WorldWideScience

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 This review focuses on recent preclinical and clinical findings, including previously unpublished data, that provide evidence that, even under controlled conditions, ketamine reward is a function of the setting of drug taking.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. 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...

  17. 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...

  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

    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

  12. 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

  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

    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.

  18. 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

  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. 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

  2. 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.

  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. 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...

  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. 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…

  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. 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 ...

  7. 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...

  8. 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

  9. 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

  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. 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.

  20. 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.

  1. 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

  2. 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.

  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. 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

  13. 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

  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. 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.

  8. 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

  9. 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)

  10. 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...

  11. 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...

  12. 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...

  13. 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

  14. 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...

  15. 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…

  16. 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…

  17. 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,"…

  18. 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

  19. 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.

  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. 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...

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  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. 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

  10. 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

  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. 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

  7. 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

  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. 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.

  14. 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

  15. 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.

  16. 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...

  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. 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 ...

  13. 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...

  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. 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

  19. 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...

  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…

  11. 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

    2014-09-01

    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 deficits have been hypothesized to contribute to high rates of relapse and are described in nonhuman primate models. Lastly, the long-term consequences of cocaine on neurobiology are discussed. PET imaging and longitudinal, within-subject behavioral studies in nonhuman primates have provided a strong framework for designing pharmacological and behavioral treatment strategies to aid drug-dependent treatment seekers. Non-invasive PET imaging will allow for individualized treatment strategies. Recent advances in radiochemistry of novel PET ligands and other imaging modalities can further advance our understanding of stimulant use on the brain. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. PMID:23458573

  12. A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder

    Keller Benjamin J

    2010-11-01

    Full Text Available Abstract Background Lithium is an effective treatment for Bipolar Disorder (BD and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania. Results Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes. Conclusions We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel

  13. Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a pre-clinical model of lung carcinoma

    Background: Radiotherapy of locally-advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. We have further investigated the role of soy isoflavones to improve the effect of a high intensity radiation and reduce lung damage in a pre-clinical lung tumor model. Methods: Human A549 NSCLC cells were injected i.v. in nude mice to generate a large tumor burden in the lungs. Mice were treated with lung irradiation at 10 Gy and with oral soy. The therapy effect on the tumor cells and surrounding lung tissue was analyzed on lung sections stained with H and E, Ki-67 and Masson’s Trichrome. Pneumonitis and vascular damage were evaluated by measurements of alveolar septa and immunofluorescent staining of vessel walls. Results: Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels. Conclusions: These studies demonstrate a differential effect of soy isoflavones on augmenting tumor destruction induced by radiation while radioprotecting the normal lung tissue and support using soy to alleviate radiotoxicity in lung cancer

  14. Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer.

    Doornebal, Chris W; Vrijland, Kim; Hau, Cheei-Sing; Coffelt, Seth B; Ciampricotti, Metamia; Jonkers, Jos; de Visser, Karin E; Hollmann, Markus W

    2015-08-01

    Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained. PMID:25734987

  15. Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

    Terence C. Tang

    2010-03-01

    Full Text Available Hepatocellular carcinoma (HCC is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG, which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX, UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

  16. Modeling of Pharmacokinetics of Cocaine in Human Reveals the Feasibility for Development of Enzyme Therapies for Drugs of Abuse

    Fang Zheng; Chang-Guo Zhan

    2012-01-01

    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 th...

  17. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

    Christina L Roland

    Full Text Available The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1beta, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1beta and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.

  18. Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model.

    Kuryk, Lukasz; Haavisto, Elina; Garofalo, Mariangela; Capasso, Cristian; Hirvinen, Mari; Pesonen, Sari; Ranki, Tuuli; Vassilev, Lotta; Cerullo, Vincenzo

    2016-10-15

    Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma. PMID:27287512

  19. Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy

    de Moraes, Luciana V.; Dechavanne, Sebastien; Sousa, Patrícia M.; Barateiro, André; Cunha, Sónia F.; Nunes-Silva, Sofia; Flávia A Lima; Murillo, Oscar; Marinho, Claudio R. F.; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A.; Chris J. Janse; Gamain, Benoit; Franke-Fayard, Blandine

    2016-01-01

    Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (doma...

  20. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma

    Kuhn, Deborah J.; Berkova, Zuzana; Jones, Richard J.; Woessner, Richard; Bjorklund, Chad C.; Ma, Wencai; Davis, R. Eric; Lin, Pei; WANG Hua; Madden, Timothy L.; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J.

    2012-01-01

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secreti...

  1. Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs

    Desaphy, Jean-François; Carbonara, Roberta; Costanza, Teresa; Conte Camerino, Diana

    2014-01-01

    Although the sodium channel blocker mexiletine is considered the first-line drug in myotonia, some patients experiment adverse effects, while others do not gain any benefit. Other antimyotonic drugs are thus needed to offer mexiletine alternatives. In the present study, we used a previously-validated rat model of myotonia congenita to compare six marketed sodium channel blockers to mexiletine. Myotonia was induced in the rat by injection of anthracen-9-carboxylic acid, a muscle chloride chann...

  2. A Novel Pre-Clinical Murine Model to Study the Life Cycle and Progression of Cervical and Anal Papillomavirus Infections

    Cladel, Nancy M.; Budgeon, Lynn R.; Balogh, Karla K.; Timothy K Cooper; Jiafen Hu; Christensen, Neil D.

    2015-01-01

    Background Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disea...

  3. Myelin Abnormalities in Schizophrenia: Insights from Proteomic Investigations of Post-Mortem Schizophrenia and Pre-Clinical Animal Models

    Farrelly, Lorna

    2014-01-01

    Accumulating evidence from epidemiologic and clinical findings report that both exposure to prenatal inflammation and prenatal iron deficiency significantly increase the risk of developing Schizophrenia in the offspring. Abnormalities in myelin are the most robust neuropathological findings in post-mortem human Schizophrenia, however the exact mechanisms at the protein and pathway levels owing to the myelin deficits are largely unknown. Animal models offer a fruitful approach to study the ...

  4. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer.

    Derek C Marshall

    Full Text Available Expression of matrix metalloproteinase 9 (MMP9 is elevated in a variety of inflammatory and oncology indications, including ulcerative colitis and colorectal cancer. MMP9 is a downstream effector and an upstream mediator of pathways involved in growth and inflammation, and has long been viewed as a promising therapeutic target. However, previous efforts to target matrix metalloproteinases (MMPs, including MMP9, have utilized broad-spectrum or semi-selective inhibitors. While some of these drugs showed signs of efficacy in patients, all MMP-targeted inhibitors have been hampered by dose-limiting toxicity or insufficient clinical benefit, likely due to their lack of specificity. Here, we show that selective inhibition of MMP9 did not induce musculoskeletal syndrome (a characteristic toxicity of pan-MMP inhibitors in a rat model, but did reduce disease severity in a dextran sodium sulfate-induced mouse model of ulcerative colitis. We also found that MMP9 inhibition decreased tumor growth and metastases incidence in a surgical orthotopic xenograft model of colorectal carcinoma, and that inhibition of either tumor- or stroma-derived MMP9 was sufficient to reduce primary tumor growth. Collectively, these data suggest that selective MMP9 inhibition is a promising therapeutic strategy for treatment of inflammatory and oncology indications in which MMP9 is upregulated and is associated with disease pathology, such as ulcerative colitis and colorectal cancer. In addition, we report the development of a potent and highly selective allosteric MMP9 inhibitor, the humanized monoclonal antibody GS-5745, which can be used to evaluate the therapeutic potential of MMP9 inhibition in patients.

  5. Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model

    Hypoxia-inducible factor 1α (HIF-1α) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1α modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model. U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1α activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging. This cell model can be used to monitor HIF-1α activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1α activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1α activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action. The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1α activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures. (orig.)

  6. Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model

    Lo Dico, A.; Martelli, C. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); Valtorta, S.; Belloli, S. [National Researches Council (CNR), Institute of Molecular Bioimaging and Physiology (IBFM), Segrate, MI (Italy); IRCCS San Raffaele Scientific Institute, Experimental Imaging Center, Milan (Italy); Raccagni, I.; Moresco, R.M. [IRCCS San Raffaele Scientific Institute, Experimental Imaging Center, Milan (Italy); University of Milano-Bicocca, Department of Health Sciences, Monza (Italy); Diceglie, C. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Doctorate School of Molecular Medicine, Milan (Italy); Gianelli, U.; Bosari, S. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Division of Pathology, Milan (Italy); Vaira, V. [Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Division of Pathology, Milan (Italy); Istituto Nazionale Genetica Molecolare ' ' Romeo ed Enrica Invernizzi' ' (INGM), Milan (Italy); Politi, L.S. [IRCCS San Raffaele Scientific Institute, Neuroradiology Department and Neuroradiology Research Group, Milan (Italy); Lucignani, G. [University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); University of Milan, Department of Health Sciences, Milan (Italy); San Paolo Hospital, Department of Diagnostic Services, Unit of Nuclear Medicine, Milan (Italy); Ottobrini, L. [University of Milan, Department of Pathophysiology and Transplantation, Milan (Italy); University of Milan, Centre of Molecular and Cellular Imaging-IMAGO, Milan (Italy); National Researches Council (CNR), Institute of Molecular Bioimaging and Physiology (IBFM), Segrate, MI (Italy)

    2015-03-27

    Hypoxia-inducible factor 1α (HIF-1α) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1α modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model. U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1α activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging. This cell model can be used to monitor HIF-1α activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1α activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1α activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action. The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1α activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures. (orig.)

  7. A Hamster Model of Diet-Induced Obesity for Preclinical Evaluation of Anti-Obesity, Anti-Diabetic and Lipid Modulating Agents.

    Louise S Dalbøge

    Full Text Available Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO and hypercholesterolemia Golden Syrian hamster model.Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days, normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4 inhibitor, linagliptin (3.0 mg/kg, PO, QD also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day or neuromedin U (NMU, 1.5 mg/kg/day, continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents.

  8. Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766 in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

    Roberta Schmieder

    2013-10-01

    Full Text Available OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK. BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

  9. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.

    Kuhn, Deborah J; Berkova, Zuzana; Jones, Richard J; Woessner, Richard; Bjorklund, Chad C; Ma, Wencai; Davis, R Eric; Lin, Pei; Wang, Hua; Madden, Timothy L; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Wang, Michael; Thomas, Sheeba K; Shah, Jatin J; Weber, Donna M; Orlowski, Robert Z

    2012-10-18

    Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bortezomib. Importantly, OSI-906 in combination with bortezomib also overcame bortezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic. PMID:22932796

  10. A novel pre-clinical murine model to study the life cycle and progression of cervical and anal papillomavirus infections.

