Ma, Qingyi; Khatibi, Nikan H; Chen, Hank; Tang, Jiping; Zhang, John H

    2011-01-01

    In order to understand a disease process, effective modeling is required that can assist scientists in understanding the pathophysiological processes that take place. Intracerebral hemorrhage (ICH), a devastating disease representing 15% of all stroke cases, is just one example of how scientists have developed models that can effectively mimic human clinical scenarios. Currently there are three models of hematoma injections that are being used to induce an ICH in subjects. They include the microballoon model introduced in 1987 by Dr. David Mendelow, the bacterial collagenase injection model introduced in 1990 by Dr. Gary Rosenberg, and the autologous blood injection model introduced by Dr. Guo-Yuan Yang in 1994. These models have been applied on various animal models beginning in 1963 with canines, followed by rats and rabbits in 1982, pigs in 1996, and mice just recently in 2003. In this review, we will explore in detail the various injection models and animal subjects that have been used to study the ICH process while comparing and analyzing the benefits and disadvantages of each. PMID:21725723

  12. Preclinical models for neuroblastoma: establishing a baseline for treatment.

    Tal Teitz

    Full Text Available BACKGROUND: Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. PRINCIPAL FINDINGS: Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. SIGNIFICANCE: The studies suggest that use of both the TH-NMYC model of neuroblastoma and the

  13. Typological and Integrative Models of Sexual Abuse

    Demidova L.Y.,; Dvorjanchikov N.V.,

    2014-01-01

    We discuss the basic typological and integrative theoretical models that explain the occurrence of child sexual abuse and the differences detected among the perpetrators of crimes against sexual integrity of minors. A comprehensive review of the theoretical concepts of sexual abuse in our country, in fact has not been carried out, and in this paper for the first time we made such an attempt. It is shown that the existing notions of sexual abuse largely overlap each other, but each of the mode...

  14. Preclinical platform for the translational research of the abuse potential of novel drug candidates

    Teuns, Greet

    2014-01-01

    To determine the abuse potential of new CNS-active molecular entities with a novel mechanism of action, considerable knowledge of the pharmacology, toxicity and kinetics is needed to enable the choice of the correct tests, the selection of an appropriate dose range of the test compound and the proper choice of the psycho-active reference compound(s) or a scheduled comparator. In addition, one must have a thorough expertise of the current overall Drug Development process and subsequent require...

  15. Rodent Models of Nicotine Reward: What do they tell us about tobacco abuse in humans?

    O'Dell, Laura E.; Khroyan, Taline V.

    2008-01-01

    Tobacco products are widely abused in humans, and it is assumed that nicotine is the key substrate in these products that produces addiction. Based on this assumption, several pre-clinical studies have utilized animal models to measure various aspects of nicotine addiction. Most of this work has focused on behavioral measures of nicotine and how other variables contribute to these effects. Here we discuss the most commonly used animal models including, self-administration (SA), place conditio...

  16. Understanding abuse of women with physical disabilities: an overview of the abuse pathways model.

    Hassouneh-Phillips, Dena

    2005-01-01

    The purpose of this article is to provide an overview of an empirically based theoretical model of abuse of women with physical disabilities. The Abuse Pathways model was developed from a critical disability life history research study conducted with 37 women who had simultaneously experienced abuse and physical disability. The model begins to address the complexity of abuse of women with physical disabilities by identifying the interactive components of the phenomenon. These components include (1) the social context of disability; (2) women's abuse trajectories; and (3) vulnerability factors for abuse. The article concludes by discussing potential applications and limitations of the model. PMID:15718940

  17. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

    Martins-de-Souza Daniel; Alsaif Murtada; Ernst Agnes; Harris Laura W; Aerts Nancy; Lenaerts Ilse; Peeters Pieter J; Amess Bob; Rahmoune Hassan; Bahn Sabine; Guest Paul C

    2012-01-01

    Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiple...

  18. Preclinical imaging in animal models of radiation therapy

    Modern radiotherapy benefits from precise and targeted diagnostic and pretherapeutic imaging. Standard imaging modalities, such as computed tomography (CT) offer high morphological detail but only limited functional information on tumors. Novel functional and molecular imaging modalities provide biological information about tumors in addition to detailed morphological information. Perfusion magnetic resonance imaging (MRI) CT or ultrasound-based perfusion imaging as well as hybrid modalities, such as positron emission tomography (PET) CT or MRI-PET have the potential to identify and precisely delineate viable and/or perfused tumor areas, enabling optimization of targeted radiotherapy. Functional information on tissue microcirculation and/or glucose metabolism allow a more precise definition and treatment of tumors while reducing the radiation dose and sparing the surrounding healthy tissue. In the development of new imaging methods for planning individualized radiotherapy, preclinical imaging and research plays a pivotal role, as the value of multimodality imaging can only be assessed, tested and adequately developed in a preclinical setting, i.e. in animal tumor models. New functional imaging modalities will play an increasing role for the surveillance of early treatment response during radiation therapy and in the assessment of the potential value of new combination therapies (e.g. combining anti-angiogenic drugs with radiotherapy). (orig.)

  19. Typological and Integrative Models of Sexual Abuse

    Demidova L.Y.,

    2014-11-01

    Full Text Available We discuss the basic typological and integrative theoretical models that explain the occurrence of child sexual abuse and the differences detected among the perpetrators of crimes against sexual integrity of minors. A comprehensive review of the theoretical concepts of sexual abuse in our country, in fact has not been carried out, and in this paper for the first time we made such an attempt. It is shown that the existing notions of sexual abuse largely overlap each other, but each of the models somehow takes into account the factors not explicitly addressed in other concepts. Systematic consideration of the theoretical models of sexual abuse can generalize and systematize the available data on the mechanisms of pedophile behavior. This review provides an opportunity to develop a new benchmark in the study of sexual abuse, get closer to building the most accurate and comprehensive model. In turn, this may contribute to solving the questions about the factors, dynamics, and the prevention of criminal sexual conduct against children

  20. Epidemiology Abuse: Epidemiological and Psychosocial Models of Drug Abuse

    Jacobs, Phillip E.

    1976-01-01

    In a paper presented at the National Drug Abuse Conference April 4-7, 1975, New Orleans, Louisiana, epidemiological and psychosocial approaches to drug abuse are discussed. An approach reflecting an appreciation of the psychological/social/political realities involved in addiction as well as a grounding in epidemiological principles and data is…

  1. A vascular access system (VAS) for preclinical models

    Berry-Pusey, Brittany Nan

    2012-01-01

    Preclinical Molecular Imaging technologies have an increasingly broader application base while they at the same time are becoming more user-friendly. Tail vein injections are a routine but critical step in most imaging applications, with poor injections greatly affectingthe experimental results. The high skills and experience required to perform successful tail vein injections leave many preclinical imaging scientists ill-suited to perform this task. In a recent study, we found that trained r...

  2. Development of a Rabbit Model for a Preclinical Comparison of Coronary Stent Types In-Vivo

    Lee, Joo Myung; Lee, Jaewon; Jeong, Heewon; Choe, Won Seok; Seo, Won-Woo; Lim, Woo-Hyun; Kim, Young-Chan; Hur, Jin; Lee, Sang Eun; Yang, Han-Mo; Cho, Hyun-Jai; Kim, Hyo-Soo

    2013-01-01

    Along with the development of innovative stent designs, preclinical trials in animal models are essential. Many animal models have been used and appear to yield comparable results to clinical trials despite substantial criticisms about their validity. Among the animal models, porcine coronary artery models have been the standard models for the preclinical evaluation of endovascular devices. However, rapid growth rate, high body weight potential, and the propensity to develop granulomatous inf...

  3. A crowdsourcing model for creating preclinical medical education study tools.

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

    2013-06-01

    During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning. PMID:23619061

  4. Excessive aggression as model of violence : a critical evaluation of current preclinical methods

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

    2013-01-01

    Preclinical experimental models of pathological aggressive behavior are a sorely understudied and difficult research area. How valid, reliable, productive, and informative are the most frequently used animal models of excessive aggressive behavior? The rationale, key methodological features, support

  5. Development of Hypoxia in a Preclinical Model of Tumor Micrometastases

    Purpose: Hypoxic regions have been shown to be a characteristic feature of a wide variety of human primary tumors, whereas the oxygenation status of subclinical micrometastases is in general unknown. The development of hypoxia in a xenograft model of microscopic metastases was investigated in this study. Methods and Materials: U-25-GFP human melanomas growing in dorsal window chamber preparations in BALB/c nu/nu mice were used as a preclinical model of micrometastases. Tumor blood supply time and morphologic parameters of the vascular network were determined from first-pass imaging movies and vascular maps recorded by use of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran as a vascular tracer. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by use of pimonidazole as a hypoxia marker. Results: Nearly half of the tumors had developed hypoxic regions when they reached a diameter of 2 to 3 mm. Tumors with multiple hypoxic foci showed a low growth rate, low blood flow velocity, high vessel tortuosity, high vessel segment length, and high vascular density, whereas tumors with a single hypoxic region showed a high growth rate, high blood flow velocity, low vessel tortuosity, low vessel segment length, and low vascular density. The tumors with hypoxic regions did not differ from those without hypoxia in any single parameter. Conclusions: U-25-GFP xenograft models of vascularized human tumor micrometastases may develop hypoxic regions as a consequence of two distinctly different morphologic abnormalities in the vascular network: high resistance against blood flow (i.e., high vessel tortuosity and high vessel segment length) or low vascular density.

  6. Modeling Substance Abuse for Applications in Proteomics

    Hemby, Scott Edwards; Tannu, Nilesh

    2009-01-01

    The ability to model aspects of human addictive behaviors in laboratory animals provides an important avenue for gaining insight into the biochemical alterations associated with drug intake and the identification of targets for medication development to treat addictive disorders. The intravenous self-administration procedure provides the means to model the reinforcing effects of abused drugs and to correlate biochemical alterations with drug reinforcement. In this chapter, we provide a detail...

  7. Healing from Childhood Sexual Abuse: A Theoretical Model

    Draucker, Claire Burke; Martsolf, Donna S.; Roller, Cynthia; Knapik, Gregory; Ross, Ratchneewan; Stidham, Andrea Warner

    2011-01-01

    Childhood sexual abuse is a prevalent social and health care problem. The processes by which individuals heal from childhood sexual abuse are not clearly understood. The purpose of this study was to develop a theoretical model to describe how adults heal from childhood sexual abuse. Community recruitment for an ongoing broader project on sexual…

  8. Effects of ezetimibe on atherosclerosis in preclinical models.

    Davis, Harry R; Lowe, Robert S; Neff, David R

    2011-04-01

    Ezetimibe (Zetia(®), Ezetrol(®), Merck, Whitehouse Station, NJ) is a potent inhibitor of sterol absorption, which selectively blocks the uptake of biliary and dietary cholesterol in the small intestine. Clinical trials have demonstrated the beneficial effects of ezetimibe on the reduction of atherogenic lipoproteins and the attainment of guideline-recommended lipid levels. Direct evidence that these improvements translate to a reduction in atherosclerosis or cardiovascular events is limited, although reductions in major atherosclerotic events that are consistent with the LDL-C lowering achieved have recently been presented for patients with chronic kidney disease treated with ezetimibe/simvastatin 10/20mg in the SHARP trial. Animal models of atherosclerosis have played a central role in defining the mechanisms involved in initiation and development of disease and have been used in drug development to evaluate potential therapeutic efficacy. The effect of ezetimibe on atherosclerosis has been examined in several of these animal model systems. ApoE knockout mice develop severe hypercholesterolemia and premature atherosclerosis with features similar to that seen in humans and techniques ranging from gross visualization of plaque to high-resolution MRI have demonstrated the consistent ability of ezetimibe to significantly inhibit atherosclerosis. sr-b1(-/-)/apoE(-/-) double knockout mice exhibit additional characteristics common to human coronary heart disease (CHD), and the one study of ezetimibe in sr-b1(-/-)/apoE(-/-) mice showed a significant reduction in aortic sinus plaque (57%), coronary arterial occlusion (68%), myocardial fibrosis (57%), and cardiomegaly (12%) compared with untreated controls. The effects of ezetimibe have also been evaluated in ldlr(-/-)/apoE(-/-) double knockout mice, demonstrating that functional LDL receptors were not required for ezetimibe-mediated reduction of plasma cholesterol or atherosclerosis. For the few studies that have been

  9. Genetically Engineered Mouse Models for Drug Development and Preclinical Trials

    Lee, Ho

    2014-01-01

    Drug development and preclinical trials are challenging processes and more than 80% to 90% of drug candidates fail to gain approval from the United States Food and Drug Administration. Predictive and efficient tools are required to discover high quality targets and increase the probability of success in the process of new drug development. One such solution to the challenges faced in the development of new drugs and combination therapies is the use of low-cost and experimentally manageable in...

  10. Lung cancer, intracellular signaling pathways, and preclinical models

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  11. Abuse

    ... Paying for Care Insurance Medicare Medicare Part D Benefits Medicaid Tax Deductions & Credits Legal Matters Planning Ahead Legal Documents alz.org » Caregiver Center » Safety » Abuse Text size: A A A Special Situations First Responders Traveling In a Disaster Abuse Find your local Chapter ...

  12. Bridging translation for acute kidney injury with better preclinical modeling of human disease.

    Skrypnyk, Nataliya I; Siskind, Leah J; Faubel, Sarah; de Caestecker, Mark P

    2016-05-15

    The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI. PMID:26962107

  13. Supporting Teachers, Strengthening Families: A Model Child Abuse Prevention Approach

    Olson, Maril

    2007-01-01

    This article talks about a model child abuse prevention approach called, "Supporting Teachers, Strengthening Families." It is NAEYC's professional development initiative to help early childhood educators play leading roles in preventing child abuse and neglect through family strengthening efforts. It focuses on six strategies that high-quality…

  14. Beneficial effects of erythropoietin in preclinical models of shock and organ failure

    Thiemermann, Christoph

    2007-01-01

    Erythropoietin protects many organs against the tissue injury and dysfunction caused by ischaemia/reperfusion and excessive inflammation. This editorial comment discusses the effects of erythropoietin in preclinical models of septic shock, endotoxemia, hemorrhagic shock, spinal cord trauma and zymosan-induced multiple organ failure.

  15. Human skeletal muscle xenograft as a new preclinical model for muscle disorders

    Zhang, Yuanfan; King, Oliver D.; Rahimov, Fedik; Jones, Takako I; Ward, Christopher W.; Kerr, Jaclyn P.; Liu, Naili; Emerson, Charles P.; Kunkel, Louis M; Partridge, Terence A.; Wagner, Kathryn R.

    2014-01-01

    Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metaboli...

  16. Behavioural evaluation of candidate genetic, environmental and developmental murine models for preclinical schizophrenia research

    Naert, Arne

    2011-01-01

    Valid mouse models of schizophrenia (SCZ) are valuable preclinical research tools to investigate pathogenetic mechanisms and possible treatment strategies for this devastating and poorly understood brain disease. The purpose of current PhD project was to develop and/or evaluate three such models in an extensive test battery that screened for schizophreniform behaviour. The three models focussed on different neurogenetic and environmental factors that have been implicated in SCZ...

  17. Rag2-/-;gammac-/- immunodeficient mice, a new preclinical model to study antitumor approaches

    Antognoli, Agnese

    2010-01-01

    Animal models have been relevant to study the molecular mechanisms of cancer and to develop new antitumor agents. Anyway, the huge divergence in mouse and human evolution made difficult the translation of the gained achievements in preclinical mouse based studies. The generation of clinically relevant murine models requires their humanization both concerning the creation of transgenic models and the generation of humanized mice in which to engraft a functional human immune system, and reprodu...

  18. Mexican-American Adolescent Inhalant Abuse: A Proposed Model.

    Dworkin, A. Gary; Stephens, Richard C.

    1980-01-01

    Drawing from literature on differences between the Mexican American experience and that of other groups, offers a model to explain the higher rates of inhalant abuse among Mexican American youth. Considers cultural, ecological, structural, and economic factors. (Author/GC)

  19. Development of a preclinical model of ischemic cardiomyopathy in swine

    Ishikawa, Kiyotake; Ladage, Dennis; Takewa, Yoshiaki; Yaniz, Elisa; Chen, Jiqiu; Tilemann, Lisa; Sakata, Susumu; Badimon, Juan J; Hajjar, Roger J.; Kawase, Yoshiaki

    2011-01-01

    A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wir...

  20. Preclinical non-human models to combat dementia

    Banik, Avijit; Anand, Akshay

    2013-01-01

    Dementia is characterized by a certain degree of memory loss with disabled intellectual functioning, which mostly presents as Alzheimer’s disease. The underlying causes range from gene mutations, lifestyle factors, and other environmental influences to brain injuries and normal aging. Although there have been many rodent and non-human primate models created by various drugs, neurotoxins and genetic ablation but the current scenario does not exhibit a well characterized animal model to evaluat...

  1. Optimizing modelling in iterative image reconstruction for preclinical pinhole PET

    Goorden, Marlies C.; van Roosmalen, Jarno; van der Have, Frans; Beekman, Freek J.

    2016-05-01

    The recently developed versatile emission computed tomography (VECTor) technology enables high-energy SPECT and simultaneous SPECT and PET of small animals at sub-mm resolutions. VECTor uses dedicated clustered pinhole collimators mounted in a scanner with three stationary large-area NaI(Tl) gamma detectors. Here, we develop and validate dedicated image reconstruction methods that compensate for image degradation by incorporating accurate models for the transport of high-energy annihilation gamma photons. Ray tracing software was used to calculate photon transport through the collimator structures and into the gamma detector. Input to this code are several geometric parameters estimated from system calibration with a scanning 99mTc point source. Effects on reconstructed images of (i) modelling variable depth-of-interaction (DOI) in the detector, (ii) incorporating photon paths that go through multiple pinholes (‘multiple-pinhole paths’ (MPP)), and (iii) including various amounts of point spread function (PSF) tail were evaluated. Imaging 18F in resolution and uniformity phantoms showed that including large parts of PSFs is essential to obtain good contrast-noise characteristics and that DOI modelling is highly effective in removing deformations of small structures, together leading to 0.75 mm resolution PET images of a hot-rod Derenzo phantom. Moreover, MPP modelling reduced the level of background noise. These improvements were also clearly visible in mouse images. Performance of VECTor can thus be significantly improved by accurately modelling annihilation gamma photon transport.

  2. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

    Martins-de-Souza Daniel

    2012-03-01

    Full Text Available Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. Methods We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1, aldolase C (Aldoc, triosephosphate isomerase (Tpi1, glyceraldehyde-3-phosphate dehydrogenase (Gapdh, phosphoglycerate mutase 1 (Pgam1, phosphoglycerate kinase 1 (Pgk1 and enolase 2 (Eno2. The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. Results Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. Conclusions This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.