    Nancy M Cladel

    Full Text Available Papillomavirus disease and associated cancers remain a significant health burden in much of the world. The current protective vaccines, Gardasil and Cervarix, are expensive and not readily available to the underprivileged. In addition, the vaccines have not gained wide acceptance in the United States nor do they provide therapeutic value. Papillomaviruses are strictly species specific and thus human viruses cannot be studied in an animal host. An appropriate model for mucosal disease has long been sought. We chose to investigate whether the newly discovered mouse papillomavirus, MmuPV1, could infect mucosal tissues in Foxn1nu/Foxn1nu mice.The vaginal and anal canals of Foxn1nu/Foxn1nu mice were gently abraded using Nonoxynol-9 and "Doctor's BrushPicks" and MmuPV1 was delivered into the vaginal tract or the anal canal.Productive vaginal, cervical and anal infections developed in all mice. Vaginal/cervical infections could be monitored by vaginal lavage. Dysplasias were evident in all animals.Anogenital tissues of a common laboratory mouse can be infected with a papillomavirus unique to that animal. This observation will pave the way for fundamental virological and immunological studies that have been challenging to carry out heretofore due to lack of a suitable model system.

  11. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

    Bonnie K Harrington

    Full Text Available Acalabrutinib (ACP-196 is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL. First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR was 25% (5/20 with a median progression free survival (PFS of 22.5 days. Clinical benefit was observed in 30% (6/20 of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL.

  12. Personal health records in the preclinical medical curriculum: modeling student responses in a simple educational environment utilizing Google Health

    Karamanlis Dimokratis A

    2012-09-01

    Full Text Available Abstract Background Various problems concerning the introduction of personal health records in everyday healthcare practice are reported to be associated with physicians’ unfamiliarity with systematic means of electronically collecting health information about their patients (e.g. electronic health records - EHRs. Such barriers may further prevent the role physicians have in their patient encounters and the influence they can have in accelerating and diffusing personal health records (PHRs to the patient community. One way to address these problems is through medical education on PHRs in the context of EHR activities within the undergraduate medical curriculum and the medical informatics courses in specific. In this paper, the development of an educational PHR activity based on Google Health is reported. Moreover, student responses on PHR’s use and utility are collected and presented. The collected responses are then modelled to relate the satisfaction level of students in such a setting to the estimation about their attitude towards PHRs in the future. Methods The study was conducted by designing an educational scenario about PHRs, which consisted of student instruction on Google Health as a model PHR and followed the guidelines of a protocol that was constructed for this purpose. This scenario was applied to a sample of 338 first-year undergraduate medical students. A questionnaire was distributed to each one of them in order to obtain Likert-like scale data on the sample’s response with respect to the PHR that was used; the data were then further analysed descriptively and in terms of a regression analysis to model hypothesised correlations. Results Students displayed, in general, satisfaction about the core PHR functions they used and they were optimistic about using them in the future, as they evaluated quite high up the level of their utility. The aspect they valued most in the PHR was its main role as a record-keeping tool, while

  13. The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets.

    Shoemaker, Robert H; Suen, Chen S; Holmes, Cathy A; Fay, Judith R; Steele, Vernon E

    2016-02-01

    The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline. PMID:26970137

  14. Tumor associated fibroblasts enhance head and neck squamous cell carcinoma proliferation, invasion, and metastasis in preclinical models

    Wheeler, Sarah Elizabeth; Shi, Huifang; Lin, Fangchen; Dasari, Sumana; Bednash, Joseph; Thorne, Stephen; Watkins, Simon; Joshi, Radhika; Thomas, Sufi Mary

    2014-01-01

    Background Head and neck squamous cell carcinoma (HNSCC) has had little improvement in mortality rates in decades. A clearer understanding of the HNSCC tumor microenvironment will aid in finding more effective targeted therapies for this disease. Tumor associated fibroblasts (TAFs) are the largest stromal cellular components of the tumor microenvironment in HNSCC. Methods We isolated TAFs from clinical HNSCC cases and propagated in vitro. The effects of TAF secreted paracrine factors on in vitro HNSCC migration, invasion and proliferation was assessed. The effect of TAFs on HNSCC growth and metastases was determined in an orthotopic floor of mouth tumor model. Results TAF conditioned media increased HNSCC cell migration, invasion and proliferation. TAFs increased HNSCC tumor growth and metastases in vivo. Conclusions TAFs play a major role in increasing tumor growth and metastasis in HNSCC. Targeting the tumor stroma may be important to reduce the rate of HNSCC metastasis. PMID:23728942

  15. Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model

    With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor. In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography. Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field. Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth

  16. Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model.

    Mya S Thu

    Full Text Available BACKGROUND: Treatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA approval. METHODOLOGY: For human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron-loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE-Pro on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model. CONCLUSION: FE-Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites

  17. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    Wen Bixiu; Burgman, Paul; Zanzonico, Pat; O' Donoghue, Joseph; Li, Gloria C.; Ling, C. Clifton [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York (United States); Cai Shangde; Finn, Ron [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Serganova, Inna [Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States); Blasberg, Ronald; Gelovani, Juri [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York (United States); Memorial Sloan-Kettering Cancer Center, Department of Neurology, New York (United States)

    2004-11-01

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the {sup 124}I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-{beta}-d-arabinofuranosyl-5-iodouracil ({sup 124}I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped {sup 124}I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of {sup 124}I-FIAU was also compared with that of an exogenous hypoxic cell marker, {sup 18}F-fluoromisonidazole (FMISO). Our results showed that {sup 124}I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of {sup 124}I-FIAU and {sup 18}F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between {sup 124}I-FIAU and {sup 18}F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future

  18. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia

    Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation therapy and chemotherapy. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. The purpose of this study was to develop and characterize a rodent tumor model with a reporter gene construct that would be transactivated by the hypoxia-inducible molecular switch, i.e., the upregulation of HIF-1. The reporter gene construct is the herpes simplex virus 1-thymidine kinase (HSV1-tk) fused with the enhanced green fluorescent protein (eGFP) under the regulation of an artificial hypoxia-responsive enhancer/promoter. In this model, tumor hypoxia would up-regulate HIF-1, and through the hypoxia-responsive promoter transactivate the HSV1-tkeGFPfusion gene. The expression of this reporter gene can be assessed with the 124I-labeled reporter substrate 2'-fluoro-2'-deoxy-1-β-d-arabinofuranosyl-5-iodouracil (124I-FIAU), which is phosphorylated by the HSV1-tk enzyme and trapped in the hypoxic cells. Animal positron emission tomography (microPET) and phosphor plate imaging (PPI) were used in this study to visualize the trapped 124I-FIAU, providing a distribution of the hypoxia-induced molecular events. The distribution of 124I-FIAU was also compared with that of an exogenous hypoxic cell marker, 18F-fluoromisonidazole (FMISO). Our results showed that 124I-FIAU microPET imaging of the hypoxia-induced reporter gene expression is feasible, and that the intratumoral distributions of 124I-FIAU and 18F-FMISO are similar. In tumor sections, detailed radioactivity distributions were obtained with PPI which also showed similarity between 124I-FIAU and 18F-FMISO. This reporter system is sufficiently sensitive to detect hypoxia-induced transcriptional activation by noninvasive imaging and might provide a valuable tool in studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. (orig.)

  19. Preclinical Assessment of Inflammatory Pain.

    Muley, Milind M; Krustev, Eugene; McDougall, Jason J

    2016-02-01

    While acute inflammation is a natural physiological response to tissue injury or infection, chronic inflammation is maladaptive and engenders a considerable amount of adverse pain. The chemical mediators responsible for tissue inflammation act on nociceptive nerve endings to lower neuronal excitation threshold and sensitize afferent firing rate leading to the development of allodynia and hyperalgesia, respectively. Animal models have aided in our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and allowed us to identify and validate numerous analgesic drug candidates. Here we review some of the commonly used models of skin, joint, and gut inflammatory pain along with their relative benefits and limitations. In addition, we describe and discuss several behavioral and electrophysiological approaches used to assess the inflammatory pain in these preclinical models. Despite significant advances having been made in this area, a gap still exists between fundamental research and the implementation of these findings into a clinical setting. As such we need to characterize inherent pathophysiological pathways and develop new endpoints in these animal models to improve their predictive value of human inflammatory diseases in order to design safer and more effective analgesics. PMID:26663896

  20. Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.

    Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

    2011-04-01

    Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID:21300126

  1. Hidden Abuse within the Home: Recognizing and Responding to Sibling Abuse

    Stutey, Diane; Clemens, Elysia V.

    2015-01-01

    Sibling abuse is a serious phenomenon in our society that often goes unaddressed. Victims of sibling abuse experience psychological effects similar to those of child abuse (Caspi, 2012; Wiehe, 2002). The purpose of this article is to provide school counselors with a definition of sibling abuse and a five-step model to recognize and respond. A…

  2. How to Handle Abuse

    ... abuse: physical, sexual, verbal or emotional, and neglect. Physical abuse: Physical abuse is hitting hard with a hand or an ... choking, painful grabbing, and kicking also can be physical abuse. Sexual abuse: Your body has private parts. These ...

  3. Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: First pre-clinical study on a murine model

    Purpose: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. Materials and method: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1® (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T−) after injecting AA in 40 (AAT−). Results: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p < 0.004), and less disorganized collagen fibers and neovessels on histology (p < 0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p > 0.05). Comparison between AAT− and T− showed no AA toxicity on tendon (p = 0.18). Conclusion: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity

  4. Trigeminal neuroplasticity underlies allodynia in a preclinical model of mild closed head traumatic brain injury (cTBI).