  3. Susceptibility of Mycobacterium abscessus to antimycobacterial drugs in preclinical models.

    Obregón-Henao, Andrés; Arnett, Kimberly A; Henao-Tamayo, Marcela; Massoudi, Lisa; Creissen, Elizabeth; Andries, Koen; Lenaerts, Anne J; Ordway, Diane J

    2015-11-01

    Over the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden. PMID:26303795

  4. Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine

    Green, Jennifer L; Dykstra, Linda A.; Carelli, Regina M.

    2015-01-01

    In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution prior to 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were qu...

  5. Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides

    Catalone, Bradley J.; Kish-Catalone, Tina M.; Budgeon, Lynn R.; Neely, Elizabeth B.; Ferguson, Maelee; Krebs, Fred C.; Howett, Mary K; Labib, Mohamed; Rando, Robert; Wigdahl, Brian

    2004-01-01

    Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, ...

  6. Interstitial 5-ALA photodynamic therapy and glioblastoma: preclinical model development and preliminary results.

    TETARD, MARIE-CHARLOTTE; Vermandel, Maximilien; Leroy, Henri-Arthur; Leroux, Bertrand; Maurage, Claude-Alain; Lejeune, Jean-Paul; Mordon, Serge; Reyns, Nicolas

    2015-01-01

    AbstractOBJECTIVE: Photodynamic therapy (PDT) has become a well-established modality for the treatment of many cancers. Photodynamic eradication of tumor cells depends on the presence of a photosensitizer, oxygen and light. However, oxygen depletion during PDT is a well known problem. Modulation of light delivery could address this issue by counteracting tumor hypoxia, thereby improving tumor cell killing. This preclinical study was designed to validate an animal model incorporating 5-aminola...

  7. Impulsivity in Animal Models for Drug Abuse Disorders

    Jentsch, J. David

    2008-01-01

    Different conceptual frameworks have been generated to explain substance abuse; of relevance to this article, dysfunction of impulse control systems that are required for avoiding or stopping drug-seeking and –taking may play a key role in addiction. This review summarizes work in animal models that explains the pervasive association between impulse control and substance abuse. It further underscores the concept that impulse control may be a critical target for pharmacological intervention in...

  8. A preclinical rodent model of radiation induced lung injury for medical countermeasure screening in accordance with the FDA animal rule

    Jackson, Isabel L.; Xu, Puting; Hadley, Caroline; Katz, Barry P.; McGurk, Ross; Down, Julian D.; Vujaskovic, Zeljko

    2012-01-01

    The purpose of pre-clinical murine model development is to establish that the pathophysiological outcome of our rodent model of radiation-induced lung injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation lung injury in humans. In this study, we assessed this issue by evaluating the relationship between morbidity (pul...

  9. A semi-automated vascular access system for preclinical models

    Murine models are used extensively in biological and translational research. For many of these studies it is necessary to access the vasculature for the injection of biologically active agents. Among the possible methods for accessing the mouse vasculature, tail vein injections are a routine but critical step for many experimental protocols. To perform successful tail vein injections, a high skill set and experience is required, leaving most scientists ill-suited to perform this task. This can lead to a high variability between injections, which can impact experimental results. To allow more scientists to perform tail vein injections and to decrease the variability between injections, a vascular access system (VAS) that semi-automatically inserts a needle into the tail vein of a mouse was developed. The VAS uses near infrared light, image processing techniques, computer controlled motors, and a pressure feedback system to insert the needle and to validate its proper placement within the vein. The VAS was tested by injecting a commonly used radiolabeled probe (FDG) into the tail veins of five mice. These mice were then imaged using micro-positron emission tomography to measure the percentage of the injected probe remaining in the tail. These studies showed that, on average, the VAS leaves 3.4% of the injected probe in the tail. With these preliminary results, the VAS system demonstrates the potential for improving the accuracy of tail vein injections in mice. (paper)

  10. 42 CFR Appendix to Part 54a - Model Notice of Individuals Receiving Substance Abuse Services

    2010-10-01

    ..., ET SEQ., FOR SUBSTANCE ABUSE PREVENTION AND TREATMENT SERVICES Pt. 54a, App. Appendix to Part 54a—Model Notice of Individuals Receiving Substance Abuse Services Model Notice to Individuals Receiving Substance Abuse Services No provider of substance abuse services receiving Federal funds from the...

  11. Preclinical Mouse Models for Analysis of the Therapeutic Potential of Engineered Oncolytic Herpes Viruses.

    Speranza, Maria-Carmela; Kasai, Kazue; Lawler, Sean E

    2016-03-31

    After more than two decades of research and development, oncolytic herpes viruses (oHSVs) are moving into the spotlight due to recent encouraging clinical trial data. oHSV and other oncolytic viruses function through direct oncolytic cancer cell-killing mechanisms and by stimulating antitumor immunity. As further viruses are developed and optimized for the treatment of various types of cancer, appropriate predictive preclinical models will be of great utility. This review will discuss existing data in this area, focusing on the mouse tumor models that are commonly used. PMID:27034396

  12. Porcine Heterotopic Composite Tissue Allograft Transplantation using A Large Animal Model for Preclinical Studies

    Yur-Ren Kuo

    2006-06-01

    Full Text Available Background: Composite tissue allograft (CTA transplantation is currently limited by therisks of side effects resulting from long-term high-dose immunosuppression.Therefore, preclinical animal models are essential to help CTA transplantationadvance into clinical reality. Evidence has shown that small-animalmodel (rodents immunotherapy protocols cannot be directly applied tohumans. This study investigated whether a miniature porcine model is reproduciblefor preclinical studies.Methods: Based on the concept of vascularized skeletal tissue allograft transplantation,limb heterotopic allograft tissue from a mismatched donor miniature pig consistingof the distal femur, knee joint, tibia, fibula, and surrounding musclewith a vascularized skin paddle model supplied by the superficial femoralvessels was transplanted into recipient pigs. Swine viability and rejectionsigns of the allograft were monitored postoperatively. Histopathologicalchanges in the allograft tissues were examined using hematoxylin and eosinstaining if the allo-skin flap was rejected.Results: The recipient pigs were ambulatory immediately following surgery. Theflaps showed no visible signs of rejection over the first 4 days of observation.The skin flaps appeared bluish-purple and edematous on postoperative days5~7, and progressed to tissue necrosis and rejection on postoperative days8~13. Histological examination revealed marked mononuclear cell infiltrationand necrotic changes in the all rejected tissues, especial in the allograftskin tissues (skin > muscle > bone > cartilage.Conclusions: The results showed this the porcine CTA model is reproducible and suitablefor preclinical training for human CTA transplantation. Monitoring of theallo-skin flap is a useful strategy to evaluate composite tissue allograft rejection.

  13. Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

    S. Giraud

    2011-01-01

    Full Text Available Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular. The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions.

  14. The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease

    Nichols, David P.; Ziady, Assem G.; Shank, Samuel L.; Eastman, Jean F.; Davis, Pamela B.

    2009-01-01

    Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have sig...

  15. Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

    Cheng eWang

    2012-10-01

    Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

  16. Current status and evolution of preclinical drug development models of epithelial ovarian cancer

    Panagiotis A Konstantinopoulos

    2013-12-01

    Full Text Available Epithelial ovarian cancer (EOC is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States. Although important advances in surgical and chemotherapeutic strategies over the last three decades have significantly improved the median survival of EOC patients, the plateau of the survival curve has not changed appreciably. Given that EOC is a genetically and biologically heterogeneous disease, identification of specific molecular abnormalities that can be targeted in each individual ovarian cancer on the basis of predictive biomarkers promises to be an effective strategy to improve outcome in this disease. However, for this promise to materialize, appropriate preclinical experimental platforms that recapitulate the complexity of these neoplasms and reliably predict antitumor activity in the clinic are critically important. In this review, we will present the current status and evolution of preclinical models of EOC, including cell lines, immortalized normal cells, xenograft models, patient-derived xenografts and animal models, and will discuss their potential for oncology drug development.

  17. The Multicultural Model in Chemical Abuse Prevention and Intervention.

    Griswold-Ezekoye, Stephanie

    1985-01-01

    Applies the concept of multiculturalism to chemical abuse prevention and intervention programs. Provides a model for implementation and describes projects with a similar conceptual basis. Acknowledges the cultural foundations for developing positive self-understanding. Promotes the development of culture-specific prevention strategies. (Author/LHW)

  18. A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT).

    Jeitany, Maya; Pineda, Jose Ramon; Liu, Qingyuan; Porreca, Rosa Maria; Hoffschir, Françoise; Desmaze, Chantal; Silvestre, David C; Mailliet, Patrick; Junier, Marie-Pierre; Londoño-Vallejo, Arturo; Ségal-Bendirdjian, Evelyne; Chneiweiss, Hervé; Boussin, François D

    2015-04-01

    Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor. PMID:25175359

  19. Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine.

    Green, Jennifer L; Dykstra, Linda A; Carelli, Regina M

    2015-06-01

    In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose. PMID:25738759

  20. Imaging axonal degeneration and repair in pre-clinical animal models of multiple sclerosis

    Soumya S Yandamuri

    2016-05-01

    Full Text Available Multiple sclerosis (MS is a central nervous system (CNS disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Over time, this neurologic damage manifests clinically as debilitating motor and cognitive symptoms. Existing MS therapies focus on symptom relief and delay of disease progression through reduction of neuroinflammation. However, long-term strategies to remyelinate, protect, or regenerate axons have remained elusive, posing a challenge to treating progressive forms of MS. Preclinical mouse models and techniques such as immunohistochemistry, flow cytometry, and genomic and proteomic analysis have provided advances in our understanding of discrete time-points of pathology following disease induction. More recently, in vivo and in situ two-photon microscopy (2P has made it possible to visualize continuous real-time cellular behavior and structural changes occurring within the CNS during neuropathology. Research utilizing 2P imaging to study axonopathy in neuroinflammatory demyelinating disease has focused on five areas: (1 axonal morphologic changes (2 organelle transport and health, (3 relationship to inflammation, (4 neuronal excitotoxicity, and (5 regenerative therapies. 2P imaging may also be used to identify novel therapeutic targets via identification and clarification of dynamic cellular and molecular mechanisms of axonal regeneration and remyelination. Here, we review tools that have made 2P accessible for imaging neuropathologies and advances in our understanding of axonal degeneration and repair in preclinical models of demyelinating diseases.

  1. Voxel-level reproducibility assessment of modality independent elastography in a pre-clinical murine model

    Flint, Katelyn M.; Weis, Jared A.; Yankeelov, Thomas E.; Miga, Michael I.

    2015-03-01

    Changes in tissue mechanical properties, measured non-invasively by elastography methods, have been shown to be an important diagnostic tool, particularly for cancer. Tissue elasticity information, tracked over the course of therapy, may be an important prognostic indicator of tumor response to treatment. While many elastography techniques exist, this work reports on the use of a novel form of elastography that uses image texture to reconstruct elastic property distributions in tissue (i.e., a modality independent elastography (MIE) method) within the context of a pre-clinical breast cancer system.1,2 The elasticity results have previously shown good correlation with independent mechanical testing.1 Furthermore, MIE has been successfully utilized to localize and characterize lesions in both phantom experiments and simulation experiments with clinical data.2,3 However, the reproducibility of this method has not been characterized in previous work. The goal of this study is to evaluate voxel-level reproducibility of MIE in a pre-clinical model of breast cancer. Bland-Altman analysis of co-registered repeat MIE scans in this preliminary study showed a reproducibility index of 24.7% (scaled to a percent of maximum stiffness) at the voxel level. As opposed to many reports in the magnetic resonance elastography (MRE) literature that speak to reproducibility measures of the bulk organ, these results establish MIE reproducibility at the voxel level; i.e., the reproducibility of locally-defined mechanical property measurements throughout the tumor volume.

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

    Hor-Yue Tan

    2016-01-01

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

  3. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described

  4. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Takuji Tanaka

    2012-07-01

    Full Text Available Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC. Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  5. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

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

    Antonio Gonzalez-Bulnes

    2016-03-01

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

  7. A highly invasive human glioblastoma pre-clinical model for testing therapeutics

    Cao Brian

    2008-12-01

    Full Text Available Abstract Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino-17-demethoxy geldanamycin (17AAG. Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2. These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents.

  8. Preclinical models of muscle spasticity: valuable tools in the development of novel treatment for neurological diseases and conditions.

    Bespalov, Anton; Mus, Liudmila; Zvartau, Edwin

    2016-05-01

    Poor validity of preclinical animal models is one of the most commonly discussed explanations for the failures to develop novel drugs in general and in neuroscience in particular. However, there are several areas of neuroscience such as injury-induced spasticity where etiological factor can be adequately recreated and models can focus on specific pathophysiological mechanisms that likely contribute to spasticity syndrome in humans (such as motoneuron hyperexcitability and spinal hyperreflexia). Methods used to study spasticity in preclinical models are expected to have a high translational value (e.g., electromyogram (EMG)-based electrophysiological tools) and can efficiently assist clinical development programs. However, validation of these models is not complete yet. First, true predictive validity of these models is not established as clinically efficacious drugs have been used to reverse validate preclinical models while newly discovered mechanisms effective in preclinical models are yet to be fully explored in humans (e.g., 5-HT2C receptor inverse agonists, fatty acid amid hydrolase inhibitors). Second, further efforts need to be invested into cross-laboratory validation of study protocols and tools, adherence to the highest quality standards (blinding, randomization, pre-specified study endpoints, etc.), and systematic efforts to replicate key sets of data. These appear to be readily achievable tasks that will enable development not only of symptomatic but also of disease-modifying therapy of spasticity, an area that seems to be currently not in focus of research efforts. PMID:26861550

  9. Animal Models of Substance Abuse and Addiction: Implications for Science, Animal Welfare, and Society

    Lynch, Wendy J.; Nicholson, Katherine L.; Dance, Mario E; Morgan, Richard W; Foley, Patricia L.

    2010-01-01

    Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial...

  10. Developmental models of substance abuse relapse

    Ramo, Danielle Elizabeth

    2008-01-01

    Most models of addiction treatment outcome and relapse have been formulated on adult populations, with only modest consideration of developmental factors which are salient issues for substance use disordered (SUD) youth. The dominant cognitive behavioral model of addiction relapse (Marlatt & Gordon, 1985) has been compelling in its description of how situational context (e.g., high risk situations) interacts with cognitive factors (e.g., self-efficacy, coping resources) to elevate risk for re...

  11. Synchrotron radiation microimaging in rabbit models of cancer for preclinical testing

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

  12. Synchrotron radiation microimaging in rabbit models of cancer for preclinical testing

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

    2009-10-01

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

  13. Synchrotron radiation microimaging in rabbit models of cancer for preclinical testing

    Umetani, Keiji [Japan Synchrotron Radiation Research Institute, SPring-8, Sayo-cho, Sayo-gun, Hyogo 679-5198 (Japan)], E-mail: umetani@spring8.or.jp; Uesugi, Kentaro [Japan Synchrotron Radiation Research Institute, SPring-8, Sayo-cho, Sayo-gun, Hyogo 679-5198 (Japan); Kobatake, Makito; Yamamoto, Akira; Yamashita, Takenori; Imai, Shigeki [Kawasaki Medical School, Matsushima, Kurashiki-shi, Okayama 701-0192 (Japan)

    2009-10-01

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

  14. Preclinical testing of a new clot-retrieving wire device using polyvinyl alcohol hydrogel vascular models

    Asakura, Fumio; Yilmaz, Hasan; Abdo, German; San Millan, Diego; Augsburger, Luca; Ruefenacht, Daniel A.; Lovblad, Karl-Olof [University Hospital of Geneva, Neuroradiology Unit, Geneva (Switzerland); Sekoranja, Lucka; Sztajzel, Roman; Perren, Fabienne [University Hospital of Geneva, Neurology Department, Geneva (Switzerland); Goto, Katsuya [Ohta Memorial Hospital, Neuroendovascular Section, Brain Attack Center, Ohta (Japan)

    2007-03-15

    Cerebral embolism is the principal cause of cerebral infarction. Recently, mechanical embolectomy has been proposed as an effective method. We performed a preclinical evaluation of a new mechanical clot-retrieving wire. This clot-retrieving wire consisted of three nitinol loops at the tip of a microguidewire. These three loops could be collapsed into a 0.018-inch wire compatible microcatheter. Each loop was 8 mm long and 3.5 mm wide. For simulation, polyvinyl alcohol (PVA) vascular anatomical models of the human carotid (eight models) and vertebrobasilar (three models) circulation were constructed. A pulsatile flow circulation system was used. Embolic clots were produced using pig blood plasma. The microcatheter and the microguidewire were advanced beyond the clot. The wire was then exchanged for the retrieving wire. The microcatheter was then pulled slightly back to open the loops. The clot was then caught by withdrawal of the system. Once caught, the clot was retrieved to the guiding catheter tip. We investigated the following points: ease of device deployment, clot capture ability, clot removal against blood flow and removal of the clot out of the introducer system. A total of 104 procedures were performed in 11 PVA models and evaluated. The drop rate was 19%. We succeeded in partial and total recanalization in 51.0% of the procedures (53/104) within 30 minutes. This new clot-retrieving wire could be useful for mechanical clot extraction in stroke. (orig.)

  15. A Model of Substance Abuse Risk

    Anne Chandrika Ismail; Rohini De Alwis Seneviratne; Newcombe, Peter A; Shamil Wanigaratne

    2009-01-01

    This study translated and validated the Substance Use Risk Profile Scale (SURPS) among 13 to 18 year old Sri Lankan adolescents attending school. A standard systematic translation procedure was followed to translate the original SURPS into Sinhala language. A Delphi process was conducted to determine judgmental validity of Sinhala SURPS. Confirmatory factor analysis was performed to test the translated version against the original theoretical model of the SURPS. Test-retest and internal consi...

  16. Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models

    HogenEsch, Harm; Yu Nikitin, Alexander

    2012-01-01

    Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinic...

  17. Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy

    Zucconi, Eder; Vieira, Natassia Moreira; Bueno, Carlos Roberto; Secco, Mariane; Jazedje, Tatiana; Costa Valadares, Marcos; Fussae Suzuki, Miriam; Bartolini, Paolo; Vainzof, Mariz; Zatz, Mayana

    2011-01-01

    Umbilical cord mesenchymal stromal cells (MSC) have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs), independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1) human umbilical cord tissue (hUCT) MSCs into the caudal vein of SJL mice; (2) hUCT and canine umbilical cord vein (cUCV) MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies. PMID:21785565

  18. Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy

    Eder Zucconi

    2011-01-01

    Full Text Available Umbilical cord mesenchymal stromal cells (MSC have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs, independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1 human umbilical cord tissue (hUCT MSCs into the caudal vein of SJL mice; (2 hUCT and canine umbilical cord vein (cUCV MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies.

  19. Experimental Psychiatric Illness and Drug Abuse Models: From Human to Animal, an Overview

    Edwards, Scott; Koob, George F.

    2012-01-01

    Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models ...

  20. Noninferiority of Shanghai Cingular biotech’s bovine pericardial valve preclinical study in juvenile ovine model

    Chen, Jin-Miao; Ding, Yu; Lu, Shu-Yang; Pan, Sun; Abudupataer, Mieradilijiang

    2016-01-01

    Background This study introduces a newly Chinese domestic-designed/manufactured bovine pericardial valve, the SCBC valve (Shanghai Cingular Biotech Corporation, Shanghai, China), and evaluates its hemodynamic performance and calcification potential compared with the Carpentier-Edwards (CE) PerimountTM valve (Edwards Lifesciences, Irvine, CA, USA) in juvenile sheep for preclinical study. Methods Five SCBC valves in study group and three CE PerimountTM valves (6900P with TFX) in control group were implanted in the mitral position of juvenile sheep and followed up for five months. Transthoracic echocardiography (TTE) for hemodynamic measurement was performed ten days, three months and five months postoperatively. Valve calcification was assessed by X-ray after euthanasia. Other collected data included macroscopic examination, blood analysis, microorganism culture and histological assessment. Results All sheep in two groups lived to sacrifice without evidence of valvular dysfunction. The SCBC valve had similar hemodynamic performance and susceptibility of calcification compared with the CE PerimountTM valve in juvenile ovine model. In all other parameters, the SCBC valve also exhibited no significant difference compared with the CE PerimountTM valve. Conclusions Our study demonstrated that the SCBC valve can exhibit similar mid-term satisfactory safety and efficacy compared with the CE PerimountTM valve in the mitral position of juvenile sheep model. PMID:27293835

  1. Cardiorenal syndrome: pathophysiological mechanism, preclinical models, novel contributors and potential therapies

    Fu Qiang; Cao Longxing; Li Huang; Wang Binghui; Li Zhiliang

    2014-01-01

    Objective To review the current knowledge about the pathophysiological mechanisms,preclinical models,novel contributors and potential therapies of cardiorenal syndrome.Data sources The literature concerning cardioranal syndrome in this review was collected from PubMed published in English up to January 2014.Study selection Original articles and critical reviews related to cardiorenal syndrome were selected and carefully analyzed.Results Cardiorenal syndrome is a condition characterized by kidney and heart failure where failure of one organ worsens the function of the other thus further accelerating the progressive failure of both organs.The pathophysiology of cardiorenal syndrome is not fully understood,but may be caused by a complex combination of neurohormonal system activation,endothelial dysfunction,proteinuria,oxidative stress,uremic toxins and other factors.Managing cardiorenal syndrome is still a major therapeutic challenge in clinical practice because many of the drugs used to control heart failure can worsen renal function,and vice versa.Non-dialyzable uremic toxins,such as indoxyl sulfate,causing detrimental effects on the heart and kidney as well as stimulation of inflammatory responses,may be an effective therapeutic target for cardiorenal syndrome.Conclusions Suitable disease models of cardiorenal syndrome are urgently needed to investigate the pathophysiology and effective therapeutic approaches to the condition.Non-dialyzable protein-bound uremic toxins that may have cardiac and renal effects may provide therapeutic benefit to cardiorenal syndrome patients.

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

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

    2016-01-01

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

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

    Panksepp, Jaak

    2015-01-01

    Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong—to the extent that the rewarding and puni...

  4. Healing from Childhood Sexual Abuse: A Theoretical Model

    Draucker, Claire Burke; Martsolf, Donna S.; Roller, Cynthia; Knapik, Gregory; Ross, Ratchneewan; Stidham, Andrea Warner

    2011-01-01

    Childhood sexual abuse (CSA) is a prevalent social and healthcare problem. The processes by which individuals heal from CSA are not clearly understood. The purpose of this study was to develop a theoretical model to describe how adults heal from CSA. Community recruitment for an on-going, broader project on sexual violence throughout the lifespan, referred to as the Sexual Violence Study, yielded a subsample of 48 women and 47 men who had experienced CSA. During semi-structured, open-ended in...

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

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

    2016-05-01

    Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients. PMID:26871935

  6. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.

    Runge, Anja; Hu, Junhao; Wieland, Matthias; Bergeest, Jan-Philip; Mogler, Carolin; Neumann, André; Géraud, Cyrill; Arnold, Bernd; Rohr, Karl; Komljenovic, Dorde; Schirmacher, Peter; Goerdt, Sergij; Augustin, Hellmut G

    2014-08-01

    The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. PMID:24906623

  7. Child Sexual Abuse Prevention: Evaluation of a Teacher Training Model.

    Kleemeier, Carol; And Others

    1988-01-01

    The effectiveness of a six-hour teacher training workshop on child sexual abuse prevention was evaluated. Findings indicated that trained teachers demonstrated significant increases in knowledge about child sexual abuse and pro-intervention opinions. Trained teachers were better able to identify behavioral indicators of abuse and suggest…

  8. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan S; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G

    2016-06-01

    cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes. PMID:26838361

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

    LI Liang-zhu; YANG Yu; YUAN Song-hua; WAN Yan-min; QIU Chao; FENG Yan-ling; XU Jian-qing; ZHANG Xiao-yan

    2010-01-01

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

  10. Novel bifunctional anthracycline and nitrosourea chemotherapy for human bladder cancer: analysis in a preclinical survival model.

    Glaves, D; Murray, M K; Raghavan, D

    1996-08-01

    A hybrid drug [N-2-chloroethylnitrosoureidodaunorubicin (AD312)] that combines structural and functional features of both anthracyclines and nitrosoureas was evaluated in a preclinical survival model of human bladder cancer. To measure the therapeutic activity of AD312, UCRU-BL13 transitional cell carcinoma cells were grown as xenografts in nude mice, and tumor growth rates were compared after i.v. administration of the drug at three dose levels. AD312 treatment at 45 and 60 mg/kg achieved 7-10-fold inhibition of tumor growth and increased host survival by 156 and 249%, respectively. Doses of 60 mg/kg showed optimal therapeutic efficacy, with sustained tumor growth inhibition, an over 2-fold increase in life span, and 40% of mice tumor free ("cured") at 120 days. Tumors were unresponsive to maximum tolerated doses of doxorubicin, a standard anthracycline used as a single agent and in combination therapies for bladder cancer. 1,3-Bis-[2-chloroethyl]-1-nitrosourea was used as a control for the apparently enhanced response of human tumors in murine hosts to nitrosoureas. 1, 3-Bis-[2-chloroethyl]-1-nitrosourea administered in three injections of 20 mg/kg did not cure mice but temporarily inhibited tumor growth by 70% and prolonged survival by 55%; its activity in this model suggests that it may be included in the repertoire of alkylating agents currently used for treatment of bladder cancers. AD312 showed increased antitumor activity with less toxicity than doxorubicin, and its bifunctional properties provide the opportunity for simultaneous treatment of individual cancer cells with two cytotoxic modalities as well as treatment of heterogeneous populations typical of bladder cancers. This novel cytotoxic drug cured doxorubicin-refractory disease and should be investigated for the clinical management of bladder cancer. PMID:9816302

  11. Anti-cancer effect and gene modulation of ET-743 in human biliary tract carcinoma preclinical models

    Peraldo-Neia, Caterina; Cavalloni, Giuliana; Soster, Marco; Gammaitoni, Loretta; Marchiò, Serena; Sassi, Francesco; Trusolino, Livio; Bertotti, Andrea; Medico, Enzo; Capussotti, Lorenzo; Aglietta, Massimo; Leone, Francesco

    2014-01-01

    Background Standard chemotherapy in unresectable biliary tract carcinoma (BTC) patients is based on gemcitabine combined with platinum derivatives. However, primary or acquired resistance is inevitable and no second-line chemotherapy is demonstrated to be effective. Thus, there is an urgent need to identify new alternative (chemo)therapy approaches. Methods We evaluated the mechanism of action of ET-743 in preclinical models of BTC. Six BTC cell lines (TFK-1, EGI-1, TGBC1, WITT, KMCH, HuH28),...

  12. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    di Clemente, Riccardo; Pietronero, Luciano

    2012-07-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  13. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    Di Clemente, Riccardo; 10.1038/srep00532

    2012-01-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  14. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.

    Enriquez-Navas, Pedro M; Kam, Yoonseok; Das, Tuhin; Hassan, Sabrina; Silva, Ariosto; Foroutan, Parastou; Ruiz, Epifanio; Martinez, Gary; Minton, Susan; Gillies, Robert J; Gatenby, Robert A

    2016-02-24

    Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors-an evolutionary phenomenon termed "competitive release." We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor-positive (ER(+)) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer. PMID:26912903

  15. Comparing Reasons for Quitting Substance Abuse with the Constructs of Behavioral Models: A Qualitative Study

    Hamid Tavakoli Ghouchani; Shamsodin Niknami; Farkhondeh Aminshokravi; Seyed Kaveh Hojat

    2015-01-01

    Background and Objectives: The world population has reached over seven billion people. Of these, 230 million individuals abuse substances. Therefore, substance abuse prevention and treatment programs have received increasing attention during the past two decades. Understanding people’s motivations for quitting drug abuse is essential to the success of treatment. This study hence sought to identify major motivations for quitting and to compare them with the constructs of health education model...

  16. Bridging the Gap between Preclinical and Clinical Microbicide Trials: Blind Evaluation of Candidate Gels in Murine Models of Efficacy and Safety

    Theodore J Segarra; Esra Fakioglu; Natalia Cheshenko; Wilson, Sarah S; Pedro M M Mesquita; Doncel, Gustavo F.; Herold, Betsy C.

    2011-01-01

    BACKGROUND: Despite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future product...

  17. HSV-2 and Substance Abuse amongst Adolescents: Insights through Mathematical Modelling

    A. Mhlanga

    2014-01-01

    Full Text Available Herpes simplex virus infection is mostly spread and occurs more commonly among substance abusing adolescents as compared to the nonsubstance abusing. In this paper, a mathematical model for the spread of HSV-2 within a community with substance abusing adolescents is developed and analysed. The impacts of condom use and educational campaigns are examined. The study suggests that condom use is highly effective among adolescents, when we have more of them quitting than becoming substance abusers. Measures such as educational campaigns can be put in place to try and reduce adolescents from becoming substance abusers. Further, we applied optimal control theory to the proposed model. The controls represent condom use and educational campaigns. The objective is based on maximising the susceptible nonsubstance abusing adolescents, while minimising the susceptible substance abusing adolescents, the infectious nonsubstance abusing adolescents, and the infectious substance abusing adolescents. We used Pontrygin’s maximum principle to characterise the optimal levels of the two controls. The resulting optimality system is solved numerically. Overall, the application of the optimal control theory suggests that more effort should be devoted to condom use as compared to educational campaigns.

  18. Recent progress towards an effective treatment of amyotrophic lateral sclerosis using the SOD1 mouse model in a preclinical setting.

    Browne, Elisse C; Abbott, Belinda M

    2016-10-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, fatal and incurable neurodegenerative disorder. Motor neurone degeneration can be caused by genetic mutation but the exact etiology of the disease, particularly for sporadic illness, still remains unclear. Therapeutics which target known pathogenic mechanisms involved in ALS, such as protein aggregation, oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and mitochondria dysfunction, are currently being pursued in order to provide neuroprotection which may be able to slow down, or perhaps even halt, disease progression. This present review focuses on the compounds which have been recently evaluated using the SOD1 mouse model, the most widely used preclinical model for ALS research. PMID:27012524

  19. Impact Evaluation of a Cognitive Behavioral Group Therapy Model in Brazilian Sexually Abused Girls

    Habigzang, Luisa Fernanda; Damasio, Bruno Figueiredo; Koller, Silvia Helena

    2013-01-01

    This study evaluated the impact of a cognitive behavioral group therapy model in Brazilian girls who had experienced sexual abuse. The effect of the waiting period before treatment and the enduring effectiveness of the treatment after six and 12 months were also evaluated. Forty-nine female sexual abuse victims between the ages of 9 and 16…

  20. A Mixed-Methodological Examination of Investment Model Variables among Abused and Nonabused College Women

    Dardis, Christina M.; Kelley, Erika L.; Edwards, Katie M.; Gidycz, Christine A.

    2013-01-01

    Objective: This study assessed abused and nonabused women's perceptions of Investment Model (IM) variables (ie, relationship investment, satisfaction, commitment, quality of alternatives) utilizing a mixed-methods design. Participants: Participants included 102 college women, approximately half of whom were in abusive dating relationships.…

  1. Abuse Potential of Pregabalin

    Schjerning, Ole; Rosenzweig, Mary; Pottegård, Anton;

    2016-01-01

    BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers...... for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known. OBJECTIVE: The...... aim of this study was to present a systematic review of the data concerning the abuse potential of pregabalin. METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin. RESULTS: We included preclinical (n...

  2. The dark side of family communication: a communication model of elder abuse and neglect.

    Lin, Mei-Chen; Giles, Howard

    2013-08-01

    To further address the potential factors that lead up to elder abuse in domestic settings, this paper proposes a model from a communication approach to explain dyadic influences between the family caregiver and the elderly care receiver that give rise to the abuse. That is, dysfunctional communication between the caregivers and care receivers may, therefore, increase the likelihood of elder abuse. Grounded in Bugental and her colleagues' work (1993, 1999, 2002) on child abuse, we propose a power-oriented communication model based, in part, on research in the fields of family violence and intergenerational communication to explain the likelihood of occurrence of elder abuse in family caregiving situations. We argue that certain risk factors pertaining to caregivers' characteristics--those who perceive high stress in caregiving, have mental health issues, have a history of substance abuse, and/or display verbal aggressiveness--may be more likely to attribute considerable power to those elderly under their custodianship. At the same time, such caregivers tend to feel powerless and experience loss of control when interacting with their elderly counterparts. When an elderly care receiver displays noncompliant behaviors, caregivers may be prone to employ abusive behaviors (in our model, it refers to physical abuse, verbal abuse, or communication neglect) to seek such compliance. Consequences of such abuse may result in lower self-esteem or lower confidence in one's ability to manage his/her life. It is suggested that researchers and practitioners investigate both parties' interactions closely and the role of elderly care receivers in order to detect, intervene, and prevent elder abuse. PMID:23388449

  3. Modeling Risk for Child Abuse and Harsh Parenting in Families with Depressed and Substance-abusing Parents

    Kelley, Michelle L.; Lawrence, Hannah R.; Milletich, Robert R.; Hollis, Brittany F.; Henson, James M.

    2015-01-01

    Children with substance abusing parents are at considerable risk for child maltreatment. The current study applied an actor-partner interdependence model to examine how father only (n = 52) and dual couple (n = 33) substance use disorder, as well as their depressive symptomology influenced parents’ own (actor effects) and the partner's (partner effects) overreactivity in disciplinary interactions with their children, as well as their risk for child maltreatment. Parents completed the Center f...

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

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

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

    Dohmen, Amy J. C., E-mail: a.dohmen@nki.nl [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Swartz, Justin E. [Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Van Den Brekel, Michiel W. M. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Willems, Stefan M. [Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Spijker, René [Medical library, Academic Medical Center, Amsterdam 1100 DE (Netherlands); Dutch Cochrane Centre, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Neefjes, Jacques [Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Zuur, Charlotte L. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands)

    2015-08-28

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

  6. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa

    Wert, Katherine J.; Davis, Richard J.; Sancho-Pelluz, Javier; Nishina, Patsy M.; Stephen H Tsang

    2012-01-01

    Approximately 36 000 cases of simplex and familial retinitis pigmentosa (RP) worldwide are caused by a loss in phosphodiesterase (PDE6) function. In the preclinical Pde6αnmf363 mouse model of this disease, defects in the α-subunit of PDE6 result in a progressive loss of photoreceptors and neuronal function. We hypothesized that increasing PDE6α levels using an AAV2/8 gene therapy vector could improve photoreceptor survival and retinal function. We utilized a vector with the cell-type-specific...

  7. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models

    Rehan Ali; Sandeep Apte; Marta Vilalta; Murugesan Subbarayan; Zheng Miao; Chin, Frederick T.; Graves, Edward E.

    2015-01-01

    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based ...

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

    Panksepp, Jaak

    2015-12-01

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

  9. A bioluminescent mouse model of proliferation to highlight early stages of pancreatic cancer: A suitable tool for preclinical studies.

    de Latouliere, Luisa; Manni, Isabella; Iacobini, Carla; Pugliese, Giuseppe; Grazi, Gian Luca; Perri, Pasquale; Cappello, Paola; Novelli, Franco; Menini, Stefano; Piaggio, Giulia

    2016-09-01

    Transgenic mouse models designed to recapitulate genetic and pathologic aspects of cancer are useful to study early stages of disease as well as its progression. Among several, two of the most sophisticated models for pancreatic ductal adenocarcinoma (PDAC) are the LSL-Kras(G12D/+);Pdx-1-Cre (KC) and LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mice, in which the Cre-recombinase regulated by a pancreas-specific promoter activates the expression of oncogenic Kras alone or in combination with a mutant p53, respectively. Non-invasive in vivo imaging offers a novel approach to preclinical studies introducing the possibility to investigate biological events in the spatio/temporal dimension. We recently developed a mouse model, MITO-Luc, engineered to express the luciferase reporter gene in cells undergoing active proliferation. In this model, proliferation events can be visualized non-invasively by bioluminescence imaging (BLI) in every body district in vivo. Here, we describe the development and characterization of MITO-Luc-KC- and -KPC mice. In these mice we have now the opportunity to follow PDAC evolution in the living animal in a time frame process. Moreover, by relating in vivo and ex vivo BLI and histopathological data we provide evidence that these mice could represents a suitable tool for pancreatic cancer preclinical studies. Our data also suggest that aberrant proliferation events take place early in pancreatic carcinogenesis, before tumour appearance. PMID:26704357

  10. Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices.