    Mustafa, Golam; Hou, Jiamei; Tsuda, Shigeharu; Nelson, Rachel; Sinharoy, Ankita; Wilkie, Zachary; Pandey, Rahul; Caudle, Robert M; Neubert, John K; Thompson, Floyd J; Bose, Prodip

    2016-08-01

    Post-traumatic headache (PTH) following TBI is a common and often persisting pain disability. PTH is often associated with a multimodal central pain sensitization on the skin surface described as allodynia. However, the particular neurobiology underlying cTBI-induced pain disorders are not known. These studies were performed to assess trigeminal sensory sensitization and to determine if sensitization measured behaviorally correlated with detectable changes in portions of the trigeminal sensory system (TSS), particularly trigeminal nucleus, thalamus, and sensory cortex. Thermal stimulation is particularly well suited to evaluate sensitization and was used in these studies. Recent advances in the use of reward/conflict paradigms permit use of operant measures of behavior, versus reflex-driven response behaviors, for thermal sensitization studies. Thus, to quantitate facial thermal sensitization (allodynia) in the setting of acute TBI, the current study utilized an operant orofacial pain reward/conflict testing paradigm to assess facial thermal sensitivity in uninjured control animals compared with those two weeks after cTBI in a rodent model. Significant reductions in facial contact/lick behaviors were observed in the TBI animals using either cool or warm challenge temperatures compared with behaviors in the normal animals. These facial thermal sensitizations correlated with detectable changes in multiple levels of the TSS. The immunohistochemical (IHC) studies revealed significant alterations in the expression of the serotonin (5-HT), neurokinin 1 receptor (NK1R), norepinephrine (NE), and gamma-aminobutyric acid (GABA) in the caudal trigeminal nucleus, thalamic VPL/VPM nucleus, and sensory cortex of the orofacial pain pathways. There was a strong correlation between increased expression of certain IHC markers and increased behavioral markers for facial sensitization. The authors conclude that TBI-induced changes observed in the TSS are consistent with the expression

  5. Acceleration of tendon healing using US guided intratendinous injection of bevacizumab: First pre-clinical study on a murine model

    Dallaudière, Benjamin, E-mail: bendallau64@hotmail.fr [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Inserm U698, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Lempicki, Marta [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Pesquer, Lionel [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Louedec, Liliane [Inserm U698, Hôpital universitaire Bichat, Paris (France); Preux, Pierre Marie [Laboratoire de Biostatistiques, Faculté de médecine, Limoges (France); Meyer, Philippe [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hess, Agathe [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Université de Médecine Paris Diderot (France); Durieux, Marie Hèlène Moreau [Centre d’Imagerie Ostéo Articulaire, Clinique du Sport de Bordeaux-Mérignac (France); Hummel, Vincent; Larbi, Ahmed [Service de Radiologie, Hôpital universitaire Bichat, Paris (France); Deschamps, Lydia [Service d’ Anatomopathologie, Hôpital universitaire Bichat, Paris (France); and others

    2013-12-01

    Purpose: Tendinopathy shows early disorganized collagen fibers with neo-angiogenesis on histology. Peri-tendinous injection of corticosteroid is the commonly accepted strategy despite the abscence of inflammation in tendinosis. The aim of our study was to assess the potential of intratendinous injection of an anti-angiogenic drug (bevacizumab, AA) to treat tendinopathy in a murine model of patellar and Achilles tendinopathy, and to evaluate its local toxicity. Materials and method: Forty rats (160 patellar and Achilles tendons) were used for this study. We induced tendinosis (T+) in 80 tendons by injecting under ultrasonography (US) guidance Collagenase 1{sup ®} (day 0 = D0, patellar = 40 and Achilles = 40). Clinical examination and tendon US were performed at D3, immediately followed by either AA (AAT+, n = 40) or physiological serum (PST+, n = 40, control) US-guided intratendinous injection. Follow-up at D6 and D13 using clinical, US and histology, and comparison between the 2 groups were performed. To study AA toxicity we compared the 80 remaining normal tendons (T−) after injecting AA in 40 (AAT−). Results: All AAT+ showed a better joint mobilization compared to PST+ at D6 (p = 0.004) with thinner US tendon diameters (p < 0.004), and less disorganized collagen fibers and neovessels on histology (p < 0.05). There was no difference at D13 regarding clinical status, US tendon diameter and histology (p > 0.05). Comparison between AAT− and T− showed no AA toxicity on tendon (p = 0.18). Conclusion: Our study suggests that high dose mono-injection of AA in tendinosis, early after the beginning of the disease, accelerates tendon's healing, with no local toxicity.

  6. A preclinical evaluation of alternative synthetic biomaterials for fascial defect repair using a rat abdominal hernia model.

    Daniela Ulrich

    Full Text Available INTRODUCTION: Fascial defects are a common problem in the abdominal wall and in the vagina leading to hernia or pelvic organ prolapse that requires mesh enhancement to reduce operation failure. However, the long-term outcome of synthetic mesh surgery may be unsatisfactory due to post-surgical complications. We hypothesized that mesh fabricated from alternative synthetic polymers may evoke a different tissue response, and provide more appropriate mechanical properties for hernia repair. Our aim was to compare the in vivo biocompatibility of new synthetic meshes with a commercial mesh. METHODS: We have fabricated 3 new warp-knitted synthetic meshes from different polymers with different tensile properties polyetheretherketone (PEEK, polyamide (PA and a composite, gelatin coated PA (PA+G. The rat abdominal hernia model was used to implant the meshes (25 × 35 mm, n = 24/ group. After 7, 30, 60, 90 days tissues were explanted for immunohistochemical assessment of foreign body reaction and tissue integration, using CD31, CD45, CD68, alpha-SMA antibodies. The images were analysed using an image analysis software program. Biomechanical properties were uniaxially evaluated using an Instron Tensile® Tester. RESULTS: This study showed that the new meshes induced complex differences in the type of foreign body reaction over the time course of implantation. The PA, and particularly the composite PA+G meshes, evoked a milder early inflammatory response, and macrophages were apparent throughout the time course. Our meshes led to better tissue integration and new collagen deposition, particularly with the PA+G meshes, as well as greater and sustained neovascularisation compared with the PP meshes. CONCLUSION: PA, PA+G and PEEK appear to be well tolerated and are biocompatible, evoking an overlapping and different host tissue response with time that might convey mechanical variations in the healing tissue. These new meshes comprising different polymers may

  7. Sanazole directed targeting of silver nanoparticle drug complex to tumor mass: A preclinical investigation in murine model

    Gopakumar Gopinathan Nair

    2014-01-01

    Full Text Available Aim of Study: To explore sanazole (AK directed targeting of the antineoplastic drug doxorubicin (DOX complexed with silver nanoparticles (SNs to tumor growth in a murine model. Materials and Methods: Sanazole (AK and DOX were complexed with SNs, individually and in combination to obtain SN-AK, SN-DOX, and SN-AK-DOX. Solid tumors were developed on hind limbs of Swiss albino mice by transplanting Dalton′s lymphoma ascitess (DLAs tumor cells. Induction of cytotoxicity and apoptosis in the DLA cells by AK and DOX complexed with SN, individually and in combination, were examined under in vitro conditions by incubating the cells with them. SN, AK, DOX, SN-AK, SN-DOX, AK-DOX, and SN-AK-DOX were administered orally to the tumor bearing mice and the therapeutic efficacy of AK-directed targeting of SN-DOX complexes to achieve tumor control was monitored. Results: Under in vitro conditions, SN, AK, DOX, SN-AK, SN-DOX, AK-DOX, and SN-AK-DOX induced cytotoxicity and apoptosis in DLA cells to varying extents. The SN-AK-DOX complex showed higher level of cytotoxicity and apoptosis-induction in DLA cells. Similarly, administration of SN, AK, DOX, SN-AK, SN-DOX, AK-DOX, and SN-AK-DOX resulted in significant reduction in tumor volume and delay in tumor growth. The animals treated with SN-AK-DOX had the highest reduction in tumor volume and tumor growth. In fact, the tumor was almost absent in the animals of this group after the treatment. Conclusion: The SN complex of sanazole and doxorubicin together (SN-AK-DOX has high anticancer activity under in vivo conditions and has great potential in tumor therapy.

  8. Optically enhanced blood-brain-barrier crossing of plasmonic-active nanoparticles in preclinical brain tumor animal models

    Yuan, Hsiangkuo; Wilson, Christy M.; Li, Shuqin; Fales, Andrew M.; Liu, Yang; Grant, Gerald; Vo-Dinh, Tuan

    2014-02-01

    Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables monitoring of the therapeutic process in each individual. Such a concept dubbed "theranostics" potentiates translational research and improves precision medicine. One particular challenging application of theranostics involves imaging and controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound), however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation. Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold nanoparticle in future brain tumor imaging and therapy.

  9. Challenges for Preclinical Investigations of Human Biofield Modalities

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-01-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in v...

  10. Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action.

    Ponnusamy, Suriyan; Lattmann, Eric; Lattmann, Pornthip; Thiyagarajan, Thirumagal; Padinjarethalakal, Balaram N; Narayanan, Ramesh

    2016-04-01

    Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genome‑wide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option. PMID:26820391

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

    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). Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2. PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2. Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent

  12. Inhalant Abuse

    ... she is likely to try other kinds of drugs, especially alcohol and marijuana. Symptoms How can I tell if my child is abusing inhalants? It can be hard to recognize the signs of inhalant abuse. Teenagers who use inhalants may have some of the ...

  13. Abusive Relationships

    ... leaving. Where to Get Help Ending abuse and violence in teen relationships is a community effort with plenty of ... other ways to get involved in making sure dating abuse doesn’t happen to people in your school. Reviewed by: D'Arcy Lyness, PhD Date reviewed: May ... For Teens For Kids For Parents MORE ON THIS TOPIC ...

  14. Determining Possible Professionals and Respective Roles and Responsibilities for a Model Comprehensive Elder Abuse Intervention: A Delphi Consensus Survey.

    Janice Du Mont

    Full Text Available We have undertaken a multi-phase, multi-method program of research to develop, implement, and evaluate a comprehensive hospital-based nurse examiner elder abuse intervention that addresses the complex functional, social, forensic, and medical needs of older women and men. In this study, we determined the importance of possible participating professionals and respective roles and responsibilities within the intervention.Using a modified Delphi methodology, recommended professionals and their associated roles and responsibilities were generated from a systematic scoping review of relevant scholarly and grey literatures. These items were reviewed, new items added for review, and rated/re-rated for their importance to the intervention on a 5-point Likert scale by an expert panel during a one day in-person meeting. Items that did not achieve consensus were subsequently re-rated in an online survey.Those items that achieved a mean Likert rating of 4+ (rated important to very important, and an interquartile range<1 in the first or second round, and/or for which 80% of ratings were 4+ in the second round were retained for the model elder abuse intervention.Twenty-two of 31 recommended professionals and 192 of 229 recommended roles and responsibilities rated were retained for our model elder abuse intervention. Retained professionals were: public guardian and trustee (mean rating = 4.88, geriatrician (4.87, police officer (4.87, GEM (geriatric emergency management nurse (4.80, GEM social worker (4.78, community health worker (4.76, social worker/counsellor (4.74, family physician in community (4.71, paramedic (4.65, financial worker (4.59, lawyer (4.59, pharmacist (4.59, emergency physician (4.57, geriatric psychiatrist (4.33, occupational therapist (4.29, family physician in hospital (4.28, Crown prosecutor (4.24, neuropsychologist (4.24, bioethicist (4.18, caregiver advocate (4.18, victim support worker (4.18, and respite care worker (4.12.A large and

  15. Testing a Model of Participant Retention in Longitudinal Substance Abuse Research

    Gilmore, Devin; Kuperminc, Gabriel P.

    2014-01-01

    Longitudinal substance abuse research has often been compromised by high rates of attrition, thought to be the result of the lifestyle that often accompanies addiction. Several studies have used strategies including collection of locator information at the baseline assessment, verification of the information, and interim contacts prior to…

  16. The Relationship between Sexual Abuse during Childhood and Parenting Outcomes: Modeling Direct and Indirect Pathways

    Schuetze, P.; Eiden, R.D.

    2005-01-01

    Objective:: This study examined the association between childhood sexual abuse (CSA) and parenting outcomes including parenting stress, feelings of competence and discipline strategies. Maternal depression and current partner violence were hypothesized to be mediators of the association between CSA and parenting. Method:: This study is based on…

  17. The Clinical-Forensic Dichotomy in Sexual Abuse Evaluations: Moving toward an Integrative Model

    Tishelman, Amy C.; Meyer, Susanne K.; Haney, Penny; McLeod, Sara K.

    2010-01-01

    We propose the use of an approach to evaluation that can be undertaken in a clinical setting when concerns regarding child sexual abuse are unclear or ambiguous and other systems are not involved, thus providing an option for the nondisclosing child often discussed in the "delayed disclosure" literature. This approach can also be appropriate for a…

  18. Social-Relational Risk Factors for Predicting Elder Physical Abuse: An Ecological Bi-Focal Model

    von Heydrich, Levente; Schiamberg, Lawrence B.; Chee, Grace

    2012-01-01

    Annually in the United States, 1 to 5 million older adults, 65 and above, are physically or sexually injured or mistreated by their caregivers in family settings. This study examined the prevalence and risk factors involved in elder physical abuse by adult child caregivers, moving from the immediate elderly parent/adult child relationship context…

  19. Preclinical Research Unit at CENTIS

    The description of the CENTIS Preclinical Research Unit. It has two purposes: Quality assurance system, and the Accreditation facing current national and international standards according with the competent authority

  20. Ovarian hormones and drug abuse.

    Moran-Santa Maria, Megan M; Flanagan, Julianne; Brady, Kathleen

    2014-11-01

    There are significant gender differences in course, symptomology, and treatment of substance use disorders. In general data from clinical and preclinical studies of substance use disorders suggest that women are more vulnerable than men to the deleterious consequences of drug use at every phase of the addiction process. In addition data from epidemiologic studies suggest that the gender gap in the prevalence of substance use is narrowing particularly among adolescence. Therefore, understanding the role of estrogen and progesterone in mediating responses to drugs of abuse is of critical importance to women's health. In this review we will discuss findings from clinical and preclinical studies of (1) reproductive cycle phase; (2) endogenous ovarian hormones; and (3) hormone replacement on responses to stimulants, nicotine, alcohol, opioids, and marijuana. In addition, we discuss data from recent studies that have advanced our understanding of the neurobiologic mechanisms that interact with estrogen and progesterone to mediate drug-seeking behavior. PMID:25224609

  1. Child Abuse and Domestic Abuse

    ... Traumatic Stress Disorder Reporting Domestic Abuse Reporting Suspected Child Abuse or Neglect Traumatic Brain Injury Family & Relationships There’s more to a military family than moving and deployments — take us along through each phase of your military ... Care and Youth Programs Parenting Military Youth on ...

  2. Preclinical studies of concomitant chemoradiation

    Animal models are widely used in preclinical studies in order to explain the mechanisms of action of chemotherapy, radiotherapy and concomitant chemoradiation, to analyze pathophysiology of tumors and to evaluate the treatment of choice for malignant tumors. The choice of murine tumor or human tumor xenograft system is still debated. Xenografted human tumors have two main advantages: their human origin and wanted pathological type, which is necessary for future clinical studies. There are a lot of disadvantages of xenografted tumors: the stroma and vascular network of transplanted tumors have murine origin, the graft is mostly ectopic, the volume of transplanted tumors at the time of chemoradiotherapy is much smaller than that of the tumor in man; due to residual immunity it is difficult to determine response to cytotoxic treatment. It is still impossible to extrapolate the results obtained in a tumor model in animal to man. These investigations are useful for interpretation of clinical results and for proposing the less empirical method of chemoradiation for phase II clinical trials. (author)

  3. Three-Dimensional Quantitative Morphometric Analysis (QMA for In Situ Joint and Tissue Assessment of Osteoarthritis in a Preclinical Rabbit Disease Model.

    Kathryn S Stok

    Full Text Available This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA. The aims are to (1 demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2 introduce a comprehensive three-dimensional (3D quantitative morphometric analysis (QMA, including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ, an angle to indicate erosion between the lateral and medial femoral condyles (ρ, a vector defining altered angulation (λ, α, β, γ and a twist angle (τ measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW, and a slope and

  4. NOD/scid IL-2Rgnull mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo

    Spranger Stefani

    2012-02-01

    Full Text Available Abstract Background To date very few systems have been described for preclinical investigations of human cellular therapeutics in vivo. However, the ability to carry out comparisons of new cellular vaccines in vivo would be of substantial interest for design of clinical studies. Here we describe a humanized mouse model to assess the efficacy of various human dendritic cell (DC preparations. Two reconstitution regimes of NOD/scid IL2Rgnull (NSG mice with adult human peripheral blood mononuclear cells (PBMC were evaluated for engraftment using 4-week and 9-week schedules. This led to selection of a simple and rapid protocol for engraftment and vaccine evaluation that encompassed 4 weeks. Methods NSG recipients of human PBMC were engrafted over 14 days and then vaccinated twice with autologous DC via intravenous injection. Three DC vaccine formulations were compared that varied generation time in vitro (3 days versus 7 days and signals for maturation (with or without Toll-like receptor (TLR3 and TLR7/8 agonists using MART-1 as a surrogate antigen, by electroporating mature DC with in vitro transcribed RNA encoding full length protein. After two weekly vaccinations, the splenocyte populations containing human lymphocytes were recovered 7 days later and assessed for MART-1-specific immune responses using MHC-multimer-binding assays and functional assessment of specific killing of melanoma tumor cell lines. Results Human monocyte-derived DC generated in vitro in 3 days induced better MART-1-specific immune responses in the autologous donor T cells present in the humanized NSG mice. Moreover, consistent with our in vitro observations, vaccination using mature DC activated with TLR3 and TLR7/8 agonists resulted in enhanced immune responses in vivo. These findings led to a ranking of the DC vaccine effects in vivo that reflected the hierarchy previously found for these mature DC variations in vitro. Conclusions This humanized mouse model system enables

  5. In vivo preclinical low field MRI monitoring of tumor growth following a suicide gene therapy in an ortho-topic mice model of human glioblastoma

    Purpose The aim of this study was to monitor in vivo with low field MRI growth of a murine ortho-topic glioma model following a suicide gene therapy. Methods The gene therapy consisted in the stereotactic injection in the mice brain of a modified vaccinia virus Ankara (M.V.A.) vector encoding for a suicide gene (FCU1) that transforms a non toxic pro-drug 5-fluoro-cytosine (5-F.C.) to its highly cytotoxic derivatives 5-fluorouracil (5-F.U.) and 5-fluoro-uridine-5 monophosphate (5-F.U.M.P.). Using a warmed-up imaging cell, sequential 3D T1 and T2 0.1T MRI brain examinations were performed on 16 Swiss female nu/nu mice bearing ortho-topic human glioblastoma (U 87-MG cells). The 6-week in vivo MRI follow-up consisted in a weekly measurement of the intracerebral tumor volume leading to a total of 65 examinations. Mice were divided in four groups: sham group (n = 4), sham group treated with 5-F.C. only (n = 4), sham group with injection of M.V.A.-FCU1 vector only (n = 4), therapy group administered with M.V.A.-FCU1 vector and 5-F.C. (n = 4). Measurements of tumor volumes were obtained after manual segmentation of T1- and T2-weighted images. Results Intra-observer and inter-observer tumor volume measurements show no significant differences. No differences were found between T1 and T2 volume tumor doubling times between the three sham groups. A significant statistical difference (p < 0.05) in T1 and T2 volume tumor doubling times between the three sham groups and the animals treated with the intratumoral injection of M.V.A.-FCU1 vector in combination with 2 weeks per os 5-F.C. administration was demonstrated. Conclusion Preclinical low field MRI was able to monitor efficacy of suicide gene therapy in delaying the tumor growth in an in vivo mouse model of ortho-topic glioblastoma. (authors)

  6. Three-Dimensional Quantitative Morphometric Analysis (QMA) for In Situ Joint and Tissue Assessment of Osteoarthritis in a Preclinical Rabbit Disease Model

    Stok, Kathryn S.; Besler, Bryce A.; Steiner, Thomas H.; Villarreal Escudero, Ana V.; Zulliger, Martin A.; Wilke, Markus; Atal, Kailash; Quintin, Aurelie; Koller, Bruno; Müller, Ralph; Nesic, Dobrila

    2016-01-01

    This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA). The aims are to (1) demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2) introduce a comprehensive three-dimensional (3D) quantitative morphometric analysis (QMA), including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ), an angle to indicate erosion between the lateral and medial femoral condyles (ρ), a vector defining altered angulation (λ, α, β, γ) and a twist angle (τ) measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW), and a slope and intercept

  7. {sup 18}F-GE-180: a novel TSPO radiotracer compared to {sup 11}C-R-PK11195 in a preclinical model of stroke

    Boutin, Herve; Gerhard, Alexander [University of Manchester, Faculty of Medical and Human Sciences, Manchester (United Kingdom); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Murray, Katie [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Pradillo, Jesus [University of Manchester, Faculty of Life Sciences, Manchester (United Kingdom); Universidad Complutense/Politecnica de Madrid, Madrid (Spain); Maroy, Renaud [SHFJ - CEA Orsay, Orsay (France); Smigova, Alison [University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom); Jones, Paul A.; Trigg, William [GE Healthcare Ltd., Amersham (United Kingdom)

    2014-10-29

    Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer {sup 11}C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer {sup 18}F-GE-180 in a rat model of stroke. Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with {sup 11}C-R-PK11195 and {sup 18}F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). {sup 18}F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of {sup 11}C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BP{sub ND} = 3.5 ± 0.4 and 2.4 ± 0.5 for {sup 18}F-GE-180 and {sup 11}C-R-PK11195, respectively, with R{sub 1} = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of {sup 18}F-GE-180 significantly displaced {sup 18}F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. The in vivo binding characteristics of {sup 18}F-GE-180 demonstrate a better signal to noise ratio than {sup 11}C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in

  8. Peer abuse

    Alikaşifoğlu, Müjgan

    2011-01-01

    Peer abuse is commonly seen as bullying behaviors The most common definition of bullying used in the literature was formulated by Dan nbsp;Olweus According to Olweus bullying is an aggressive behavior that: a is intended to cause harm or distress b occurs repeatedly over nbsp;time and c occurs in a relationship in which there is an imbalance of power Peer abuse shares many characteristics with other types of nbsp;abuse namely child maltreatment and domestic violence Bullying behaviors may be ...