    Schomberg, Dominic T; Tellez, Armando; Meudt, Jennifer J; Brady, Dane A; Dillon, Krista N; Arowolo, Folagbayi K; Wicks, Joan; Rousselle, Serge D; Shanmuganayagam, Dhanansayan

    2016-04-01

    Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices. PMID:26839324

  11. Disruption of Learning Processes by Chemotherapeutic Agents in Childhood Survivors of Acute Lymphoblastic Leukemia and Preclinical Models

    Emily B. Bisen-Hersh, Philip N. Hineline, Ellen A. Walker

    2011-01-01

    Full Text Available Objective: With the survival rate of acute lymphoblastic leukemia (ALL surpassing 90 percent within this decade, new research is emerging in the field of late effects. A review of the research investigating the relationship of treatment regimens for ALL to specific late effect deficits, underlying mechanisms, and possible remediation is warranted to support continued studies.Methods: The clinical literature was briefly surveyed to describe the occurrence and topography of late effects, specifically neurocognitive deficits. Additionally, the preclinical literature was reviewed to uncover potential underlying mechanisms of these deficits. The advantages of using rodent models to answer these questions are outlined, as is an assessment of the limited number of rodent models of childhood cancer treatment.Results: The literature supports that childhood survivors of ALL exhibit academic difficulties and are more likely to be placed in a special education program. Behavioral evidence has highlighted impairments in the areas of attention, working memory, and processing speed, leading to a decrease in full scale IQ. Neurophysiological and preclinical evidence for these deficits has implicated white matter abnormalities and acquired brain damage resulting from specific chemotherapeutic agents commonly used during treatment.Conclusions: The exact role of chemotherapeutic agents in learning deficits remains mostly unknown. Recommendations for an improved rodent model of learning deficits in childhood cancer survivors are proposed, along with suggestions for future directions in this area of research, in hopes that forthcoming treatment regimens will reduce or eliminate these types of impairments.

  12. Antecedents and outcomes of abusive supervision: test of a trickle-down model.

    Aryee, Samuel; Chen, Zhen Xiong; Sun, Li-Yun; Debrah, Yaw A

    2007-01-01

    The authors examined antecedents of abusive supervision and the relative importance of interactional and procedural justice as mediators of the relationship between abusive supervision and the work outcomes of affective organizational commitment and individual- and organization-directed citizenship behaviors. Data were obtained from subordinate-supervisor dyads from a telecommunication company located in southeastern China. Results of moderated regression analysis revealed that authoritarian leadership style moderated the relationship between supervisors' perceptions of interactional justice and abusive supervision such that the relationship was stronger for supervisors high rather than low in authoritarian leadership style. In addition, results of structural equation modeling analysis revealed that subordinates' perceptions of interactional but not procedural justice fully mediated the relationship between abusive supervision and the work outcomes. Implications for future investigations of abusive supervision are discussed. PMID:17227160

  13. Childhood Sexual Abuse

    Evrim Aktepe

    2009-08-01

    behavioral and psychological results by itself, early trauma may also lead to biological effects. Especially traumas during neuron plasticity phase may lead hypersensitivity of neuroendocrine stress response. Early life stresses are shown to lead changes in corticotrophin releasing factor system in preclinical and clinical phase studies. In the treatment of sexual abuse, emotional process related with trauma should be focused on. This process may be conducted with play therapy. Development of higher level defense mechanism, increasing ego capacity, orientation to social activity and personal activity according to skills is aimed. For the elimination of guiltiness related with stigmatization, the child should be told that it is not herhis fault to incorporate into sexual interaction and the culprit is abuser. It is fairly important for medical staff, school and family to have sufficient information about sexual abuse for prevention and early recognition.

  14. In vitro and in vivo evaluation of tubulin inhibitors with non-small cell lung cancer pre-clinical models

    Lama R

    2015-05-01

    Full Text Available Synthetic small molecule tubulin inhibitors have many advantages as novel anti-cancer agents compared to the current tubulin inhibitors generated from natural products. Our previous studies led to the design and synthesis of a series of novel tubulin inhibitors. Some of these compounds also inhibited heat shock protein 27 (Hsp27, and showed promising in vitro anti-cancer activities in several breast cancer cell lines at sub nano-molar concentrations. However, whether these compounds could suppress tumor growth in animals was not investigated yet. In the current study, to identify the best drug candidates, therapeutic efficacy of the representative compounds from previous analyses was evaluated using non-small cell lung cancer preclinical models. These agents dose-dependently inhibited the growth of lung cancer cells in both monolayer cultures and three-dimensional multicellular spheroids. Several compounds also showed promising tumor growth suppressive activity in nude mice xenograft model

  15. Modeling risk for child abuse and harsh parenting in families with depressed and substance-abusing parents.

    Kelley, Michelle L; Lawrence, Hannah R; Milletich, Robert J; Hollis, Brittany F; Henson, James M

    2015-05-01

    Children with substance abusing parents are at considerable risk for child maltreatment. The current study applied an actor-partner interdependence model to examine how father only (n=52) and dual couple (n=33) substance use disorder, as well as their depressive symptomology influenced parents' own (actor effects) and the partner's (partner effects) overreactivity in disciplinary interactions with their children, as well as their risk for child maltreatment. Parents completed the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977), the overreactivity subscale from the Parenting Scale (Arnold, O'Leary, Wolff, & Acker, 1993), and the Brief Child Abuse Potential Inventory (Ondersma, Chaffin, Mullins, & LeBreton, 2005). Results of multigroup structural equation models revealed that a parent's own report of depressive symptoms predicted their risk for child maltreatment in both father SUD and dual SUD couples. Similarly, a parent's report of their own depressive symptoms predicted their overreactivity in disciplinary encounters both in father SUD and dual SUD couples. In all models, partners' depressive symptoms did not predict their partner's risk for child maltreatment or overreactivity. Findings underscore the importance of a parent's own level of depressive symptoms in their risk for child maltreatment and for engaging in overreactivity during disciplinary episodes. PMID:25724658

  16. Alcohol Abuse and Dependence Symptoms: A Multidimensional Model of Common and Specific Etiology

    Simons, Jeffrey S.; Carey, Kate B.; Wills, Thomas A.

    2009-01-01

    This study tested a theoretical model hypothesizing differential pathways from five predictors to alcohol abuse and dependence symptoms. The participants were college students (N= 2,270) surveyed on two occasions in a 6-month prospective design. Social norms, perceived utility of alcohol use, and family history of alcohol problems were indirectly associated with Time 2 (T2) abuse and dependence symptoms through influencing level of alcohol consumption. Poor behavioral control had a direct eff...

  17. Longitudinal histories as predictors of future diagnoses of domestic abuse: modelling study

    Reis, Ben Y.; Kohane, Isaac Samuel; Mandl, Kenneth David

    2009-01-01

    Objective: To determine whether longitudinal data in patients’ historical records, commonly available in electronic health record systems, can be used to predict a patient’s future risk of receiving a diagnosis of domestic abuse. Design: Bayesian models, known as intelligent histories, used to predict a patient’s risk of receiving a future diagnosis of abuse, based on the patient’s diagnostic history. Retrospective evaluation of the model’s predictions using an independent testing set. Set...

  18. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  19. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

    Katherine M Ku

    Full Text Available The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD, allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD and Long-Evans (LE, between the ages of postnatal day (PND 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii the testing environment may profoundly influence the expression of strain-specific social behavior and (iii simple, automated measures of sociability may not capture the complexities of rat social interactions.

  20. In vivo preclinical evaluation of the accuracy of toroidal-shaped HIFU treatments using a tumor-mimic model

    The pig is an ideal animal model for preclinical evaluation of HIFU treatments, especially in the liver. However, there is no liver tumor model available for pigs. In this work, we propose to study an in vivo tumor-mimic model as a tool for evaluating if a sonographycally guided HIFU treatment, delivered by a toroidal-shaped device dedicated for the treatment of liver metastases, is correctly located in the liver. One centimeter tumor-mimics were created in liver tissues. These tumor-mimics were detectable on ultrasound imaging and on gross pathology. Two studies were carried out. First, an in vivo study of tolerance at mid-term (30 days, 10 pigs) revealed that tumor-mimics are suitable for studying HIFU treatments at a preclinical stage, since local and biological tolerances were excellent. The dimensions of the tumor-mimics were reproducible (diameter at day 0: 9.7 ± 2.0 mm) and were the same as a function of time (p = 0.64). A second in vivo study was carried out in ten pigs. Tumor mimics were used as targets in liver tissues in order to determine if the HIFU treatment is correctly located in the liver. A procedure of extensive HIFU ablation using multiple HIFU lesions juxtaposed manually was then tested on eight tumor-mimics. In 88% of the cases (seven out of eight), tumor-mimics were treated with negative margins (≥1 mm) in all directions. On average, negative margins measured 10.0 ± 6.7 mm. These tumor-mimics constitute an excellent reference for studying in vivo the accuracy of HIFU therapy in the liver.

  1. In vivo preclinical evaluation of the accuracy of toroidal-shaped HIFU treatments using a tumor-mimic model

    N' Djin, W A; Melodelima, D; Parmentier, H; Chapelon, J Y [Inserm, U556, Lyon, F-69003 (France); Universite de Lyon, Lyon, F-69003 (France); Rivoire, M [Institute of Experimental Surgery-Centre Leon Berard, Lyon, F-69008 (France); Universite de Lyon, Lyon, F-69003 (France)], E-mail: apoutou.ndjin@inserm.fr

    2010-04-21

    The pig is an ideal animal model for preclinical evaluation of HIFU treatments, especially in the liver. However, there is no liver tumor model available for pigs. In this work, we propose to study an in vivo tumor-mimic model as a tool for evaluating if a sonographycally guided HIFU treatment, delivered by a toroidal-shaped device dedicated for the treatment of liver metastases, is correctly located in the liver. One centimeter tumor-mimics were created in liver tissues. These tumor-mimics were detectable on ultrasound imaging and on gross pathology. Two studies were carried out. First, an in vivo study of tolerance at mid-term (30 days, 10 pigs) revealed that tumor-mimics are suitable for studying HIFU treatments at a preclinical stage, since local and biological tolerances were excellent. The dimensions of the tumor-mimics were reproducible (diameter at day 0: 9.7 {+-} 2.0 mm) and were the same as a function of time (p = 0.64). A second in vivo study was carried out in ten pigs. Tumor mimics were used as targets in liver tissues in order to determine if the HIFU treatment is correctly located in the liver. A procedure of extensive HIFU ablation using multiple HIFU lesions juxtaposed manually was then tested on eight tumor-mimics. In 88% of the cases (seven out of eight), tumor-mimics were treated with negative margins ({>=}1 mm) in all directions. On average, negative margins measured 10.0 {+-} 6.7 mm. These tumor-mimics constitute an excellent reference for studying in vivo the accuracy of HIFU therapy in the liver.

  2. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

    Ku, Katherine M; Weir, Ruth K; Silverman, Jill L; Berman, Robert F; Bauman, Melissa D

    2016-01-01

    The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions. PMID:27351457

  3. Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders

    Ku, Katherine M.; Weir, Ruth K.; Silverman, Jill L.; Berman, Robert F.; Bauman, Melissa D.

    2016-01-01

    The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26–56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions. PMID:27351457

  4. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.

    Fernández-Ruiz, Javier; Moro, María A; Martínez-Orgado, José

    2015-10-01

    Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects. PMID:26260390

  5. Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model.

    Nelson K F Chen

    Full Text Available BACKGROUND: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes. METHODS AND RESULTS: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs. The vector was comprised of a bifunctional, glucose-responsive promoter linked to human insulin cDNA. Ambient glucose concentrations appropriately altered human insulin mRNA expression and C-peptide secretion within minutes in vitro and in vivo. Treated swine showed correction of hyperglycemia, glucose intolerance, dyslipidemia and other metabolic abnormalities for > or = 47 weeks. Metabolic correction correlated significantly with the number of hepatocytes implanted. Importantly, we observed no hypoglycemia even under fasting conditions. Direct intrahepatic implantation of hepatocytes did not alter biochemical indices of liver function or induce abnormal hepatic lobular architecture. About 70% of implanted hepatocytes functionally engrafted, appeared histologically normal, retained vector DNA and expressed human insulin for > or = 47 weeks. Based on structural tissue analyses and transcriptome data, we showed that early correction of diabetes attenuated and even prevented pathological changes in the eye, kidney, liver and aorta. CONCLUSIONS: We demonstrate that autologous hepatocytes can be efficiently, simply and safely modified by electroporation of a nonviral vector to express, process and secrete insulin durably. This strategy, which achieved significant

  6. The relevance of preclinical research models for the development of antimigraine drugs: Focus on 5-HT1B/1D and CGRP receptors

    Gupta, S.; Villalon, C.M.

    2010-01-01

    the relief of migraineurs. Pathophysiological factors culminating into migraine headaches have not yet been completely deciphered and, thus, pose an additional challenge for preclinical research in the absence of any direct experimental marker. Migraine provocation experiments in humans use a head......-score to evaluate migraine, as articulated by the volunteer, which cannot be applied to laboratory animals. Therefore, basic research focuses on different symptoms and putative mechanisms, one at a time or in combination, to validate the hypotheses. Studies in several species, utilizing different...... preclinical approaches, have significantly contributed to the two antimigraine principles in therapeutics, namely: 5-HT1B/1D receptor agonists (known as triptans) and CGRP receptor antagonists (known as gepants). This review will analyze the preclinical experimental models currently known for the development...

  7. Concise review: Preclinical studies on human cell-based therapy in rodent ischemic stroke models: where are we now after a decade?

    Leong, Wai Khay; Lewis, Martin D; Koblar, Simon A

    2013-06-01

    Stroke, a debilitating brain insult, afflicts millions of individuals globally each year. In the last decade, researchers have investigated cell-based therapy as an alternative strategy to improve neurological outcome following stroke. This concise review critically examines preclinical reports using human adult and fetal stem/progenitor cells in rodent models of ischemic stroke. As we enter the second decade of study, we should aim to optimize our collective likelihood to translational success for stroke victims worldwide. We advocate international consensus recommendations be developed for future preclinical research. PMID:23390084

  8. Beyond abuse: the association among parenting style, abdominal pain, and somatization in IBS patients.

    Lackner, Jeffrey M; Gudleski, Gregory D; Blanchard, Edward B

    2004-01-01

    This study assessed the relative strength of the association between abuse, negative parenting style, and somatization in irritable bowel syndrome (IBS) patients. Drawing from preclinical stress physiology and abuse research identifying the family social climate as a frequently stronger and independent determinant of long-term health effects than abuse-specific variables, we predicted that negative parenting behaviors would more strongly correlate with somatization than abuse. Subjects were 81 consecutively evaluated patients, who at baseline underwent psychological testing, measuring perceived parental style, abuse history, somatization, and pain. Although abuse correlated with maternal and paternal rejection, abuse was not associated with somatization. Higher levels of rejection and/or hostility among fathers (not mothers) were more strongly correlated with somatization than was abuse. Further, paternal parenting behaviors were more predictive of somatization than abuse, age, and gender. The lack of an association between abuse and somatization is discussed in light of limitations of biopsychosocial IBS models, whose strong focus on "pathological stressors" (e.g., abuse, trauma) as risk factors may overlook the importance of "less extreme" parenting variables in influencing somatic complaints. The relationship between parenting and somatization is discussed in the context of broader behavioral science research linking disruptions in the quality of parenting to dramatic and long-term changes in patterns of stress reactivity and brain abnormalities seen in IBS patients. PMID:14744522

  9. Childhood physical abuse and midlife physical health: testing a multi-pathway life course model.

    Springer, Kristen W

    2009-07-01

    Although prior research has established that childhood abuse adversely affects midlife physical health, it is unclear how abuse continues to harm health decades after the abuse has ended. In this project, I assess four life course pathways (health behaviors, cognition, mental health, and social relation) that plausibly link childhood physical abuse to three midlife physical health outcomes (bronchitis diagnosis, ulcer diagnosis, and general physical health). These three outcomes are etiologically distinct, leading to unique testable hypotheses. Multivariate models controlling for childhood background and early adversity were estimated using data from over 3000 respondents in the Wisconsin Longitudinal Study, USA. The results indicate that midlife social relations and cognition do not function as pathways for any outcome. However, smoking is a crucial pathway connecting childhood abuse with bronchitis; mental health is important for ulcers; and BMI, smoking, and mental health are paramount for general physical health. These findings suggest that abuse survivors' coping mechanisms can lead to an array of midlife health problems. Furthermore, the results validate the use of etiologically distinct outcomes for understanding plausible causal pathways when using cross-sectional data. PMID:19446943

  10. Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer

    Bisht, Savita; Mizuma, Masamichi; Feldmann, Georg; Ottenhof, Niki A.; Hong, Seung-Mo; Pramanik, Dipankar; Chenna, Venugopal; Karikari, Collins; Sharma, Rajni; Goggins, Michael G.; Rudek, Michelle A.; Ravi, Rajani; Maitra, Amarnath; Maitra, Anirban

    2010-01-01

    Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Neve

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

    Shang, M; Sands, M; Bolch, W [University of Florida, Gainesville, FL (United States)

    2015-06-15

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

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

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

  13. Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

    McOmish, Caitlin E; Burrows, Emma L; Hannan, Anthony J

    2014-10-01

    Psychiatric disorders affect a substantial proportion of the population worldwide. This high prevalence, combined with the chronicity of the disorders and the major social and economic impacts, creates a significant burden. As a result, an important priority is the development of novel and effective interventional strategies for reducing incidence rates and improving outcomes. This review explores the progress that has been made to date in establishing valid animal models of psychiatric disorders, while beginning to unravel the complex factors that may be contributing to the limitations of current methodological approaches. We propose some approaches for optimizing the validity of animal models and developing effective interventions. We use schizophrenia and autism spectrum disorders as examples of disorders for which development of valid preclinical models, and fully effective therapeutics, have proven particularly challenging. However, the conclusions have relevance to various other psychiatric conditions, including depression, anxiety and bipolar disorders. We address the key aspects of construct, face and predictive validity in animal models, incorporating genetic and environmental factors. Our understanding of psychiatric disorders is accelerating exponentially, revealing extraordinary levels of genetic complexity, heterogeneity and pleiotropy. The environmental factors contributing to individual, and multiple, disorders also exhibit breathtaking complexity, requiring systematic analysis to experimentally explore the environmental mediators and modulators which constitute the 'envirome' of each psychiatric disorder. Ultimately, genetic and environmental factors need to be integrated via animal models incorporating the spatiotemporal complexity of gene-environment interactions and experience-dependent plasticity, thus better recapitulating the dynamic nature of brain development, function and dysfunction. PMID:24846457

  14. Elder Abuse and Substance Abuse

    Navigation Physical Abuse Sexual Abuse Domestic Violence Psychological Abuse Financial Abuse Neglect Critical Issues The Role of Culture in Elder ... factor in all types of elder abuse, including physical mistreatment, emotional abuse, financial exploitation, and neglect. It is also a ...

  15. Comparing Reasons for Quitting Substance Abuse with the Constructs of Behavioral Models: A Qualitative Study

    Hamid Tavakoli Ghouchani

    2015-03-01

    Full Text Available Background and Objectives: The world population has reached over seven billion people. Of these, 230 million individuals abuse substances. Therefore, substance abuse prevention and treatment programs have received increasing attention during the past two decades. Understanding people’s motivations for quitting drug abuse is essential to the success of treatment. This study hence sought to identify major motivations for quitting and to compare them with the constructs of health education models. Materials and Methods: In the present study, qualitative content analysis was used to determine the main motivations for quitting substance abuse. Overall, 22 patients, physicians, and psychotherapists were selected from several addiction treatment clinics in Bojnord (Iran during 2014. Purposeful sampling method was applied and continued until data saturation was achieved. Data were collected through semi-structured, face-to-face interviews and field notes. All interviews were recorded and transcribed. Results: Content analysis revealed 33 sub-categories and nine categories including economic problems, drug-related concerns, individual problems, family and social problems, family expectations, attention to social status, beliefs about drug addiction, and valuing the quitting behavior. Accordingly, four themes, i.e. perceived threat, perceived barriers, attitude toward the behavior, and subjective norms, were extracted. Conclusion: Reasons for quitting substance abuse match the constructs of different behavioral models (e.g. the health belief model and the theory of planned behavior.