  9. Everyone's business: developing an integrated model of care to respond to child abuse in a pediatric hospital setting.

    Connolly, Sarah

    2012-01-01

    In pediatric hospitals, social work plays a central role in the prevention, identification, and management of child abuse. Children who are suspected of having been abused or neglected require an evaluation of their psychosocial situation. As an integral member of the health care team, the social worker is well placed to undertake comprehensive psychosocial assessments including information on the child's development, parental capacity, family, and community supports. Current practice approaches have seen a shift away from a narrow, "expert" approach to child protection. This article describes the development of an integrated model of social work service delivery to better respond to vulnerable and at-risk children in a pediatric hospital setting. Developing a new model of service required strategic planning, consultation, and endorsement from senior hospital management. The new model aimed to ensure a high quality, responsive social work service to children at risk of physical abuse, neglect, or cumulative harm. The change necessitated understanding of current research evidence, development of best practice guidelines, and effective communication with staff and external stakeholders. Policy development, implementation of practice guidelines, staff training, data collection, and service evaluation are described. The role of social work management and leadership were central in creating change. Visionary leadership is widely regarded as key to successful organizational change. The management approach included consultation with staff, building commitment to the need for change, addressing staff concerns, and providing a vision of enhanced client outcomes as a result of the change process. This article provides a candid overview of challenges and barriers to change. Change strategies described are easily transferable to other social work settings. PMID:22251389

  10. Preventing Child Abuse and Neglect

    ... Abuse & Neglect Fatalities Preventing Child Abuse & Neglect National Child Abuse Prevention Month Overview Promoting Child & Family Well-Being Public ... Abuse & Neglect Preventing Child Abuse & Neglect Resources on child abuse prevention, protecting children from risk of abuse, and strengthening ...

  11. Drug abuse

    This paper reports that this study used SPECT to examine patients who have abused drugs to determine whether SPECT could identify abnormalities and whether these findings have clinical importance. Fifteen patients with a history of substance abuse (eight with cocaine, six with amphetamine, and one with organic solvent) underwent SPECT performed with a triple-headed camera and Tc-99m HMPAO both early for blood flow and later for functional information. These images were then processed into a 3D videotaped display used in group therapy. All 15 patients had multiple areas of decreased tracer uptake peppered throughout the cortex but mainly affecting the parietal lobes, expect for the organic solvent abuser who had a large parietal defect. The videotapes were subjectively described by a therapist as an exceptional tool that countered patient denial of physical damage from substance abuse. Statistical studies of recidivism between groups is under way

  12. A Structural Model of the Influence of Family Problems and Child Abuse Factors on Serious Delinquency among Youths Processed at a Juvenile Assessment Center.

    Dembo, Richard; Wothke, Werner; Shemwell, Marina; Pacheco, Kimberly; Seeberger, William; Rollie, Matthew; Schmeidler, James; Livingston, Stephen

    2000-01-01

    Authors tested model of the influence of arrested youths' family problem factors, including sexual victimization, physical abuse experiences, drug use, frequency of involvement in index offences. Hypothesized model was supported by data overall for males; female data suggested they use alcohol and marijuana for different reasons. Findings…

  13. The Good Way Model: A Strengths-Based Approach for Working with Young People, Especially Those with Intellectual Difficulties, Who Have Sexually Abusive Behaviour

    Ayland, Lesley; West, Bill

    2006-01-01

    The Good Way model was originally developed for working with youth with intellectual difficulties who have sexually abused and is also now being used with adults with intellectual disabilities and non-disabled adolescents. The model is practical and has been developed to address the need for a common, coherent narrative with which clients and…

  14. Reform in Teaching Preclinical Pathophysiology

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

    2015-01-01

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

  15. Challenges for Preclinical Investigations of Human Biofield Modalities.

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-11-01

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

  16. Early childhood sexual abuse increases suicidal intent.

    Lopez-Castroman, Jorge; Melhem, Nadine; Birmaher, Boris; Greenhill, Laurence; Kolko, David; Stanley, Barbara; Zelazny, Jamie; Brodsky, Beth; Garcia-Nieto, Rebeca; Burke, Ainsley K; Mann, J John; Brent, David A; Oquendo, Maria A

    2013-06-01

    Childhood sexual abuse has been consistently associated with suicidal behavior. We studied suicide attempt features in depressed individuals sexually abused as children. On average, sexual abuse started before age 9. It frequently coexisted with physical abuse. Suicide attempters more often had personality disorders and had endured abuse for longer, but did not differ in terms of other clinical characteristics from non-attempters. Earlier onset of sexual abuse and its duration were associated with more suicide attempts. However, when personality disorders were included in the regression model, only these disorders predicted number of attempts. The severity of sexual abuse and the coexistence of physical abuse were correlated with age at first suicide attempt. However, only severity of sexual abuse was marginally associated with age at first suicide attempt in the regression model. Finally, the earlier the age of onset of sexual abuse, the higher the intent, even after controlling for age, sex and personality disorders. This suggests that the characteristics of childhood sexual abuse, especially age of onset, should be considered when studying the risk for suicidal behavior in abused populations. PMID:23737424

  17. Multimodal imaging based on MRI and PET reveals [{sup 18}F]FLT PET as a specific and early indicator of treatment efficacy in a preclinical model of recurrent glioblastoma

    Corroyer-Dulmont, Aurelien; Peres, Elodie A.; Gerault, Aurelie N.; Divoux, Didier; Toutain, Jerome; Ibazizene, Meziane; MacKenzie, Eric T.; Barre, Louisa; Bernaudin, Myriam; Petit, Edwige; Valable, Samuel [CNRS, UMR 6301 ISTCT, CERVOxy and LDM-TEP groups. GIP CYCERON, Caen (France); CEA, DSV/I2BM, UMR 6301 ISTCT, CERVOxy et LDM-TEP Groups, GIP CYCERON, Caen (France); UNICAEN, UMR 6301 ISTCT, CERVOxy et LDM-TEP Groups, GIP CYCERON, Caen (France); Normandie Univ., Caen(France); Savina, Ariel; Bouquet, Fanny [Roche SAS, Boulogne-Billancourt (France)

    2016-04-15

    The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([{sup 18}F]FDG and [{sup 18}F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [{sup 18}F]FLT uptake, cerebral blood volume and oedema. [{sup 18}F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [{sup 18}F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [{sup 18}F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations. (orig.)

  18. Multimodal imaging based on MRI and PET reveals [18F]FLT PET as a specific and early indicator of treatment efficacy in a preclinical model of recurrent glioblastoma

    The primary objective of this study was to compare the ability of PET and MRI biomarkers to predict treatment efficacy in a preclinical model of recurrent glioblastoma multiforme. MRI (anatomical, diffusion, vasculature and oxygenation) and PET ([18F]FDG and [18F]FLT) parameters were obtained 3 days after the end of treatment and compared with late tumour growth and survival. Early after tumour recurrence, no effect of treatment with temozolomide combined with bevacizumab was observed on tumour volume as assessed by T2-W MRI. At later times, the treatment decreased tumour volume and increased survival. Interestingly, at the earlier time, temozolomide + bevacizumab decreased [18F]FLT uptake, cerebral blood volume and oedema. [18F]FLT uptake, oedema and cerebral blood volume were correlated with overall survival but [18F]FLT uptake had the highest specificity and sensitivity for the early prediction of treatment efficacy. The present investigation in a preclinical model of glioblastoma recurrence underscores the importance of multimodal imaging in the assessment of oedema, tumour vascular status and cell proliferation. Finally, [18F]FLT holds the greatest promise for the early assessment of treatment efficacy. These findings may translate clinically in that individualized treatment for recurrent glioma could be prescribed for patients selected after PET/MRI examinations. (orig.)

  19. Validation of the Indicators of Abuse (IOA) Screen.

    Reis, Myrna; Nahmiash, Daphne

    1998-01-01

    Reports on the validity of the Indicators of Abuse (IOA) Screen, used by social-services-agency practitioners as an abuse screening tool. An abuse-indicator model evolving from the IOA suggests three main types of abuse signals: caregivers' personal problems/issues, caregivers interpersonal problems, and care receivers' social-support shortages…

  20. Physical Abuse of Children: A Look at Professional Intervention.

    Finch, Joe M.

    The physical abuse of children is a serious and growing problem. In spite of increasing knowledge and skill in treating physical abuse, many professionals continue to be dissatisfied with the effectiveness of treatment. This study examined the myths and beliefs about abuse and abusers and the theoretical models of cause and treatment that are…

  1. Coupled mechanical-electrical-thermal modeling for short-circuit prediction in a lithium-ion cell under mechanical abuse

    Zhang, Chao; Santhanagopalan, Shriram; Sprague, Michael A.; Pesaran, Ahmad A.

    2015-09-01

    In order to better understand the behavior of lithium-ion batteries under mechanical abuse, a coupled modeling methodology encompassing the mechanical, electrical and thermal response is presented for predicting short-circuit under external crush. The combined mechanical-electrical-thermal response is simulated in a commercial finite element software LS-DYNA® using a representative-sandwich finite-element model, where electrical-thermal modeling is conducted after an instantaneous mechanical crush. The model includes an explicit representation of each individual component such as the active material, current collector, separator, etc., and predicts their mechanical deformation under quasi-static indentation. Model predictions show good agreement with experiments: the fracture of the battery structure under an indentation test is accurately predicted. The electrical-thermal simulation predicts the current density and temperature distribution in a reasonable manner. Whereas previously reported models consider the mechanical response exclusively, we use the electrical contact between active materials following the failure of the separator as a criterion for short-circuit. These results are used to build a lumped representative sandwich model that is computationally efficient and captures behavior at the cell level without resolving the individual layers.

  2. Coupling of Geant4-DNA physics models into the GATE Monte Carlo platform: Evaluation of radiation-induced damage for clinical and preclinical radiation therapy beams

    Pham, Q. T.; Anne, A.; Bony, M.; Delage, E.; Donnarieix, D.; Dufaure, A.; Gautier, M.; Lee, S. B.; Micheau, P.; Montarou, G.; Perrot, Y.; Shin, J. I.; Incerti, S.; Maigne, L.

    2015-06-01

    The GATE Monte Carlo simulation platform based on the Geant4 toolkit is in constant improvement for dosimetric calculations. In this paper, we present the integration of Geant4-DNA processes into the GATE 7.0 platform in the objective to perform multi-scale simulations (from macroscopic to nanometer scale). We simulated three types of clinical and preclinical beams: a 6 MeV electron clinical beam, a X-ray irradiator beam and a clinical proton beam for which we validated depth dose distributions against measurements in water. Frequencies of energy depositions and DNA damage were evaluated using a specific algorithm in charge of allocating energy depositions to atoms constituting DNA molecules represented by their PDB (Protein Data Bank) description.

  3. Coupling of Geant4-DNA physics models into the GATE Monte Carlo platform: Evaluation of radiation-induced damage for clinical and preclinical radiation therapy beams

    The GATE Monte Carlo simulation platform based on the Geant4 toolkit is in constant improvement for dosimetric calculations. In this paper, we present the integration of Geant4-DNA processes into the GATE 7.0 platform in the objective to perform multi-scale simulations (from macroscopic to nanometer scale). We simulated three types of clinical and preclinical beams: a 6 MeV electron clinical beam, a X-ray irradiator beam and a clinical proton beam for which we validated depth dose distributions against measurements in water. Frequencies of energy depositions and DNA damage were evaluated using a specific algorithm in charge of allocating energy depositions to atoms constituting DNA molecules represented by their PDB (Protein Data Bank) description

  4. Coupling of Geant4-DNA physics models into the GATE Monte Carlo platform: Evaluation of radiation-induced damage for clinical and preclinical radiation therapy beams

    Pham, Q.T.; Anne, A.; Bony, M.; Delage, E. [Clermont Université, Université Blaise Pascal, CNRS/IN2P3, Laboratoire de Physique Corpusculaire, BP 10448, F-63000 Clermont-Ferrand (France); Donnarieix, D. [Centre Jean Perrin, Service de physique médicale, 58 rue Montalembert, 63011 Clermont-Ferrand Cedex (France); Dufaure, A.; Gautier, M. [Clermont Université, Université Blaise Pascal, CNRS/IN2P3, Laboratoire de Physique Corpusculaire, BP 10448, F-63000 Clermont-Ferrand (France); Lee, S.B. [Proton Therapy Center, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769 (Korea, Republic of); Micheau, P.; Montarou, G.; Perrot, Y. [Clermont Université, Université Blaise Pascal, CNRS/IN2P3, Laboratoire de Physique Corpusculaire, BP 10448, F-63000 Clermont-Ferrand (France); Shin, J.I. [Proton Therapy Center, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769 (Korea, Republic of); Incerti, S. [Université de Bordeaux, Centre d’Études Nucléaires de Bordeaux-Gradignan, UMR-5797, Chemin du Solarium, 33175 Gradignan (France); CNRS-IN2P3, Centre d’Études Nucléaires de Bordeaux-Gradignan, UMR-5797, Chemin du Solarium, 33175 Gradignan (France); Maigne, L., E-mail: maigne@clermont.in2p3.fr [Clermont Université, Université Blaise Pascal, CNRS/IN2P3, Laboratoire de Physique Corpusculaire, BP 10448, F-63000 Clermont-Ferrand (France)

    2015-06-15

    The GATE Monte Carlo simulation platform based on the Geant4 toolkit is in constant improvement for dosimetric calculations. In this paper, we present the integration of Geant4-DNA processes into the GATE 7.0 platform in the objective to perform multi-scale simulations (from macroscopic to nanometer scale). We simulated three types of clinical and preclinical beams: a 6 MeV electron clinical beam, a X-ray irradiator beam and a clinical proton beam for which we validated depth dose distributions against measurements in water. Frequencies of energy depositions and DNA damage were evaluated using a specific algorithm in charge of allocating energy depositions to atoms constituting DNA molecules represented by their PDB (Protein Data Bank) description.

  5. A Qualitative Study of Childhood Sexual Abuse Survivors in Taiwan: Toward a Transactional and Ecological Model of Coping

    Wang, Yu-Wei; Heppner, P. Paul

    2011-01-01

    In this study, we aimed to explore the experiences of 10 female Taiwanese childhood sexual abuse (CSA) survivors (age range = 20-39 years) to broaden our understanding of the post-abuse coping process in a Chinese sociocultural context. This investigation was grounded on a feminist paradigm, and the consensual qualitative research method (Hill et…

  6. Childhood history of abuse and child abuse potential: the role of parent's gender and timing of childhood abuse.

    Romero-Martínez, A; Figueiredo, B; Moya-Albiol, L

    2014-03-01

    It has been suggested that being physically abused leads to someone becoming a perpetrator of abuse which could be associated to parents' gender, timing of the physical abuse and specific socio-demographic variables. This study aims to investigate the role the parents' gender, timing of childhood abuse and socio-demographic variables on the relationship between parents' history of childhood physical abuse and current risk for children. The sample consisted of 920 parents (414 fathers, 506 mothers) from the Portuguese National Representative Study of Psychosocial Context of Child Abuse and Neglect who completed the Childhood History Questionnaire and the Child Abuse Potential Inventory. The results showed that fathers had lower current potential risk of becoming physical abuse perpetrators with their children than mothers although they did not differed in their physical victimization history. Moreover, the risk was higher in parents (both genders) with continuous history of victimization than in parents without victimization. Prediction models showed that for fathers and mothers separately similar socio-demographic variables (family income, number of children at home, employment status and marital status) predicted the potential risk of becoming physical abuses perpetrators. Nevertheless, the timing of victimization was different for fathers (before 13 years old) and mothers (after 13 years old). Then our study targets specific variables (timing of physical abuse, parents' gender and specific socio-demographic variables), which may enable professionals to select groups of parents at greater need of participating in abuse prevention programs. PMID:24269330

  7. Chemical and preclinical studies on Hedyotis diffusa with anticancer potential.

    Niu, Yu; Meng, Qiu-Xia

    2013-01-01

    This paper presents the chemical and preclinical anticancer research on Hedyotis diffusa Willd. in detail, one of the most renowned herbs often prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicine. Anthraquinones, flavonoids, and terpenoids constitute the majority of the 69 compounds that have been isolated and identified from H. diffusa. The anticancer effects of the methanolic, ethanolic, and aqueous extracts in various preclinical cancer models have been described. This review also summarized the anticancer activity of constituents of the herb and the mechanisms of action. All the studies suggest that H. diffusa has enormous potential in the therapy of cancer and warrants further chemical and pharmacological investigation. PMID:23600735

  8. Prevent Child Abuse America

    ... call the police . Crisis and support contacts For Child Abuse Reporting Numbers in your State please visit: Child ... suspected child abuse and neglect. Parent Resources Prevent Child Abuse America (800) CHILDREN A resource for tips, referrals, ...

  9. Child Sexual Abuse

    Sexual abuse is one form of child abuse. It includes a wide range of actions between a child ... to children or pressuring them for sex is sexual abuse. Using a child for pornography is also sexual ...

  10. What is Elder Abuse?

    ... to another, but broadly defined, abuse may be: Physical Abuse —inflicting physical pain or injury on a senior, ... abrasions, and burns may be an indication of physical abuse, neglect, or mistreatment. Unexplained withdrawal from normal activities, ...

  11. Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.

    Bachegowda, Lohith; Morrone, Kerry; Winski, Shannon L; Mantzaris, Ioannis; Bartenstein, Matthias; Ramachandra, Nandini; Giricz, Orsi; Sukrithan, Vineeth; Nwankwo, George; Shahnaz, Samira; Bhagat, Tushar D; Bhattacharyya, Sanchari; Assal, Amer; Shastri, Aditi; Gordon-Mitchell, Shanisha; Pellagatti, Andrea; Boultwood, Jacqueline; Schinke, Carolina; Yu, Yiting; Guha, Chandan; Rizzi, James; Garrus, Jennifer; Brown, Suzy; Wollenberg, Lance; Hogeland, Grant; Wright, Dale; Munson, Mark; Rodriguez, Mareli; Gross, Stefan; Chantry, David; Zou, Yiyu; Platanias, Leonidas C; Burgess, Laurence E; Pradhan, Kith; Steidl, Ulrich; Verma, Amit

    2016-08-15

    Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR. PMID:27287719

  12. Preclinical evaluation of racotumomab, an anti-idiotype monoclonal antibody to N-glycolyl-containing gangliosides, with or without chemotherapy in a mouse model of non-small cell lung cancer

    DanielFAlonso

    2012-11-01

    Full Text Available N-glycolylneuraminic acid (NeuGc is a sialic acid molecule usually found in mammalian cells as terminal constituents of different membrane glycoconjugates such as gangliosides. The NeuGcGM3 ganglioside has been described as a tumor antigen for non-small cell lung cancer (NSCLC in humans. Racotumomab is an anti-NeuGc-containing gangliosides anti-idiotype monoclonal antibody (formerly known as 1E10 that has received attention as a potential active immunotherapy for advanced lung cancer in clinical trials. In this work, we have examined the antitumor activity of racotumomab in combination or not with chemotherapy, using the 3LL Lewis lung carcinoma as a preclinical model of NSCLC in C57BL/6 mice. Vaccination with biweekly doses of racotumomab at 50-200 μg/dose formulated in aluminum hydroxide (racotumomab-alum vaccine demonstrated a significant antitumor effect against the progression of lung tumor nodules. Racotumomab-alum vaccination exerted a comparable effect on lung disease to that of pemetrexed-based chemotherapy (100 mg/kg weekly. Interestingly, chemo-immunotherapy was highly effective against lung nodules and well tolerated, although no significant synergistic effect was observed as compared to each treatment alone in the present model. We also obtained evidence on the role of the exogenous incorporation of NeuGc in the metastatic potential of 3LL cells. Our preclinical data provide support for the combination of chemotherapy with the anti-idiotype monoclonal antibody racotumomab, and also reinforce the biological significance of NeuGc in lung cancer.