  16. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases. PMID:26944053

  17. Practice Makes Perfect? The Role of Participant Modeling in Sexual Abuse Prevention Programs.

    Wurtele, Sandy K.; And Others

    1987-01-01

    Assigned 26 kindergarten children to either a sexual abuse prevention program which taught self-protective skills through modeling and active rehearsal (PM) or a program which taught the same skills by having children watch skills modeled by experimenter (SM). Results provide support for greater efficacy of PM relative to SM for learning of…

  18. Validating animal models for preclinical research: a scientific and ethical discussion

    Varga, Orsolya E.; Axel K. Hansen; Sandøe, Peter; Olsson, I Anna S

    2010-01-01

    The use of animals to model humans in biomedical research relies on the notion that basic processes are sufficiently similar across species to allow extrapolation. Animal model validity is discussed in terms of the similarity between the model and human condition it is intended to model, but no formal validation of models is applied. There is a stark contrast here with non-animal alternatives in toxicology and safety studies, for which an extensive validation is required. In the present paper...

  19. Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

    Becker, Marc; Graf, Claudine; Tonak, Marcus; Radsak, Markus P.; Bopp, Tobias; Bals, Robert; Bohle, Rainer M.; Theobald, Matthias; Rommens, Pol-Maria; Proschek, Dirk; Wehler, Thomas C.

    2016-01-01

    Undifferentiated pleomorphic sarcoma not otherwise specified belongs to the heterogeneous group of soft tissue tumors. It is preferentially located in the upper and lower extremities of the body, and surgical resection remains the only curative treatment. Preclinical animal models are crucial to improve the development of novel chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma. However, this approach has been hampered by the lack of reproducible animal models. The present study established two xenograft animal models generated from stable non-clonal cell cultures, and investigated the difference in chemotherapeutic effects on tumor growth between undifferentiated pleomorphic sarcoma in vivo and in vitro. The cell cultures were generated from freshly isolated tumor tissues of two patients with undifferentiated pleomorphic sarcoma. For the in vivo analysis, these cells were injected subcutaneously into immunodeficient mice. The mice were monitored for tumor appearance and treated with the most common or innovative chemotherapeutic agents available to date. Furthermore, the same drugs were administered to in vitro cell cultures. The most effective tumor growth inhibition in vitro was observed with doxorubicin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat. In the in vivo xenograft mouse model, the combination of doxorubicin and the tyrosine kinase inhibitor pazopanib induced a significant tumor reduction. By contrast, treatment with vorinostat did not reduce the tumor growth. Taken together, the results obtained from drug testing in vitro differed significantly from the in vivo results. Therefore, the novel and reproducible xenograft animal model established in the present study demonstrated that in vivo models are required to test potential chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma prior to clinical use, since animal models are more similar

  20. Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

    Jung, Joohee

    2014-01-01

    Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-der...

  1. Re-evaluate the effect of hyperbaric oxygen therapy in cancer - a preclinical therapeutic small animal model study.

    Sneha Pande

    Full Text Available Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model.

  2. Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

    Hauet, T.; Maiga, S.; Thuillier, R.; Chatauret, N.; Favreau, F; Giraud, S

    2011-01-01

    Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge ...

  3. Large animal induced pluripotent stem cells as pre-clinical models for studying human disease

    Jordan R Plews; Gu, Mingxia; Longaker, Michael T.; Joseph C. Wu

    2012-01-01

    Abstract The derivation of human embryonic stem cells and subsequently human induced pluripotent stem cells (iPSCs) has energized regenerative medicine research and enabled seemingly limitless applications. Although small animal models, such as mouse models, have played an important role in the progression of the field, typically, they are poor representations of the human disease phenotype. As an alternative, large animal models should be explored as a potentially better approach for clinica...

  4. Elder Abuse

    ... nursing home . Types of Abuse There are many types of abuse: Physical abuse happens when someone causes bodily harm by hitting, pushing, or slapping. Emotional abuse , sometimes called psychological abuse, can include a caregiver saying hurtful words, ...

  5. MR imaging features of high-grade gliomas in murine models: How they compare with human disease, reflect tumor biology, and play a role in preclinical trials

    Borges, A. R.; López-Larrubia, Pilar; Marques, J. B.; Cerdán, Sebastián

    2012-01-01

    Murine models are the most commonly used and best investigated among the animal models of HGG. They constitute an important weapon in the development and testing of new anticancer drugs and have long been used in preclinical trials. Neuroimaging methods, particularly MR imaging, offer important advantages for the evaluation of treatment response: shorter and more reliable treatment end points and insight on tumor biology and physiology through the use of functional imaging DWI, PWI, BOLD, and...

  6. Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies.

    Klymiuk, Nikolai; Seeliger, Frank; Bohlooly-Y, Mohammad; Blutke, Andreas; Rudmann, Daniel G; Wolf, Eckhard

    2016-04-01

    Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine. PMID:26511847

  7. Preclinical, fluorescence and diffuse optical tomography: non-contact instrumentation, modeling and time-resolved 3D reconstruction

    Time-Resolved Diffuse Optical Tomography (TR-DOT) is a new non-invasive imaging technique increasingly used in the clinical and preclinical fields. It yields optical absorption and scattering maps of the explored organs, and related physiological parameters. Time-Resolved Fluorescence Diffuse Optical Tomography (TR-FDOT) is based on the detection of fluorescence photons. It provides spatio-temporal maps of fluorescent probe concentrations and life times, and allows access to metabolic and molecular imaging which is important for diagnosis and therapeutic monitoring, particularly in oncology. The main goal of this thesis was to reconstruct 3D TR-DOT/TR-FDOT images of small animals using time-resolved optical technology. Data were acquired using optical fibers fixed around the animal without contact with its surface. The work was achieved in four steps: 1)- Setting up an imaging device to record the 3D coordinates of an animal's surface; 2)- Modeling the no-contact approach to solve the forward problem; 3)- Processing of the measured signals taking into account the impulse response of the device; 4)- Implementation of a new image reconstruction method based on a selection of carefully chosen points. As a result, good-quality 3D optical images were obtained owing to reduced cross-talk between absorption and scattering. Moreover, the computation time was cut down, compared to full-time methods using whole temporal profiles. (author)

  8. Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models

    Andre Cassell

    2012-11-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is characterized by overexpression of the epidermal growth factor receptor (EGFR where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473, phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

  9. Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models.

    Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

    2012-11-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC. PMID:23226094

  10. Clinical Supervision in Alcohol and Drug Abuse Counseling: Principles, Models, Methods.

    Powell, David J.

    A case is made for professionalism in clinical training as substance abuse counseling becomes a unique field. Part 1, "Principles," includes: (1) "A Historical Review of Supervision"; (2) "A Working Definition of Supervision"; (3) "Leadership Principles for Supervisors" and; (4) "Traits of an Effective Clinical Supervisor." Part 2, "Models,"…

  11. Remaining in an Abusive Relationship: An Investment Model Analysis of Nonvoluntary Dependence.

    Rusbult, Caryl E.; Martz, John M.

    1995-01-01

    Analyzes the nature of interdependence in ongoing relationships, using an investment model to understand decisions to remain in abusive relationships. Found that feelings of commitment were greater among women who had poorer-quality economic alternatives, were more heavily invested in their relationship, and who experienced less dissatisfaction…

  12. Alcohol Abuse and Alcoholism Prevention Model Learning Systems: Preliminary Designs. Final Report.

    Jacobs, Saul H.

    The final report on a project designed to develop a model learning system for alcohol abuse and alcoholism prevention contains format details of four specific programs. Each program is geared to obtain maximum success in reinforcing responsible behavior, to change learner behavior, and to insure effective implementation in a variety of…

  13. A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis

    Halliday, Alice; Guimaraes, Ana F.; Tyrer, Hayley E.; Metuge, Haelly Mejane; Patrick, Chounna Ndongmo Winston; Arnaud, Kengne-Ouafo Jonas; Kwenti, Tayong Dizzle Bita; Forsbrook, George; Steven, Andrew; Cook, Darren; Enyong, Peter; Wanji, Samuel; Taylor, Mark J; Joseph D Turner

    2014-01-01

    Background New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-Onchocerca drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model. Methods The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-Wolbachia macrofilaricide, minocycline (MIN) were tested in Brug...

  14. Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

    2011-01-01

    There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG...

  15. Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research

    Liu, Yewei; YIN Ting; Feng, Yuanbo; Cona, Marlein Miranda; Huang, Gang; Liu, Jianjun; Song, Shaoli; Jiang, Yansheng; Xia, Qian; Swinnen, Johannes V; Bormans, Guy; Himmelreich, Uwe; Oyen, Raymond; Ni, Yicheng

    2015-01-01

    Compared with transplanted tumor models or genetically engineered cancer models, chemically induced primary malignancies in experimental animals can mimic the clinical cancer progress from the early stage on. Cancer caused by chemical carcinogens generally develops through three phases namely initiation, promotion and progression. Based on different mechanisms, chemical carcinogens can be divided into genotoxic and non-genotoxic ones, or complete and incomplete ones, usually with an organ-spe...

  16. Choosing preclinical study models of diabetic retinopathy: key problems for consideration

    Mi XS

    2014-11-01

    Full Text Available Xue-Song Mi,1,2 Ti-Fei Yuan,3,4 Yong Ding,1 Jing-Xiang Zhong,1 Kwok-Fai So4,5 1Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 3School of Psychology, Nanjing Normal University, Nanjing, People’s Republic of China; 4Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; 5Guangdong-Hongkong-Macau Institute of Central Nervous System, Jinan University, Guangzhou, People’s Republic of China Abstract: Diabetic retinopathy (DR is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. Keywords: animal model, in vitro culture, ex vivo culture, neurovascular dysfunction

  17. Validating of the pre-clinical mouse model for metastatic breast cancer to the mandible

    Young Sun HWANG; Han, Sang-Sun; Kim, Ki-Rim; Lee, Ye-Jin; Lee, Sun-Kyung; PARK Kwang-Kyun; Chung, Won-Yoon

    2015-01-01

    Metastatic breast carcinoma has a great tendency to spread to the mandible. It is concomitantly associated with bone destruction, food intake disorder, and a poorer prognosis. Appropriate animal models need to be developed for a better understanding of the mechanisms underlying the metastatic process of breast cancer cells to mandible and to test the effects of potential lead compounds. Here, we assessed the metastasis model of intracardiac injection using luciferase-transfected metastatic br...

  18. Preclinical imaging and treatment of cancer: the use of animal models beyond rodents

    The development of novel radiopharmaceutical agents for imaging and therapy of neoplastic diseases relies on accurate and reproducible animal models. Rodent models are often used to demonstrate the proof-of-principle tracer and therapeutic agent development, but their small size can make tissue sampling challenging. The dosimetry of decay emissions in the much smaller rodent tumors do not model dosimetry in human tumors well. In addition, rodent models of cancer represent a simplified version of a very complex process. Spontaneous tumors are heterogenous and the response to intervention can be unpredictable; tumor cells can adopt alternate signaling pathways and modify their interaction with the microenvironment. These inconsistencies, while present in humans, are difficult to fully reproduce in a genetically-engineered rodent model. Companion animals, primarily dogs and cats, offer translational models that more accurately reflect the intricate nature of spontaneous neoplasia in humans. Their larger size facilitates tissue and blood sampling when needed, and allows radiopharmaceutical tracers to be studied on human-scale imaging systems to better mimic the clinical application of the agent. This article will review the growing body of literature surrounding the use of radiopharmaceutical agents for both imaging and therapy in companion dogs and cats. Previous investigations have been performed both for the advancement of routine, high-level veterinary care, and in the context of translational research from which the results of imaging and treatment can be readily applied to people. Studies utilizing the spontaneously occurring cancer model in companion animals involving positron emission tomography, radiotracers, dosimetry, theranostics, targeted radiopharmaceuticals, brachytherapy, and boron neutron capture therapy are discussed.

  19. Preclinical imaging and treatment of cancer: the use of animal models beyond rodents.

    Axiak-Bechtel, S M; Maitz, C A; Selting, K A; Bryan, J N

    2015-09-01

    The development of novel radiopharmaceutical agents for imaging and therapy of neoplastic diseases relies on accurate and reproducible animal models. Rodent models are often used to demonstrate the proof-of-principle tracer and therapeutic agent development, but their small size can make tissue sampling challenging. The dosimetry of decay emissions in the much smaller rodent tumors do not model dosimetry in human tumors well. In addition, rodent models of cancer represent a simplified version of a very complex process. Spontaneous tumors are heterogenous and the response to intervention can be unpredictable; tumor cells can adopt alternate signaling pathways and modify their interaction with the microenvironment. These inconsistencies, while present in humans, are difficult to fully reproduce in a genetically-engineered rodent model. Companion animals, primarily dogs and cats, offer translational models that more accurately reflect the intricate nature of spontaneous neoplasia in humans. Their larger size facilitates tissue and blood sampling when needed, and allows radiopharmaceutical tracers to be studied on human-scale imaging systems to better mimic the clinical application of the agent. This article will review the growing body of literature surrounding the use of radiopharmaceutical agents for both imaging and therapy in companion dogs and cats. Previous investigations have been performed both for the advancement of routine, high-level veterinary care, and in the context of translational research from which the results of imaging and treatment can be readily applied to people. Studies utilizing the spontaneously occurring cancer model in companion animals involving positron emission tomography, radiotracers, dosimetry, theranostics, targeted radiopharmaceuticals, brachytherapy, and boron neutron capture therapy are discussed. PMID:26200223

  20. Validating of the pre-clinical mouse model for metastatic breast cancer to the mandible

    Young Sun HWANG

    2015-02-01

    Full Text Available Metastatic breast carcinoma has a great tendency to spread to the mandible. It is concomitantly associated with bone destruction, food intake disorder, and a poorer prognosis. Appropriate animal models need to be developed for a better understanding of the mechanisms underlying the metastatic process of breast cancer cells to mandible and to test the effects of potential lead compounds. Here, we assessed the metastasis model of intracardiac injection using luciferase-transfected metastatic breast cancer cells (MDA-MB-231Luc+ by determining the incidences of metastasis, mCT images, and histopathological results. A high bioluminescence signal mainly detected mandibular lesions with less frequent distal femora and proximal tibiae lesions. Extensive mandibular bone destruction occurred in nude mice grafted with metastatic breast cancer cells. This type of animal model might be a useful tool in assessing therapeutic implications and the efficacy of anti-cancer drugs for osteolytic cancers.

  1. Characterization of a Pre-Clinical Mini-Pig Model of Scaphoid Non-Union

    Dominique Andre Behrends; Leticia Khendek; Chan Gao; Nadia Zayed; Janet Elizabeth Henderson; Paul Andre Martineau

    2015-01-01

    A fractured scaphoid is a common disabling injury that is frequently complicated by non-union. The treatment of non-union remains challenging because of the scaphoid’s small size and delicate blood supply. Large animal models are the most reliable method to evaluate the efficacy of new treatment modalities before their translation into clinical practice. The goal of this study was to model a human scaphoid fracture complicated by non-union in Yucatan mini-pigs. Imaging and perfusion studies ...

  2. Acute porcine model of huntington´s disease- a candidate for pre-clinical tests

    Hruška-Plocháň, Marian; Juhás, Štefan; Juhásová, Jana; Galik, J.; Miyanohara, A.; Maršala, M.; Bjarkam, C. R.; Cattaneo, E.; Difiglia, M.

    Amsterdam : European Neuroscience Society, 2010. s. 109-109. [FENS Forum of European Neuroscience /7./. 03.07.2010-07.07.2010, Amsterdam] Institutional research plan: CEZ:AV0Z50450515 Keywords : Huntington ´s disease * Animal model * Neurodegeneration Subject RIV: FH - Neurology

  3. Characterization of a Pre-Clinical Mini-Pig Model of Scaphoid Non-Union.

    Behrends, Dominique Andre; Khendek, Leticia; Gao, Chan; Zayed, Nadia; Henderson, Janet Elizabeth; Martineau, Paul Andre

    2015-01-01

    A fractured scaphoid is a common disabling injury that is frequently complicated by non-union. The treatment of non-union remains challenging because of the scaphoid's small size and delicate blood supply. Large animal models are the most reliable method to evaluate the efficacy of new treatment modalities before their translation into clinical practice. The goal of this study was to model a human scaphoid fracture complicated by non-union in Yucatan mini-pigs. Imaging and perfusion studies were used to confirm that the anatomy and blood supply of the radiocarpal bone in mini-pigs were similar to the human scaphoid. A 3 mm osteotomy of the radiocarpal bone was generated and treated with immediate fixation or filled with a dense collagen gel followed by delayed fixation. Bone healing was assessed using quantitative micro computed tomography and histology. With immediate fixation, the osteotomy site was filled with new bone across its whole length resulting in complete bridging. The dense collagen gel, previously shown to impede neo-vascularization, followed by delayed fixation resulted in impaired bridging with less bone of lower quality. This model is an appropriate, easily reproducible model for the evaluation of novel approaches for the repair of human scaphoid fractures. PMID:26086923

  4. Characterization of a Pre-Clinical Mini-Pig Model of Scaphoid Non-Union

    Dominique Andre Behrends

    2015-06-01

    Full Text Available A fractured scaphoid is a common disabling injury that is frequently complicated by non-union. The treatment of non-union remains challenging because of the scaphoid’s small size and delicate blood supply. Large animal models are the most reliable method to evaluate the efficacy of new treatment modalities before their translation into clinical practice. The goal of this study was to model a human scaphoid fracture complicated by non-union in Yucatan mini-pigs. Imaging and perfusion studies were used to confirm that the anatomy and blood supply of the radiocarpal bone in mini-pigs were similar to the human scaphoid. A 3 mm osteotomy of the radiocarpal bone was generated and treated with immediate fixation or filled with a dense collagen gel followed by delayed fixation. Bone healing was assessed using quantitative micro computed tomography and histology. With immediate fixation, the osteotomy site was filled with new bone across its whole length resulting in complete bridging. The dense collagen gel, previously shown to impede neo-vascularization, followed by delayed fixation resulted in impaired bridging with less bone of lower quality. This model is an appropriate, easily reproducible model for the evaluation of novel approaches for the repair of human scaphoid fractures.