  13. Screening for pre-clinical disability in different residential settings

    Newstead Stuart

    2010-08-01

    Full Text Available Abstract Background Preventing disability and offering effective interventions to older people during early decline in function is most likely to be effective if those most at risk of progressive disablement are able to be identified. Similarly the ability to easily identify a group with similar functional profile from disparate sectors of the community is of significant benefit to researchers. This study aimed to (1 describe the use of a pre-clinical disability screening tool to select a functionally comparable group of older men and women with early functional limitation from different settings, and (2 explore factors associated with function and disability. Methods Self-reported function and disability measured with the Late-Life Function and Disability Instrument along with a range of physical performance measurements were compared across residential settings and gender in a sample of 471 trial participants identified as pre-clinically disabled after being screened with the Fried pre-clinical disability tool. Factors that might lie on the pathway to progressive disablement were identified using multiple linear regression analysis. Results We found that a sample population, screened for pre-clinical disability, had a functional status and disability profile reflecting early functional limitation, regardless of residential setting or gender. Statistical models identified a range of factors associated with function and disability which explained a greater degree of the variation in function, than disability. Conclusions We selected a group of people with a comparable function and disability profile, consistent with the pre-clinical stage of disability, from a sample of older Australian men and women from different residential settings using the Fried pre-clinical disability screening tool. The results suggest that the screening tool can be used with greater confidence for research, clinical and population health purposes. Further research is

  14. The basics of preclinical drug development for neurodegenerative disease indications.

    Steinmetz, Karen L; Spack, Edward G

    2009-01-01

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

  15. The basics of preclinical drug development for neurodegenerative disease indications

    Spack Edward G

    2009-06-01

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

  16. Prevalence of abuse and related factors in a Colombian medical school

    César Augusto Guevara Cuéllar

    2011-11-01

    Full Text Available Introduction: Different forms of abusive practices are very common in medical schools and have serious implications on vocational and professional formation. The aim of this study is to determine the prevalence of perception of abuse in a university in Colombia and to identify associated factors.Methods: A cross-sectional study was conducted from September to December 2008 in a private medical school. A proportional cycle-based stratified sampling technique and randomized sampling per semester was done. Socio demographic, academic, and abuse-related variables were obtained.Results: One hundred twenty-eight students participated in the study. The prevalence of perception of abuse was 40.6%. The most common type of abuse was psychological (98% and unjustified critique (10.9%, ridiculing (10.7%, shouting (10%, and discredit (9.5% were the most frequent manifestations. Professors in preclinical courses were reported as the most prevalent abusers (25.9%, followed by clinical professors (19.8%. The frequency of abusive manifestations was rare (15.8% and 11.5% in preclinical and clinical years, respectively. The abusive manifestations were most frequent in pathology and pediatrics in the preclinical and clinical years,  espectively. Nineteen percent of the victims of abuse reported such to somebody. The main consequences were desire to withdraw from the career (63.2% and change of career (36.8%. Increased perception of abuse (OR: 4.74 95% IC: 1.9-11.4 p=0.001 was associated during the clinical years.Conclusions: Although abusive practices are more frequent during clinical years, they do not constitute a systematic behavior among medical students from a private university in Colombia in comparison with other  tudies.

  17. Young workers' experiences of abusive leadership

    Starratt, Alison; Grandy, Gina

    2010-01-01

    Purpose – The purpose of this paper is to develop a model of abusive leadership as experienced by young workers. Abusive leadership is understood to be subjective and as such this research seeks to explore the experience of abusive leadership through a qualitative approach. Design/methodology/approach – Drawing on interviews with 30 young workers who identified themselves as having a “bad” boss, this study employs a constructivist grounded theory approach in order to identify behaviours, mode...

  18. [Preclinical study of noopept toxicity].

    Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O

    2002-01-01

    Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice. PMID:12025790

  19. Principles of assessment of abuse liability: US legal framework and regulatory environment.

    Rocha, Beatriz A

    2013-09-01

    Identifying the abuse potential of drug products in the premarketing and postmarketing environment has been a critical component in the implementation of drug abuse control laws worldwide. In the US, the Controlled Substances Act of 1970 (CSA) is a comprehensive federal law enacted to prevent the abuse or diversion of substances with abuse liability or addiction potential (for present purposes, these terms are used interchangeably). Under the jurisdiction of the Drug Enforcement Administration, the law applies to the manufacture and distribution of narcotics and other drug substances with potential of abuse. The CSA classifies substances with abuse potential into schedules I-V based on the substance's risk of diversion or abuse, and thus provides a legal framework for the assessment of abuse liability of New Molecular Entities. When the Food and Drug Administration reviews the safety and efficacy of a New Drug Application it also determines whether the drug has potential for abuse, and if so, will begin the process to schedule the drug under the CSA. As the assessment of abuse potential is a critical component of a marketing application, pharmaceutical companies (sponsors) bear the responsibility of generating a comprehensive preclinical and clinical data package for regulators to review and make decisions on labeling and the corresponding postmarketing surveillance. Recent regulatory guidelines adopted in the European Union (EU) (2006), Canada (2007), and USA (2010) provide recommendations to sponsors on preclinical and clinical methodologies for the assessment of abuse potential. This paper reviews the legal framework of the assessment of abuse liability and scheduling of controlled substances in the USA and describes the current global regulatory environment and the challenges that sponsors and regulators face when assessing abuse liability of New Molecular Entities, from the early stages of development through the late stages, review, and approval. PMID

  20. An Integrated, Multidimensional Treatment Model for Individuals Living with HIV, Mental Illness, and Substance Abuse

    Bouis, Stephanie; Reif, Susan; Whetten, Kathryn; Scovil, Janet; Murray, Andrea; Swartz, Marvin

    2007-01-01

    The challenge of providing effective treatment services for the growing population of HIV-positive individuals who are also dually diagnosed with substance use and mental disorders has only recently been recognized as an important public health concern affecting both HIV treatment and prevention. This article describes a treatment model that was…

  1. Combining Child Welfare and Substance Abuse Services: A Blended Model of Intervention.

    McAlpine, Catherine; Marshall, Cynthia Courts; Doran, Nancy Harper

    2001-01-01

    Several policy and practice issues impede successful implementation of the federal Adoption and Safe Families Act of 1997. Montgomery County, Maryland devised a blended model of intervention to achieve the dual mandates of county Child Welfare Services and alcohol and drug services. The approach made use of graduated levels of intensity in…

  2. Opportunities for computer abuse

    Willison, Robert Andrew; Backhouse, James

    2005-01-01

    Systems risk refers to the likelihood that an IS is inadequately guarded against certain types of damage or loss. While risks are posed by acts of God, hackers and viruses, consideration should also be given to the `insider' threat of dishonest employees, intent on undertaking some form of computer...... for the offender. To achieve this goal a model known as the `Crime Specific Opportunity Structure' is advanced. Focussing on the opportunities for computer abuse, the model addresses the nature of such opportunities with regards to the organisational context and the threats posed by rogue employees. Drawing...

  3. Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models

    Setlow, Barry; Mendez, Ian A.; Mitchell, Marci R; Simon, Nicholas W.

    2009-01-01

    Drug addicted individuals demonstrate high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human dru...

  4. Active Surveillance of Child Abuse Fatalities.

    Schloesser, Patricia; And Others

    1992-01-01

    Birth and death certificates were correlated with information in the state Child Abuse and Neglect Registry on 104 abuse-related fatalities. Significant findings included young age of parents at first pregnancy; high rate of single parenthood; and lower educational achievement among mothers. A model for data collection is discussed. (Author/BRM)

  5. Childhood sexual abuse.

    Evrim Aktepe

    1993-01-01

    Sexual abuse is defined as use of child or adolescent by the adults for satisfying of sexual urges and needs with forcing, threatening or tricking. Sexual abuse can be in the form of sexual abuse without touch, sexual touch, interfemoral intercourse, sexual penetration, and sexual exploitation. The prevalence of sexual abuse is reported as 10-40%. It is seen in female four times more than in males. Abusers are frequently male, only 5-15% of them are female. The abuse by females is usually tow...

  6. Childhood Sexual Abuse

    Aktepe, Evrim

    2009-01-01

    Sexual abuse is defined as use of child or adolescent by the adults for satisfying of sexual urges and needs with forcing, threatening or tricking. Sexual abuse can be in the form of sexual abuse without touch, sexual touch, interfemoral intercourse, sexual penetration, and sexual exploitation. The prevalence of sexual abuse is reported as 10-40%. It is seen in female four times more than in males. Abusers are frequently male, only 5-15% of them are female. The abuse by females is usually tow...

  7. Applying Behavioral Economics to the Challenge of Reducing Cocaine Abuse

    Higgins, Stephen T.

    1998-01-01

    This paper focuses on potential contributions of behavioral economics to reducing cocaine abuse. More specifically, this paper underscores the fundamental role of reinforcement in the genesis and maintenance of cocaine use and explores how reinforcement and consumer-demand theory might be translated into effective strategies for reducing cocaine use. A broad range of relevant research findings are discussed, including preclinical studies conducted with laboratory animals, laboratory and treat...

  8. Cough and Cold Medicine Abuse

    ... and Cold Medicine Abuse DrugFacts: Cough and Cold Medicine Abuse Email Facebook Twitter Revised May 2014 Some ... diverted for abuse. How Are Cough and Cold Medicines Abused? Cough and cold medicines are usually consumed ...