  5. Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: a model for preclinical studies

    Thim, Troels; Hagensen, Mette; Drouet, L.; Bal Dit, Sollier C.; Bonneau, M.; Granada, J.F.; Nielsen, Lars Bo; Paaske, W.P.; Botker, H.E.; Falk, E.

    2010-01-01

    years but then weigh >200 kg making them impractical and costly. We aimed at down-sizing this pig and accelerating coronary plaque development to make the model more useful and affordable. METHODS AND RESULTS: Familial hypercholesterolaemic farm pigs were downsized by crossing them with smaller pigs...

  6. Reverse translation of failed treatments can help improving the validity of preclinical animal models

    't Hart, Bert A.

    2015-01-01

    A major challenge in translational research is to reduce the currently high proportion of new candidate treatment agents for neuroinflammatory disease, which fail to reproduce promising effects observed in animal models when tested in patients. This disturbing situation has raised criticism against

  7. Pig Models of Neurodegenerative Disorders: Utilization in Cell Replacement-Based Preclinical Safety and Efficacy Studies

    Doležalová, D.; Hruška-Plocháň, M.; Bjarkam, C. R.; Sorensen, J. C. H.; Cunningham, M.; Weingarten, D.; Ciacci, J. D.; Juhás, Štefan; Juhásová, Jana; Motlík, Jan; Hefferan, M. P.; Hazel, T.; Johe, K.; Carromeu, C.; Muotri, A.; Bui, J. D.; Strnádel, J.; Marsala, M.

    2014-01-01

    Roč. 522, č. 12 (2014), s. 2784-2801. ISSN 0021-9967 R&D Projects: GA TA ČR(CZ) TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : pig * neurodegenerative models * stem cells Subject RIV: FH - Neurology Impact factor: 3.225, year: 2014

  8. α7 Nicotinic receptor-mediated astrocytic gliotransmitter release: Aβ effects in a preclinical Alzheimer's mouse model.

    Tiina Maria Pirttimaki

    Full Text Available It is now recognized that astrocytes participate in synaptic communication through intimate interactions with neurons. A principal mechanism is through the release of gliotransmitters (GTs such as ATP, D-serine and most notably, glutamate, in response to astrocytic calcium elevations. We and others have shown that amyloid-β (Aβ, the toxic trigger for Alzheimer's disease (AD, interacts with hippocampal α7 nicotinic acetylcholine receptors (nAChRs. Since α7nAChRs are highly permeable to calcium and are expressed on hippocampal astrocytes, we investigated whether Aβ could activate astrocytic α7nAChRs in hippocampal slices and induce GT glutamate release. We found that biologically-relevant concentrations of Aβ1-42 elicited α7nAChR-dependent calcium elevations in hippocampal CA1 astrocytes and induced NMDAR-mediated slow inward currents (SICs in CA1 neurons. In the Tg2576 AD mouse model for Aβ over-production and accumulation, we found that spontaneous astrocytic calcium elevations were of higher frequency compared to wildtype (WT. The frequency and kinetic parameters of AD mice SICs indicated enhanced gliotransmission, possibly due to increased endogenous Aβ observed in this model. Activation of α7nAChRs on WT astrocytes increased spontaneous inward currents on pyramidal neurons while α7nAChRs on astrocytes of AD mice were abrogated. These findings suggest that, at an age that far precedes the emergence of cognitive deficits and plaque deposition, this mouse model for AD-like amyloidosis exhibits augmented astrocytic activity and glutamate GT release suggesting possible repercussions for preclinical AD hippocampal neural networks that contribute to subsequent cognitive decline.

  9. Addiction-related genes in gambling disorders: new insights from parallel human and pre-clinical models.

    Lobo, D S S; Aleksandrova, L; Knight, J; Casey, D M; el-Guebaly, N; Nobrega, J N; Kennedy, J L

    2015-08-01

    Neurobiological research supports the characterization of disordered gambling (DG) as a behavioral addiction. Recently, an animal model of gambling behavior was developed (rat gambling task, rGT), expanding the available tools to investigate DG neurobiology. We investigated whether rGT performance and associated risk gene expression in the rat's brain could provide cross-translational understanding of the neuromolecular mechanisms of addiction in DG. We genotyped tagSNPs (single-nucleotide polymorphisms) in 38 addiction-related genes in 400 DG and 345 non-DG subjects. Genes with P<0.1 in the human association analyses were selected to be investigated in the animal arm to determine whether their mRNA expression in rats was associated with the rat's performance on the rGT. In humans, DG was significantly associated with tagSNPs in DRD3 (rs167771) and CAMK2D (rs3815072). Our results suggest that age and gender might moderate the association between CAMK2D and DG. Moderation effects could not be investigated due to sample power. In the animal arm, only the association between rGT performance and Drd3 expression remained significant after Bonferroni correction for 59 brain regions. As male rats were used, gender effects could not be investigated. Our results corroborate previous findings reporting the involvement of DRD3 receptor in addictions. To our knowledge, the use of human genetics, pre-clinical models and gene expression as a cross-translation paradigm has not previously been attempted in the field of addictions. The cross-validation of human findings in animal models is crucial for improving the translation of basic research into clinical treatments, which could accelerate neurobiological and pharmacological investigations in addictions. PMID:25266122

  10. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

    2016-01-01

    cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes. PMID:26838361

  11. Time-varying effect models for ordinal responses with applications in substance abuse research

    Dziak, John J.; Li, Runze; Zimmerman, Marc A.; Buu, Anne

    2014-01-01

    Ordinal responses are very common in longitudinal data collected from substance abuse research or other behavioral research. This study develops a new statistical model with free SAS macro’s that can be applied to characterize time-varying effects on ordinal responses. Our simulation study shows that the ordinal-scale time-varying effects model has very low estimation bias and sometimes offers considerably better performance when fitting data with ordinal responses than a model that treats th...

  12. Internal Working Models and Adjustment of Physically Abused Children: The Mediating Role of Self-Regulatory Abilities

    Hawkins, Amy L.; Haskett, Mary E.

    2014-01-01

    Background: Abused children's internal working models (IWM) of relationships are known to relate to their socioemotional adjustment, but mechanisms through which negative representations increase vulnerability to maladjustment have not been explored. We sought to expand the understanding of individual differences in IWM of abused children and…

  13. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model

    Lacerda, Lara; Debeb, Bisrat G; Smith, Daniel; Larson, Richard; Solley, Travis; Xu, Wei; Krishnamurthy, Savitri; Gong, Yun; Levy, Lawrence B; Buchholz, Thomas; Ueno, Naoto T.; Klopp, Ann; Woodward, Wendy A.

    2015-01-01

    Introduction Inflammatory breast cancer (IBC) is an aggressive type of breast cancer, characterized by very rapid progression, enlargement of the breast, skin edema causing an orange peel appearance (peau d’orange), erythema, thickening, and dermal lymphatic invasion. It is characterized by E-cadherin overexpression in the primary and metastatic disease, but to date no robust molecular features that specifically identify IBC have been reported. Further, models that recapitulate all of these c...

  14. Clinical experiences during preclinical training: the function of modeled behavior and the evidence of professionalism principles

    Barret Michalec

    2012-03-01

    Full Text Available Objectives: Following the fundamental tenets of Bandura's social learning theory, this study examines the functions of modeled behavior during clinical experiences in the first two years of medical training from the students' perspective, and explores the potential presence of professionalism principles in students' narratives. Methods: Data were gathered through in-depth interviews with ten first year and ten second year medical students. Data were analyzed utilizing a subset of deductive codes extracted from previous literature, as well as inductive codes and particular categories and themes that followed from subsequent analysis procedures. Results: Although not explicitly prompted during inter-views, students offered basic principles of professionalism through their descriptions of behaviors and attributes exhibited by shadowed physicians and preceptors as characteristics that they found appealing and desirable to emulate. Also, students not only actively distinguish between role models and anti-models, but the data suggests that antimodels may even serve as effective mechanisms of social learning processes during these early clinical experiences. Furthermore, the data point to the probable influence of anticipatory socialization processes prior to medical training in that students present, as early as their first week of training, conceptions of how a doctor should act towards patients and other health care professionals. Conclusions: Students actively engage in the social learning process, and early clinical exposure provides opportunities for students to refine their understandings and perceptions of their future role through analysis of the attitudes and behaviors displayed by physicians they deem as positive and negative models of the physician role.

  15. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modif...

  16. A Model of Sexual Risk Behaviors Among Young Gay and Bisexual Men: Longitudinal Associations of Mental Health, Substance Abuse, Sexual Abuse, and the Coming-Out Process

    Rosario, Margaret; Schrimshaw, Eric W.; Hunter, Joyce

    2006-01-01

    Sexual risk behaviors of young gay and bisexual men must be understood within the context of other health concerns (e.g., anxiety, substance abuse), population-specific factors (i.e., the coming-out process and gay-related stress), childhood sexual abuse, and other theoretical factors (e.g., safer sex intentions). The current report proposes and longitudinally examines a model of risk factors for subsequent sexual risk behaviors among young gay and bisexual men in New York City. As hypothesiz...

  17. Swept-sine noise-induced damage as a hearing loss model for preclinical assays

    Lorena eSanz

    2015-02-01

    Full Text Available Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz (violet noises to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 inhibitors P17 and P144 on noise-induced hearing loss. CBA mice were exposed to violet swept-sine noise with different frequency ranges (2-20 or 9-13 kHz and levels (105 or 120 dB SPL for 30 minutes. Mice were evaluated by auditory brainstem response and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by violet swept-sine noise depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL, whereas permanent cochlear damage resulted from the exposure to 120 dB SPL. Exposure to 9-13 kHz noise caused an auditory threshold shift in those frequencies that correlated with hair cell loss in the corresponding areas of the cochlea that were spotted on the cytocochleogram. In summary, we present mouse models of noise-induced hearing loss, which depending on the sound properties of the noise, cause different degrees of cochlear damage, and could therefore be used to study molecules which are potential players in hearing loss protection and repair.

  18. 5-azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

    Yu, Changpu; Anderson, Martha; Zeng, Weiping; van Rooijen, Nico; Sievers, Eric L; Grewal, Iqbal S; Law, Che-Leung

    2010-01-01

    Despite therapeutic advances, the poor prognoses for acute myeloid leukemia (AML) and intermediate and high-risk myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, induced meaningful responses in a Phase 1 clinical trial and demonstrated anti-leukemic activity in preclinical models. Recently, it was reported that 5-azacytidine (Vidaza™) prolonged the overall survival of a group of high risk MDS and AML patients. To determine whether the combination of lintuzumab and 5-azacytidine would be beneficial, a mouse xenograft model of disseminated AML was used to evaluate the combination. There was a significant reduction in tumor burden and an increase in overall survival in mice treated with lintuzumab and 5-azacytidine. The effects were greater than that obtained with either agent alone. As the in vivo anti-leukemic activity of lintuzumab was dependent upon the presence of mouse effector cells including macrophages and neutrophils, in vitro effector function assays were used to assess the impact of 5-azacytidine on lintuzumab activity. The results show that 5-azacytidine significantly enhanced the ability of lintuzumab to promote tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytic (ADCP) activities. These results suggest that lintuzumab and 5-azacytidine act in concert to promote tumor cell killing. Additionally, these findings provide the rationale to evaluate this combination in the clinic. PMID:20495353

  19. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    Kawano, Satoshi; Grassian, Alexandra R; Tsuda, Masumi; Knutson, Sarah K; Warholic, Natalie M; Kuznetsov, Galina; Xu, Shanqin; Xiao, Yonghong; Pollock, Roy M; Smith, Jesse S; Kuntz, Kevin K; Ribich, Scott; Minoshima, Yukinori; Matsui, Junji; Copeland, Robert A; Tanaka, Shinya; Keilhack, Heike

    2016-01-01

    The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers. PMID:27391784

  20. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    Satoshi Kawano

    Full Text Available The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2 methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1 has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.

  1. Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis.

    Costantino, Valeria V; Lobos-Gonzalez, Lorena; Ibañez, Jorge; Fernandez, Dario; Cuello-Carrión, F Darío; Valenzuela, Manuel A; Barbieri, Manuel A; Semino, Silvana N; Jahn, Graciela A; Quest, Andrew F G; Lopez, Luis A

    2016-03-01

    Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide. Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive, simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively. DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental data. Extrapolation beyond experimental time points revealed that DhL administration following preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with DhL in restricting tumor growth. PMID:26718258

  2. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    Fichou, Nolwenn; Gouard, Sébastien; Maurel, Catherine; Barbet, Jacques; Ferrer, Ludovic; Morgenstern, Alfred; Bruchertseifer, Frank; Faivre-Chauvet, Alain; Bigot-Corbel, Edith; Davodeau, François; Gaschet, Joëlle; Chérel, Michel

    2015-01-01

    Objectives Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic eff...

  3. Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

    Huang, Liqun; WONG, CHI C.; Mackenzie, Gerardo G; Sun, Yu; Cheng, Ka Wing; Vrankova, Kvetoslava; Alston, Ninche; Ouyang, Nengtai; Rigas, Basil

    2014-01-01

    Background The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). Methods Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic stud...

  4. Solitaire FR revascularization device 4×40: safety study and effectiveness in preclinical models.

    Wainwright, John Michael; Jahan, Reza

    2016-07-01

    Recent randomized clinical trials have shown the benefit of stent retrievers for endovascular intervention in patients with acute ischemic stroke. The Solitaire 2 FR 4×40 device was developed to address longer clots as well as procedural difficulties. This study was undertaken to evaluate the safety of the new device in a swine model at 0, 30, and 90 days as well as its in vitro effectiveness. There were no significant differences in the overall animal health, tissue injury, hemorrhagic or thrombogenic events related to device usage. Based on the comparison at multiple time points, the Solitaire 2 4×40 device was similar in safety and usability to the Solitaire 2 4×20 device. Due to the additional length of the device, the Solitaire 2 4×40 device may in fact provide a number of additional technical benefits in the neurothrombectomy treatment of ischemic stroke. PMID:26101268

  5. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modification of mouse T cells for adoptive transfer by using retrovirus expressing genes of interest are provided. Additional sections, including growing B16 melanoma, enumerating pulmonary metastases, tumor imaging technique and use of recombinant viruses for vaccination, are discussed together with safety concerns. PMID:25640991

  6. OKN-007 decreases VEGFR-2 levels in a preclinical GL261 mouse glioma model.

    de Souza, Patricia Coutinho; Smith, Nataliya; Pody, Richard; He, Ting; Njoku, Charity; Silasi-Mansat, Robert; Lupu, Florea; Meek, Bill; Chen, Hong; Dong, Yunzhou; Saunders, Debra; Orock, Albert; Hodges, Erik; Colijn, Sarah; Mamedova, Nadezda; Towner, Rheal A

    2015-01-01

    Angiogenesis is essential to tumor progression, and the precise imaging of the angiogenic marker vascular endothelial growth factor receptor 2 (VEGFR-2) may provide an accurate evaluation for angiogenesis during a therapeutic response. With the use of molecular magnetic resonance imaging (mMRI), an in vitro cell assay indicated significantly decreased T1 relaxation values when tumor endothelial cells (TEC), which positively expressed VEGFR-2 (Western blot), were in the presence of the VEGFR-2 probe compared to TEC alone (P mMRI evaluations, we assessed VEGFR-2 levels in untreated and OKN-007-treated GL261 mouse gliomas. Regarding treatment response, OKN-007 was also able to significantly decrease tumor volumes (P < 0.01) and increase survival (P < 0.001) in treated animals. Regarding in vivo detection of VEGFR-2, OKN-007 was found to significantly decrease the amount of VEGFR-2 probe (P < 0.05) compared to an untreated control group. Fluorescence imaging for the VEGFR-2 probe indicated that there was colocalization with the endothelial marker CD31 in an untreated tumor bearing mouse and decreased levels for an OKN-007-treated animal. Immuno-fluorescence imaging for VEGFR-2 indicated that OKN-007 treatment significantly decreased VEGFR-2 levels (P < 0.0001) when compared to untreated tumors. Immuno-electron microscopy was used with gold-labeled anti-biotin to detect the anti-VEGFR-2 probe within the plasma membrane of GL261 tumor endothelial cells. This is the first attempt at detecting in vivo levels of VEGFR-2 in a mouse GL261 glioma model and assessing the anti-angiogenic capability of an anticancer nitrone. The results indicate that OKN-007 treatment substantially decreased VEGFR-2 levels in a GL261 glioma model, and can be considered as an anti-angiogenic therapy in human gliomas. PMID:26269774

  7. Preclinical models for in vitro mechanical loading of bone-derived cells.

    Michael Delaine-Smith, Robin; Javaheri, Behzad; Helen Edwards, Jennifer; Vazquez, Marisol; Rumney, Robin Mark Howard

    2015-01-01

    It is well established that bone responds to mechanical stimuli whereby physical forces are translated into chemical signals between cells, via mechanotransduction. It is difficult however to study the precise cellular and molecular responses using in vivo systems. In vitro loading models, which aim to replicate forces found within the bone microenvironment, make the underlying processes of mechanotransduction accessible to the researcher. Direct measurements in vivo and predictive modeling have been used to define these forces in normal physiological and pathological states. The types of mechanical stimuli present in the bone include vibration, fluid shear, substrate deformation and compressive loading, which can all be applied in vitro to monolayer and three-dimensional (3D) cultures. In monolayer, vibration can be readily applied to cultures via a low-magnitude, high-frequency loading rig. Fluid shear can be applied to cultures in multiwell plates via a simple rocking platform to engender gravitational fluid movement or via a pump to cells attached to a slide within a parallel-plate flow chamber, which may be micropatterned for use with osteocytes. Substrate strain can be applied via the vacuum-driven FlexCell system or via a four-point loading jig. 3D cultures better replicate the bone microenvironment and can also be subjected to the same forms of mechanical stimuli as monolayer, including vibration, fluid shear via perfusion flow, strain or compression. 3D cocultures that more closely replicate the bone microenvironment can be used to study the collective response of several cell types to loading. This technical review summarizes the methods for applying mechanical stimuli to bone cells in vitro. PMID:26331007

  8. Conditions for NIR fluorescence-guided tumor resectioning in preclinical lung cancer model (Conference Presentation)

    Kim, Minji; Quan, Yuhua; Choi, Byeong Hyun; Choi, Yeonho; Kim, Hyun Koo; Kim, Beop-Min

    2016-03-01

    Pulmonary nodule could be identified by intraoperative fluorescence imaging system from systemic injection of indocyanine green (ICG) which achieves enhanced permeability and retention (EPR) effects. This study was performed to evaluate optimal injection time of ICG for detecting cancer during surgery in rabbit lung cancer model. VX2 carcinoma cell was injected in rabbit lung under fluoroscopic computed tomography-guidance. Solitary lung cancer was confirmed on positron emitting tomography with CT (PET/CT) 2 weeks after inoculation. ICG was administered intravenously and fluorescent intensity of lung tumor was measured using the custom-built intraoperative color and fluorescence merged imaging system (ICFIS) for 15 hours. Solitary lung cancer was resected through thoracoscopic version of ICFIS. ICG was observed in all animals. Because Lung has fast blood pulmonary circulation, Fluorescent signal showed maximum intensity earlier than previous studies in other organs. Fluorescent intensity showed maximum intensity within 6-9 hours in rabbit lung cancer. Overall, Fluorescent intensity decreased with increasing time, however, all tumors were detectable using fluorescent images until 12 hours. In conclusion, while there had been studies in other organs showed that optimal injection time was at least 24 hours before operation, this study showed shorter optimal injection time at lung cancer. Since fluorescent signal showed the maximum intensity within 6-9 hours, cancer resection could be performed during this time. This data informed us that optimal injection time of ICG should be evaluated in each different solid organ tumor for fluorescent image guided surgery.

  9. Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model.

    Pathak, Rupak; Wang, Junru; Garg, Sarita; Aykin-Burns, Nukhet; Petersen, Karl-Uwe; Hauer-Jensen, Martin

    2016-08-01

    Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, anti-inflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-β) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage. PMID:27459702

  10. The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma

    Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM

  11. Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

    Pathak, Rupak; Wang, Junru; Garg, Sarita; Aykin-Burns, Nukhet; Petersen, Karl-Uwe; Hauer-Jensen, Martin

    2016-01-01

    Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, antiinflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-β) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage. PMID:27459702

  12. Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.

    Brown, Jordan W; Rueter, Lynne E; Zhang, Min

    2014-03-01

    Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS. PMID:24269664

  13. Bridging the Gap: A Hybrid Model to Link Efficacy and Effectiveness Research in Substance Abuse Treatment

    Carroll, Kathleen M.; Rounsaville, Bruce J

    2003-01-01

    Many behavioral and pharmacologic treatments for which there is strong empirical support are rarely used in clinical practice in the treatment of substance dependence. In an effort to facilitate greater emphasis on issues such as utility, practicality, and cost earlier in the evaluation of promising therapies, the authors propose a hybrid model to link efficacy and effectiveness research. A hybrid model may foster broader use of empirically validated treatments in substance abuse treatment pr...

  14. In vivo biocompatibility of Resilon compared with gutta-percha in a pre-clinical model

    Miguel Cardoso

    2013-01-01

    Full Text Available Background: The aim of this study was to investigate in vivo biocompatibility of Resilon, compared with gutta-percha, at short and long-term following implantation in a rat subcutaneous implantation model. Materials and Methods: Male Wistar rats were implanted subcutaneously with either Resilon or gutta-percha or were sham controls. Tissues were harvested at 8 days or 60 days after implantation and were evaluated histologically for inflammation and fibrous encapsulation. The severity of histologic injury, scored on a scale of 0-4 and quantitative analysis of the capsule wall thickness were determined for statistical analysis. Data were analyzed by Student t-test, one-way analysis of variance, Kruskal-Wallis or Mann-Whitney′s tests as appropriate. A value of P ≤ 0.05 was considered statistically significant. Results: No behavioral changes or visible signs of physical impairment were observed at 8 days or 60 days post-implantation. Histopathologic observation of the implanted sites at each time-point showed that both Resilon and gutta-percha implants induced foreign body reaction, showing minimal to mild inflammatory reactions in most cases, which diminished significantly with time. Compared with gutta-percha, the capsule wall was thinner (P > 0.05 after Resilon implantation at day 8 and significantly (P = 0.01 thicker at day 60. In addition, capsule wall thickness showed a trend to increase with time after implantation in the Resilon groups (P > 0.05, opposed to the significant decrease (P = 0.016 observed after implantation in the gutta-percha groups, suggesting lesser long-term biocompatibility of Resilon. Conclusion: Our findings validate Resilon as an in vivo biocompatible material. However, our data suggest that long-term biocompatibility of Resilon, despite validated, is inferior to that of gutta-percha control.

  15. A modified collagen gel dressing promotes angiogenesis in a preclinical swine model of chronic ischemic wounds.

    Elgharably, Haytham; Ganesh, Kasturi; Dickerson, Jennifer; Khanna, Savita; Abas, Motaz; Ghatak, Piya Das; Dixit, Sriteja; Bergdall, Valerie; Roy, Sashwati; Sen, Chandan K

    2014-01-01

    We recently performed proteomic characterization of a modified collagen gel (MCG) dressing and reported promising effects of the gel in healing full-thickness excisional wounds. In this work, we test the translational relevance of our aforesaid findings by testing the dressing in a swine model of chronic ischemic wounds recently reported by our laboratory. Full-thickness excisional wounds were established in the center of bipedicle ischemic skin flaps on the backs of animals. Ischemia was verified by laser Doppler imaging, and MCG was applied to the test group of wounds. Seven days post wounding, macrophage recruitment to the wound was significantly higher in MCG-treated ischemic wounds. In vitro, MCG up-regulated expression of Mrc-1 (a reparative M2 macrophage marker) and induced the expression of anti-inflammatory cytokine interleukin (IL)-10 and of fibroblast growth factor-basic (β-FGF). An increased expression of CCR2, an M2 macrophage marker, was noted in the macrophages from MCG treated wounds. Furthermore, analyses of wound tissues 7 days post wounding showed up-regulation of transforming growth factor-β, vascular endothelial growth factor, von Willebrand's factor, and collagen type I expression in MCG-treated ischemic wounds. At 21 days post wounding, MCG-treated ischemic wounds displayed higher abundance of proliferating endothelial cells that formed mature vascular structures and increased blood flow to the wound. Fibroblast count was markedly higher in MCG-treated ischemic wound-edge tissue. In addition, MCG-treated wound-edge tissues displayed higher abundance of mature collagen with increased collagen type I : III deposition. Taken together, MCG helped mount a more robust inflammatory response that resolved in a timely manner, followed by an enhanced proliferative phase, angiogenic outcome, and postwound tissue remodeling. Findings of the current study warrant clinical testing of MCG in a setting of ischemic chronic wounds. PMID:25224310

  16. Spatial Frequency Domain Imaging: Applications in Preclinical Models of Alzheimer's Disease

    Lin, Alexander Justin

    A clinical challenge in Alzheimer's disease (AD) is diagnosing and treating patients earlier, before symptoms of cognitive dysfunction occur. A good screening test would be sensitive to the AD brain pathology, safe, and cost-effective. Diffuse optical imaging, which measures how non-ionizing light is absorbed and scattered in tissue, may fulfill these three parameters. We imaged the brains of transgenic AD mouse models in vivo with a quantitative, camera-based, diffuse optical imaging technology called spatial frequency domain imaging (SFDI) to characterize near-infrared (650-970nm) optical biomarkers of AD. Compared to age-matched control mice, we found a decrease in light absorption --- due to lower oxygenated and total hemoglobin concentrations in the brain --- correlating to decreased blood vessel volume and density in histology. Light scattering also increased in AD mice, correlating to brain structural changes caused by neuron loss and activation of inflammatory cells. Furthermore, inhaled gas challenges revealed brain vascular function was diminished. To investigate how AD affects the small changes in blood perfusion caused by increased brain activity, we built a new SFDI system from a commercial light-emitting diode microprojector and off-the-shelf optical components and cameras to measure optical properties in the visible range (460-632nm). Our measurements showed a reduced amplitude and duration of blood vessel dilation to increased brain activity in the AD mice. Altogether, this work increased our understanding of AD pathogenesis, explored optical biomarkers of AD, and improved technology access to other research labs. These results and technologies can further be used to facilitate longitudinal drug therapy trials in mice and provide a roadmap to diffuse optical spectroscopy studies in humans.

  17. P-glycoprotein Mediated Efflux Limits Substrate and Drug Uptake in a Preclinical Brain Metastases of Breast Cancer Model

    Chris E Adkins

    2013-11-01

    Full Text Available The blood-brain barrier (BBB is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB. What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-gp in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker (14C-AIB and a tracer subject to P-gp efflux (rhodamine 123 into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p>0.05; n=756-1214 vessels evaluated at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p>0.05 different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.

  18. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

    Ali, Rehan; Apte, Sandeep; Vilalta, Marta; Subbarayan, Murugesan; Miao, Zheng; Chin, Frederick T; Graves, Edward E

    2015-01-01

    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology. PMID:26431331

  19. 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

    Rehan Ali

    Full Text Available We evaluated the relationship between pre-treatment positron emission tomography (PET using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl-N-(2,2,3,3,3- pentafluoropropyl acetamide] (18F-EF5 and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.

  20. Aminochrome as New Preclinical Model to Find New Pharmacological Treatment that Stop the Development of Parkinson's Disease.

    Segura-Aguilar, Juan; Muñoz, Patricia; Paris, Irmgard

    2016-01-01

    The pharmacological treatment of Parkinson's disease (PD) is limited to dopamine agonists and anti-cholinergic drugs that do not stop the progress of disease. LDopa was introduced to the treatment in 1967; this drug is still the best and most commonly used drug since it generates a real improvement in patient quality of life, but the disadvantage of L-dopa is that this positive effect is followed by severe side effects such as dyskinesia. The search for a new drug in the treatment of PD is limited to compounds which decrease the side effects of the drugs used in the treatment of the disease, such as L-dopa-induced dyskinesia. One possible explanation for pharmaceutical companies not developing new drugs to stop disease development is because the mechanism which induces the loss of dopaminergic neurons containing neuromelanin of the nigrostriatal system is still unknown. The discovery of genes (alpha-synuclein, parkin, pink-1, DJ- 1, LRRK2, GBA1, etc.) associated with familial forms of PD resulted in an enormous input into basic research in order to understand the role of these proteins in the disease. It is generally accepted that the loss of dopaminergic neurons containing neuromelanin involves mitochondrial dysfunction, protein degradation dysfunction, the aggregation of alpha-synuclein to neurotoxic oligomers, oxidative neuroinflammation and endoplasmic reticulum stress, but the question of what induces these mechanisms remains unanswered. Aminochrome, the product of dopamine oxidation and the precursor of neuromelanin, is directly involved in five of the six mechanisms and may be a better PD preclinical model. PMID:26695514

  1. Effect of drugs of abuse on social behaviour: a review of animal models.

    Blanco-Gandía, Maria C; Mateos-García, Ana; García-Pardo, Maria P; Montagud-Romero, Sandra; Rodríguez-Arias, Marta; Miñarro, José; Aguilar, María A

    2015-09-01

    Social behaviour is disturbed in many substance abuse and psychiatric disorders. Given the consensus that social behaviours of lower mammals may help to understand some human emotional reactions, the aim of the present work was to provide an up-to-date review of studies on the changes in social behaviour induced by drugs of abuse. Various animal models have been used to study the relationship between drugs of abuse and social behaviour. Herein, we describe the effects of different substances of abuse on the three most commonly used animal models of social behaviour: the social play test, the social interaction test and the resident-intruder paradigm. The first is the most widely used test to assess adolescent behaviour in rodents, the second is generally used to evaluate a wide repertoire of behaviours in adulthood and the latter is specific to aggressive behaviour. Throughout the review we will explore the most relevant studies carried out to date to evaluate the effects of alcohol, cocaine, opioids, 3,4-methylenedioxymethamphetamine (MDMA), cannabinoids, nicotine and other drugs of abuse on these three paradigms, taking into account the influence of different variables, such as social history, age and type of exposure. Drugs of diverse pharmacological classes induce alterations in social behaviour, although they can be contrasting depending on several factors (drug, individual differences and environmental conditions). Ethanol and nicotine increase social interaction at low doses but reduce it at high doses. Psychostimulants, MDMA and cannabinoids reduce social interaction, whereas opiates increase it. Ethanol and psychostimulants enhance aggression, whereas MDMA, opiates, cannabinoids and nicotine reduce it. Prenatal drug exposure alters social behaviour, whereas drug withdrawal decreases sociability and enhances aggression. As a whole, this evidence has improved our understanding of the social dimension of drug addiction. PMID:26221831

  2. A rationale and model for addressing tobacco dependence in substance abuse treatment

    Richter Kimber P

    2006-08-01

    Full Text Available Abstract Most persons in drug treatment smoke cigarettes. Until drug treatment facilities systematically treat their patients' tobacco use, millions will flow through the drug treatment system, overcome their primary drug of abuse, but die prematurely from tobacco-related illnesses. This paper reviews the literature on the health benefits of quitting smoking for drug treatment patients, whether smoking causes relapse to other drug or alcohol abuse, the treatment of tobacco dependence, and good and bad times for quitting smoking among drug treatment patients. It also presents a conceptual model and recommendations for treating tobacco in substance abuse treatment, and provides references to internet and paper-copy tools and information for treating tobacco dependence. At present, research on tobacco treatment in drug treatment is in its infancy. Although few drug treatment programs currently offer formal services, many more will likely begin to treat nicotine dependence as external forces and patient demand for these services increases. In the absence of clear guidelines and attention to quality of care, drug treatment programs may adopt smoking cessation services based on cost, convenience, or selection criteria other than efficacy. Because research in this field is relatively new, substance abuse treatment professionals should adhere to the standards of care for the general population, but be prepared to update their practices with emerging interventions that have proven to be effective for patients in drug treatment.

  3. Preclinical profile of cabazitaxel.

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

    2014-01-01

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

  4. An empirical model to describe performance degradation for warranty abuse detection in portable electronics

    Portable electronics makers have introduced liquid damage indicators (LDIs) into their products to detect warranty abuse caused by water damage. However, under certain conditions, these indicators can exhibit inconsistencies in detecting liquid damage. This study is motivated by the fact that the reliability of LDIs in portable electronics is suspected. In this paper, first, the scheme of life tests is devised for LDIs in conjunction with a robust color classification rule. Second, a degradation model is proposed by considering the two physical mechanisms—(1) phase change from vapor to water and (2) water transport in the porous paper—for LDIs. Finally, the degradation model is validated with additional tests using actual smartphone sets subjected to the thermal cycling of −15 °C to 25 °C and the relative humidity of 95%. By employing the innovative life testing scheme and the novel performance degradation model, it is expected that the performance of LDIs for a particular application can be assessed quickly and accurately. - Highlights: • Devise an efficient scheme of life testing for a warranty abuse detector in portable electronics. • Develop a performance degradation model for the warranty abuse detector used in portable electronics. • Validate the performance degradation model with life tests of actual smartphone sets. • Help make a decision on warranty service in portable electronics manufacturers

  5. Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

    Stavropoulos, Andreas; Sculean, Anton; Bosshardt, Dieter D; Buser, Daniel; Klinge, Björn

    2015-06-01

    Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice. PMID:25867979

  6. Quetiapine: recent developments in preclinical research

    Marco Orsetti

    2010-03-01

    Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

  7. Physical Abuse

    ... Additional Resources Return to: What is Elder Abuse? Physical Abuse Physical abuse is physical force or violence that results in ... may be acquaintances, sons, daughters, grandchildren, or others. Physical abuse that is perpetrated by spouses or intimate partners ...

  8. A forensic assessment model for the sexually abused child in the South African context / Sufran Smith

    Smith, Sufran

    2014-01-01

    Currently no guidelines exist for South African professionals that work with sexually abused children. Professionals in this field are in desperate need of such guidelines. Section A refers to the problem statement, research objectives, research procedures and research methodology. The keywords as well as the limitations of the research are investigated. The research was conducted in two phases. In phase one the researcher compared international forensic assessment models and protocols and...

  9. PET Studies in Nonhuman Primate Models of Cocaine Abuse: Translational Research Related to Vulnerability and Neuroadaptations

    Gould, Robert W.; Duke, Angela N.; Nader, Michael A.

    2013-01-01

    The current review highlights the utility of positron emission tomography (PET) imaging to study the neurobiological substrates underlying vulnerability to cocaine addiction and subsequent adaptations following chronic cocaine self-administration in nonhuman primate models of cocaine abuse. Environmental (e.g., social rank) and sex-specific influences on dopaminergic function and sensitivity to the reinforcing effects of cocaine are discussed. Cocaine-related cognitive defic...

  10. Sexual Abuse

    Navigation Physical Abuse Sexual Abuse Domestic Violence Psychological Abuse Financial Abuse Neglect Critical Issues What Communities Can Do The Role ... Abuse and Neglect Ramsey-Klawsnik, H. (1996). Assessing physical and sexual abuse in health care settings. In L.A. Baumhover & S. ...

  11. 5-azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

    Sutherland, May Kung; Yu, Changpu; Anderson, Martha; Zeng, Weiping; van Rooijen, Nico; Sievers, Eric L; Grewal, Iqbal S; Law, Che-Leung

    2010-01-01

    Despite therapeutic advances, the poor prognoses for acute myeloid leukemia (AML) and intermediate and high-risk myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, induced meaningful responses in a Phase 1 clinical trial and demonstrated anti-leukemic activity in preclinical m...

  12. Intravenous Immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer’s disease

    Counts, Scott; Ray, Balmiki; Mufson, Elliott J.; Perez, Sylvia E.; He, Bin; Lahiri, Debomoy K.

    2014-01-01

    Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer’s disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanism in vivo. Based on these results, w...

  13. Combined AKT and MEK Pathway Blockade in Pre-Clinical Models of Enzalutamide-Resistant Prostate Cancer

    Toren, Paul; Kim, Soojin; Johnson, Fraser; Zoubeidi, Amina

    2016-01-01

    Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting ...

  14. Engaging stakeholders in review and recommendations for models of outcome monitoring for substance abuse treatment.

    Rush, Brian; Martin, Garth; Corea, Larry; Rotondi, Nooshin Khobzi

    2012-10-01

    We present an example of a collaborative process designed to review models of outcome monitoring for substance abuse services, with a view to assessing the feasibility of different approaches in Ontario, Canada. A conceptual framework that describes the parameters of an outcome monitoring system and four models of outcome monitoring were identified. Consultations were held with stakeholders (managers, directors, researchers, clinicians, and governmental representatives) about the types of information they would like to obtain from an outcome monitoring system. Our process is useful as a model for collaborative research with respect to performance measurement. The study's implications and limitations are noted. PMID:22780842

  15. Use and abuse of mixing models (MixSIAR)

    Background/Question/MethodsCharacterizing trophic links in food webs is a fundamental ecological question. In our efforts to quantify energy flow through food webs, ecologists have increasingly used mixing models to analyze biological tracer data, often from stable isotopes. Whil...

  16. Assessment of Substance Abuse Behaviors in Adolescents’: Integration of Self-Control into Extended Parallel Process Model

    K Witte

    2005-04-01

    Full Text Available Introduction: An effective preventive health education program on drug abuse can be delivered by applying behavior change theories in a complementary fashion. Methods: The aim of this study was to assess the effectiveness of integrating self-control into Extended Parallel Process Model in drug substance abuse behaviors. A sample of 189 governmental high school students participated in this survey. Information was collected individually by completing researcher designed questionnaire and a urinary rapid immuno-chromatography test for opium and marijuana. Results: The results of the study show that 6.9% of students used drugs (especially opium and marijuana and also peer pressure was determinant factor for using drugs. Moreover the EPPM theoretical variables of perceived severity and perceived self-efficacy with self-control are predictive factors to behavior intention against substance abuse. In this manner, self-control had a significant effect on protective motivation and perceived efficacy. Low self- control was a predictive factor of drug abuse and low self-control students had drug abuse experience. Conclusion: The results of this study suggest that an integration of self-control into EPPM can be effective in expressing and designing primary preventive programs against drug abuse, and assessing abused behavior and deviance behaviors among adolescent population, especially risk seekers

  17. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

    Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

    2015-07-15

    Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

  18. Assessment of Substance Abuse Behaviors in Adolescents’: Integration of Self-Control into Extended Parallel Process Model

    de Witte, K.; E Mirzaee; AR Hidarnia; A KAZEMNEJAD; F Shafii; P. Azad Fallah; H Allahverdipour

    2005-01-01

    Introduction: An effective preventive health education program on drug abuse can be delivered by applying behavior change theories in a complementary fashion. Methods: The aim of this study was to assess the effectiveness of integrating self-control into Extended Parallel Process Model in drug substance abuse behaviors. A sample of 189 governmental high school students participated in this survey. Information was collected individually by completing researcher designed questionnaire and a uri...

  19. Preclinical profile of cabazitaxel

    Vrignaud P

    2014-10-01

    Full Text Available Patricia Vrignaud,1 Dorothée Semiond,2 Veronique Benning,2 Eric Beys,2 Hervé Bouchard,3 Sunil Gupta4 1Sanofi Oncology, Vitry-sur-Seine, France; 2Sanofi DSAR, Alfortville, France; 3Sanofi LGCR, Vitry-sur-Seine, France; 4Sanofi Oncology, Cambridge, MA, USA Abstract: First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS, and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported

  20. An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.

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

    2015-01-01

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

  1. Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis

    Li, Feng; Zhou, Changlin; Xu, Liang; Tao, Shuqing; Zhao, Jingyi; Gu, Qun

    2016-01-01

    Background Preclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence. Methods Pubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes. Results Pooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001). Conclusions Stem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies. PMID:26882451

  2. The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury.

    Rau, Thomas; Ziemniak, John; Poulsen, David

    2016-01-01

    Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide. Under conditions of abuse, which involve the administration of high repetitive doses, methamphetamine can produce considerable neurotoxic effects. However, recent evidence from our laboratory indicates that low doses of methamphetamine can produce robust neuroprotection when administered within 12h after severe traumatic brain injury (TBI) in rodents. Thus, it appears that methamphetamine under certain circumstances and correct dosing can produce a neuroprotective effect. This review addresses the neuroprotective potential of methamphetamine and focuses on the potential beneficial application for TBI. PMID:25724762

  3. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

    Wilkes D

    2012-10-01

    Full Text Available Denise Wilkes,1 Guangwen Li,2 Carmina F Angeles,3 Joel T Patterson,4 Li-Yen Mae Huang21Department of Anesthesiology, 2Department of Neuroscience and Cell Biology, 3Department of Neurosurgery University of Texas Medical Branch, Galveston, TX, USA; 4Neurospine Institute, Eugene, OR, USABackground: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.Results: Peroneal nerve injury (PNI produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50 for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain

  4. Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma.

    Laursen, Maria Bach; Falgreen, Steffen; Bødker, Julie Støve; Schmitz, Alexander; Kjeldsen, Malene Krag; Sørensen, Suzette; Madsen, Jakob; El-Galaly, Tarec Christoffer; Bøgsted, Martin; Dybkær, Karen; Johnsen, Hans Erik

    2014-11-01

    Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms. PMID:25072621

  5. Elder Abuse

    ... facilities or nursing homes. The mistreatment may be Physical, sexual, or emotional abuse Neglect or abandonment Financial abuse - stealing of money or belongings Possible signs of elder abuse include unexplained bruises, burns, ...

  6. Child Abuse

    ... puts a child at risk of harm. Child abuse can be physical, sexual or emotional. Neglect, or not providing for a child's needs, is also a form of abuse. Most abused children suffer greater emotional than physical ...

  7. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

    Wilkes D; Li G; Angeles CF; Patterson JT; Huang LY

    2012-01-01

    Denise Wilkes,1 Guangwen Li,2 Carmina F Angeles,3 Joel T Patterson,4 Li-Yen Mae Huang21Department of Anesthesiology, 2Department of Neuroscience and Cell Biology, 3Department of Neurosurgery University of Texas Medical Branch, Galveston, TX, USA; 4Neurospine Institute, Eugene, OR, USABackground: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large ...

  8. Guidelines for pre-clinical assessment of the acetylcholine receptor--specific passive transfer myasthenia gravis model-Recommendations for methods and experimental designs.

    Kusner, Linda L; Losen, Mario; Vincent, Angela; Lindstrom, Jon; Tzartos, Socrates; Lazaridis, Konstantinos; Martinez-Martinez, Pilar

    2015-08-01

    Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID:25743217

  9. Optimised and rapid pre-clinical screening in the SOD1(G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS.

    Richard J Mead

    Full Text Available The human SOD1(G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS. In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6 SOD1(G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

  10. Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility.

    Zaveri, Nurulain T

    2016-08-11

    In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral), and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression, and motor symptoms in Parkinson's disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress toward validating the NOP-N/OFQ system as a therapeutic target. PMID:26878436

  11. Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

    Ghosh Anamitra

    2012-10-01

    Full Text Available Abstract Background Parkinson’s disease (PD is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of PD. Methods Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1, glial fibrillary acidic protein (GFAP, gp91phox and inducible nitric oxide synthase (iNOS, were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT, 4-hydroxynonenal (4-HNE and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. Results Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN. MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in

  12. Clinical Traumatic Brain Injury in the Preclinical Setting.

    Berkner, Justin; Mannix, Rebekah; Qiu, Jianhua

    2016-01-01

    Traumatic brain injury (TBI) is the leading cause of death and disability for people under 45 years of age. Clinical TBI is often the result of disparate forces resulting in heterogeneous injuries. Preclinical modeling of TBI is a vital tool for studying the complex cascade of metabolic, cellular, and molecular post-TBI events collectively termed secondary injury. Preclinical models also provide an important platform for studying therapeutic interventions. However, modeling TBI in the preclinical setting is challenging, and most models replicate only certain aspects of clinical TBI. This chapter details the most widely used models of preclinical TBI, including the controlled cortical impact, fluid percussion, blast, and closed head models. Each of these models replicates particular critical aspects of clinical TBI. Prior to selecting a preclinical TBI model, it is important to address what aspect of human TBI is being sought to evaluate. PMID:27604710

  13. College Women's Stay/Leave Decisions in Abusive Dating Relationships: A Prospective Analysis of an Expanded Investment Model

    Edwards, Katie M.; Gidycz, Christine A.; Murphy, Megan J.

    2011-01-01

    The purpose of the current study was to explore college women's stay/ leave decisions in abusive relationships using a prospective methodology. Participants (N = 323) completed surveys at the beginning and end of a 10-week academic quarter for course credit. A path analysis suggested that the model--which included investment model variables (i.e.,…

  14. PREDICTIVE MODEL FOR SURVIVAL AND GROWTH OF SALMONELLA TYPHIMURIUM DT104 ON CHICKEN SKIN DURING TEMPERATURE ABUSE

    To better predict risk of Salmonella infection from chicken subjected to temperature abuse, a study was undertaken to develop a predictive model for survival and growth of Salmonella Typhimurium DT104 on chicken skin with native micro flora. For model development, chicken skin portions were inocula...

  15. Effects of Methadone Maintenance Treatment on Decision-Making Processes in Heroin-Abusers: A Cognitive Modeling Analysis

    Arash Khodadadi

    2010-05-01

    Full Text Available A B S T R A C TIntroduction: Although decision-making processes have become a principal target of study among addiction researchers, few researches are published according to effects of different treatment methods on the cognitive processes underlying decision making up to now. Utilizing cognitive modeling method, in this paper we examine the effects of Methadone maintenance treatment (MMT on cognitive processes underlying decision-making disorders in heroin-abusers. Methods: For this purpose, for the first time, we use the balloon analog risk task (BART to assess the decision-making ability of heroin-abusers before and after treatment and compare it to the non heroin-dependent subjects. Results: Results demonstrate that heroin-abusers show more risky behavior than other groups. But, there is no difference between the performance of heroin-abusers after 6 months of MMT and control group. Modeling subjects’ behavior in BART reveals that poor performance in heroin-abusers is due to reward-dependency and insensitivity to evaluation. Discussion: Results show that 6 months of MMT decreases reward-dependency and increases sensitivity to evaluation.

  16. Bridging the gap between preclinical and clinical microbicide trials: blind evaluation of candidate gels in murine models of efficacy and safety.

    Theodore J Segarra

    Full Text Available BACKGROUND: Despite significant protection in preclinical studies, cellulose sulfate (CS failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future products. METHODS: Four coded formulations, including 6% CS, 2% PRO 2000 and two placebo gels, were administered intravaginally to medroxyprogesterone-treated mice and their ability to prevent genital herpes (efficacy or to alter the susceptibility to low dose HSV challenge (safety was determined. Nonoyxnol-9 served as a positive toxicity control. RESULTS: CS and PRO 2000 significantly protected mice from genital herpes following infection with a laboratory or clinical isolate of HSV-2 introduced in buffer (p<0.001. However, protection was reduced when virus was introduced in seminal plasma. Moreover, mice were significantly more susceptible to infection with low doses of HSV-2 when challenged 12 h after the 7th daily dose of CS or nonoxynol-9 (p<0.05. The increased susceptibility was associated with alterations in epithelial architecture. CONCLUSIONS: CS prevented genital herpes when present at the time of viral challenge, but increased the rate of infection when gel was applied daily for 7 days with a vaginal wash prior to viral inoculation. The findings presumably reflect altered epithelial architecture, which may have contributed to the trend towards increased HIV observed clinically.

  17. Preclinical evaluation of Sunitinib as a single agent in the prophylactic setting in a mouse model of bone metastases

    A substantial number of breast cancer patients are identified as being at high risk of developing metastatic disease. With increasing number of targeted therapeutics entering clinical trials, chronic administration of these agents may be a feasible approach for the prevention of metastases within this subgroup of patients. In this preclinical study we examined whether Sunitinib, a multi-tyrosine kinase inhibitor which has anti-angiogenic and anti-resorptive activity, is effective in the prevention of bone metastases. Sunitinib was administered daily with the first dose commencing prior to tumor cell inoculation. Intracardiac injection was performed with MDA-MB23 bone-seeking cells, which were stably transfected with DsRed2. In vivo plain radiography and fluorescent imaging (Berthold NightOwl) was used in the analysis of bone metastases. Histomorphometry was used for the quantification of TRAP+ cells from bone sections and immunohistochemistry was performed using an antibody reactive to CD34 for quantification of microvessel density. Preventive dosing administration of Sunitinib does not inhibit colonization of tumor cells to bone or reduce the size of osteolytic lesions. There was a decrease in the number of TRAP+ cells with Sunitinib treatment but this did not reach significance. Sunitinib inhibited tumor growth as determined by imaging of fluorescent tumor area. Immunohistochemical analyses of microvessel density revealed a concomitant decrease in the number of tumor blood vessels. The findings suggest that Sunitinib can be used as a therapeutic agent for the treatment of bone metastases but as a single agent it is not effective in terms of prevention. Therefore a combination approach with other cytostatic drugs should be pursued

  18. Using the Good Way Model to Work Positively with Adults and Youth with Intellectual Difficulties and Sexually Abusive Behaviour

    West, Bill

    2007-01-01

    The Good Way model is being used increasingly in New Zealand and Australia in both community-based and residential programmes for the treatment of adolescents and adults with intellectual difficulties who have sexually abusive behaviour. It is also being used with children and, in adapted forms, with mainstream adolescents and people of indigenous…

  19. A Model of Sexual Abuse's Effects on Suicidal Behavior and Delinquency: The Role of Emotions as Mediating Factors

    Sigfusdottir, Inga Dora; Asgeirsdottir, Bryndis Bjork; Gudjonsson, Gisli H.; Sigurdsson, Jon Fridrik

    2008-01-01

    Drawing on Agnew's general strain theory, we examined whether depressed mood and anger mediated the effects of sexual abuse on suicidal behavior and delinquency. Participants included 9,113 students attending high schools in Iceland. Structural equation modeling showed that, while controlling for family structure and parental education, being…

  20. A Model Linking Diverse Women's Child Sexual Abuse History with Sexual Risk Taking

    Watson, Laurel B.; Matheny, Kenneth B.; Gagne, Phill; Brack, Greg; Ancis, Julie R.

    2013-01-01

    The purpose of our study was to examine the role that child sexual abuse may play in body surveillance and sexual risk behaviors among undergraduate women. First, a measured variable path analysis was conducted, which assessed the relations among a history of child sexual abuse, body surveillance, and sexual risk behaviors. Furthermore, body…

  1. Dissolution DNP for in vivo preclinical studies

    Comment, Arnaud

    2016-03-01

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

  2. Nanocapsular forms of preparations in preclinical studies

    Ekaterina Grinevich

    2010-07-01

    Full Text Available The paper examines preclinical study of nanocapsule deliverysystem, particularly the influence of nanocapsule with a vasodilatorin the process of programmed myocardial cells death. Isosorbidedinitrate was loaded in nanocapsules. To investigate the effectnanocapsule isosorbide dinitrate on the process of apoptosis incardiomyocytes, a series of experimental works wereperformed. For this purpose, a model of coronary insufficiency in 4groups of animals were elaborated. The experimental works onlaboratory animals were conducted in accordance withrequirements of the European Convention for the protection ofvertebrate animals. The first preclinical trials showed the presenceof specific activity of obtained drugs. The basis of nanocapsularsystem was phosphatidylinositol, and the active loading substanceswere alprostadil, interferon alpha.

  3. Drug Abuse

    ... as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms unborn babies and destroys families. There are different types of treatment for drug abuse. But the best is to prevent drug ...

  4. Elder abuse

    1999-01-01

    Elder abuse takes many forms and occurs in a variety of settings; it is both under-recognised and under-reported. Despite a lack of statutory guidelines or legislation, effective management is possible. More could be done to recognise abuse, and healthcare workers need to be vigilant, paying attention to both the circumstances in which abuse occurs and its warning signs.

  5. Single-dose anti-CD138 radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment of multiple myeloma in a preclinical model

    Nolwenn eFichou

    2015-11-01

    Full Text Available Objectives: Radioimmunotherapy (RIT has emerged as a potential treatment option for multiple myeloma (MM. In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to 213Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with 213Bi for α-RIT or 177Lu for β-RIT.Methods: A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution and α-RIT studies. Then, a β-RIT dose-escalation assay with the 177Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10 days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity.Results: α-RIT performed with 3.7 MBq of 213Bi-labeled 9E7.4 anti-CD138 mAb increased median survival to 80 days compared to 37 days for the untreated control and effected cure in 45% of animals. β-RIT performed with 18.5 MBq of 177Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 versus 37 days in the control group; however, no mice were cured with this treatment.Conclusion: This study revealed the advantages of α-RIT in the treatment of MM in a preclinical model where β-RIT shows almost no efficacy.

  6. Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

    Bell, Richard L.; Sable, Helen J. K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

    2012-01-01

    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models f...

  7. The management of child abuse and neglect cases in schools: the Toronto model.

    McClare, G

    1983-01-01

    School staffs have a major role in the prevention, identification and referral of cases of child abuse and neglect. School administrators, teachers and school support staffs require knowledge about abuse and neglect, as well as a clear set of guidelines and procedures for dealing with it if they are to carry out these responsibilities effectively. The Toronto Board of Education has developed a program that has involved superintendents, principals, teachers, pupil personnel staff, caretakers, secretaries and community resources in an educational program oriented to the management of child abuse cases in their schools. The Board's Child Abuse Committee has developed a document which outlines employees' responsibilities under the legislation, provides assistance in the identification of child abuse and neglect cases, and outlines procedures for referral both internally and to the community. The document was used as the base for an extensive staff development program during the school year 1979-80, in which all of the system's 6,000 school based employees participated. The Toronto Board's Child Abuse Program incorporated the establishment of the position "Resource Person, Child Abuse" for the purpose of consultation with school staffs, as well as the ongoing provision of resource material and staff training. The paper outlines the development of the program, includes guidelines and procedures for school staffs, the legislation under which it operates, the content of the training program, and an evaluation of the program with suggestions for replication. PMID:6684980

  8. Cytotoxic capacity of IL-15-stimulated cytokine-induced killer cells against human acute myeloid leukemia and rhabdomyosarcoma in humanized preclinical mouse models

    Eva eRettinger

    2012-04-01

    Full Text Available Allogeneic stem cell transplantation (allo-SCT has become an important treatment modality for patients with high risk acute myeloid leukemia (AML and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions (DLI based on MRD status using IL-15-expanded cytokine-induced killer (CIK cells may prevent relapse without causing graft-versus-host-disease (GvHD. To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL2Rγc-, NSG were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction (qPCR for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow (BM followed by liver, lung, spleen, peripheral blood (PB, and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at an effector to target cell (E:T ratio of 1:1 were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells an E:T ratio of 250:1 was needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliably 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells

  9. Child abuse

    Child abuse is common in most, if not all, Western nations; it probably occurs worldwide. It may be a major factor in the increase in violence throughout much of the world. Radiologists who treat children should think of the possibilitys of abuse whenever they diagnose a fracture, intracranial bleed, ar visceral injury, especially when the history is not compatible with their findings. Metaphyseal 'corner' fractures in infants usually are caused by abuse. Less than 20% of abused children, however, present injuries that can be recognized by radiologic techniques. Consequently normal roentgenograms, nuclear medicine scans, ultrasound studies, and computed tomograms do not exclude child abuse. (orig.)

  10. A Model of Sexual Risk Behaviors among Young Gay and Bisexual Men: Longitudinal Associations of Mental Health, Substance Abuse, Sexual Abuse, and the Coming-Out Process

    Rosario, Margaret; Schrimshaw, Eric W.; Hunter, Joyce

    2006-01-01

    Sexual risk behaviors of young gay and bisexualmen must be understood within the context of other health concerns (e.g., anxiety, substance abuse), population specific factors (i.e., the coming-out process and gay-related stress), childhood sexual abuse, and other theoretical factors (e.g., safer-sex intentions). The current report proposes and…