  9. A Comparative Study of the Hypoxia PET Tracers [{sup 18}F]HX4, [{sup 18}F]FAZA, and [{sup 18}F]FMISO in a Preclinical Tumor Model

    Peeters, Sarah G.J.A., E-mail: sarah.peeters@maastrichtuniversity.nl [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands); Zegers, Catharina M.L.; Lieuwes, Natasja G.; Elmpt, Wouter van [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands); Eriksson, Jonas; Dongen, Guus A.M.S. van [Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, Amsterdam (Netherlands); Dubois, Ludwig; Lambin, Philippe [Department of Radiation Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht (Netherlands)

    2015-02-01

    Purpose: Several individual clinical and preclinical studies have shown the possibility of evaluating tumor hypoxia by using noninvasive positron emission tomography (PET). The current study compared 3 hypoxia PET tracers frequently used in the clinic, [{sup 18}F]FMISO, [{sup 18}F]FAZA, and [{sup 18}F]HX4, in a preclinical tumor model. Tracer uptake was evaluated for the optimal time point for imaging, tumor-to-blood ratios (TBR), spatial reproducibility, and sensitivity to oxygen modification. Methods and Materials: PET/computed tomography (CT) images of rhabdomyosarcoma R1-bearing WAG/Rij rats were acquired at multiple time points post injection (p.i.) with one of the hypoxia tracers. TBR values were calculated, and reproducibility was investigated by voxel-to-voxel analysis, represented as correlation coefficients (R) or Dice similarity coefficient of the high-uptake volume. Tumor oxygen modifications were induced by exposure to either carbogen/nicotinamide treatment or 7% oxygen breathing. Results: TBR was stabilized and maximal at 2 hours p.i. for [{sup 18}F]FAZA (4.0 ± 0.5) and at 3 hours p.i. for [{sup 18}F]HX4 (7.2 ± 0.7), whereas [{sup 18}F]FMISO showed a constant increasing TBR (9.0 ± 0.8 at 6 hours p.i.). High spatial reproducibility was observed by voxel-to-voxel comparisons and Dice similarity coefficient calculations on the 30% highest uptake volume for both [{sup 18}F]FMISO (R = 0.86; Dice coefficient = 0.76) and [{sup 18}F]HX4 (R = 0.76; Dice coefficient = 0.70), whereas [{sup 18}F]FAZA was less reproducible (R = 0.52; Dice coefficient = 0.49). Modifying the hypoxic fraction resulted in enhanced mean standardized uptake values for both [{sup 18}F]HX4 and [{sup 18}F]FAZA upon 7% oxygen breathing. Only [{sup 18}F]FMISO uptake was found to be reversible upon exposure to nicotinamide and carbogen. Conclusions: This study indicates that each tracer has its own strengths and, depending on the question to be answered, a different tracer can be put

  10. Preclinical assessment of infant formula.

    Lönnerdal, Bo

    2012-01-01

    Infant formulas are the sole or predominant source of nutrition for many infants and are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. Preclinical safety assessment therefore needs to include both short-term and long-term studies in animals. It is recommended that procedures are instituted by which experts may serve as independent scientists for companies developing novel products, without having their integrity compromised, and later serve the legislative institutions. A two-level assessment approach to determine the potential toxicity of a novel ingredient, its metabolites, and their effects in the matrix on developing organ systems has been suggested by IOM. This appears reasonable, as novel ingredients can be of different levels of concern. The use of modern methods in genomics and proteomics should be considered in these evaluation processes as well as novel methods to evaluate outcomes, including metabolomics and molecular techniques to assess the microbiome. PMID:22699767

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

    Mead, Richard J.; Bennett, Ellen J.; Kennerley, Aneurin J; Paul Sharp; Claire Sunyach; Paul Kasher; Jason Berwick; Brigitte Pettmann; Guiseppe Battaglia; Mimoun Azzouz; Andrew Grierson; Shaw, Pamela J.

    2011-01-01

    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 p...

  12. Skin manifestations of child abuse

    Ermertcan Aylin; Ertan Pelin

    2010-01-01

    Child abuse is a major public health problem all over the world. There are four major types of abuse: physical abuse, sexual abuse, emotional abuse and neglect. The most common manifestations of child abuse are cutaneous and their recognition; and differential diagnosis is of great importance. Clinicians, especially dermatologists, should be alert about the skin lesions of child abuse. In the diagnosis and management of child abuse, a multidisciplinary approach with ethical and legal procedur...

  13. Preclinical evaluation of collagen type I scaffolds, including gelatin-collagen microparticles and loaded with a hydroglycolic Calendula officinalis extract in a lagomorph model of full-thickness skin wound.

    Millán, D; Jiménez, R A; Nieto, L E; Linero, I; Laverde, M; Fontanilla, M R

    2016-02-01

    Previously, we have developed collagen type I scaffolds including microparticles of gelatin-collagen type I (SGC) that are able to control the release of a hydroglycolic extract of the Calendula officinalis flower. The main goal of the present work was to carry out the preclinical evaluation of SGC alone or loaded with the C. officinalis extract (SGC-E) in a lagomorph model of full-thickness skin wound. A total of 39 rabbits were distributed in three groups, of 13 animals each. The first group was used to compare wound healing by secondary intention (control) with wound healing observed when wounds were grafted with SGC alone. Comparison of control wounds with wounds grafted with SGC-E was performed in the second group, and comparison of wounds grafted with SGC with wounds grafted with SGC-E was performed in the third group. Clinical follow-ups were carried in all animals after surgery, and histological and histomorphometric analyses were performed on tissues taken from the healed area and healthy surrounding tissue. Histological and histomorphometric results indicate that grafting of SGC alone favors wound healing and brings a better clinical outcome than grafting SGC-E. In vitro collagenase digestion data suggested that the association of the C. officinalis extract to SGC increased the SGC-E cross-linking, making it difficult to degrade and affecting its biocompatibility. PMID:26597789

  14. A Preclinical Model of Inflammatory Breast Cancer to Study the Involvement of CXCR4 and ACKR3 in the Metastatic Process

    Roberto Wurth; Kevin Tarn; Danielle Jernigan; Fernandez, Sandra V.; Massimo Cristofanilli; Alessandro Fatatis; Olimpia Meucci

    2015-01-01

    Inflammatory breast cancer (IBC) is an aggressive and invasive tumor, accounting for 2.5% of all breast cancer cases, and characterized by rapid progression, regional and distant metastases, younger age of onset, and lower overall survival. Presently, there are no effective therapies against IBC and a paucity of model systems. Our aim was to develop a clinically relevant IBC model that would allow investigations on the role of chemokine receptors in IBC metastasis. Primary cultures of tumor c...

  15. Development and validation of brain and spinal cord vector and cell-delivery techniques in pre-clinical minipig models of neurodegenerative disorders

    Juhás, Štefan; Juhásová, Jana; Klíma, Jiří; Maršala, M.; Maršala, S.; Atsushi, Y.; Johe, K.; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 9-10. ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : minipig models of neurodegenerative disorders * brin and spinal cord cell delivery techniques Subject RIV: EB - Genetics ; Molecular Biology

  16. Multimodal imaging of bone metastases: From preclinical to clinical applications

    Stephan Ellmann

    2015-10-01

    Full Text Available Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

  17. Child abuse - physical

    ... this page: //medlineplus.gov/ency/article/001552.htm Child abuse - physical To use the sharing features on this page, please enable JavaScript. Physical child abuse is a serious problem. Here are some facts: ...

  18. Alcoholism and Alcohol Abuse

    ... their drinking causes distress and harm. It includes alcoholism and alcohol abuse. Alcoholism, or alcohol dependence, is a disease that causes ... groups. NIH: National Institute on Alcohol Abuse and Alcoholism

  19. Who Owns Child Abuse?

    Gerald Cradock

    2014-11-01

    Full Text Available Expectations of contemporary child protection apparatuses are strongly influenced by beliefs inherited from the nineteenth century child rescue movement. In particular, the belief that child abuse determination is obvious. However, this assumption fails to make a distinction between nineteenth century’s emphasis on impoverished environments and the twentieth century introduction of the pathological child abuser. Moreover, the proliferation of kinds of child abuse, and the need to distinguish child abusers from non-abusers, means knowledge is now spread across an array of disciplines and professions, which necessarily destabilizes the definition of child abuse. The increasing exposure of alternate care systems as potentially abusive has similarly destabilized the old common sense solution to neglected children—namely removal. Finally, as uncertainty increases, and definitions become more divergent, the question of what child abuse is, and what should be done about it, becomes increasingly politicized.

  20. Prescription Drug Abuse

    ... what the doctor prescribed, it is called prescription drug abuse. It could be Taking a medicine that ... purpose, such as getting high Abusing some prescription drugs can lead to addiction. These include narcotic painkillers, ...

  1. Abuse during Pregnancy

    ... partner may try to hurt your body. This physical abuse can include hitting, slapping, kicking, choking, pushing or ... your unborn baby in grave danger. During pregnancy, physical abuse can lead to miscarriage and vaginal bleeding . It ...

  2. Prescription Drug Abuse

    ... a drug abuser aggressive or paranoid. Although stimulant abuse might not lead to physical dependence and withdrawal, the feelings these drugs give people can cause them to use the drugs more and more ...

  3. Spatial Navigation in Preclinical Alzheimer's Disease.

    Allison, Samantha L; Fagan, Anne M; Morris, John C; Head, Denise

    2016-02-01

    Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID:26967209

  4. A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies.

    Ngen, Ethel J; Wang, Lee; Gandhi, Nishant; Kato, Yoshinori; Armour, Michael; Zhu, Wenlian; Wong, John; Gabrielson, Kathleen L; Artemov, Dmitri

    2016-06-01

    Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term. PMID:27021492

  5. Drug and Substance Abuse

    ... are common in later life. The Most Common Types of Drug and Substance Abuse Prescription and Over-the-Counter Medications Abuse Among ... older population than in younger people. But, other types of substance abuse, such as inappropriate use of prescription and over- ...

  6. Child Abuse and Neglect

    Yaşar Tıraşçı; Süleyman Gören

    2007-01-01

    Child abuse is the physical or psychological maltreatment of a child by an adult. In recent years, the affinity and aware of child abuse have been increased in Turkey. But, it is not enough. The purpose of this article was to defined child abuse and to attract attention of population and medical worker.

  7. Preventing Child Abuse

    Alvy, Kerby T.

    1975-01-01

    Focuses on two major and general approaches to analyzing the problems of child abuse; briefly discusses the prevention implications; deals with the individual physical abuse of children, with particular emphasis on the relationship between theoretical formulations of the causes of individual physical abuse and preventative programs; and, finally,…

  8. A Preclinical Model for ERα-Positive Breast Cancer Points to the Epithelial Microenvironment as Determinant of Luminal Phenotype and Hormone Response.

    Sflomos, George; Dormoy, Valerian; Metsalu, Tauno; Jeitziner, Rachel; Battista, Laura; Scabia, Valentina; Raffoul, Wassim; Delaloye, Jean-Francois; Treboux, Assya; Fiche, Maryse; Vilo, Jaak; Ayyanan, Ayyakkannu; Brisken, Cathrin

    2016-03-14

    Seventy-five percent of breast cancers are estrogen receptor α positive (ER(+)). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER(+) tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER(+) tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER(+) PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis. PMID:26947176

  9. Successful Regional Delivery and Long-term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies

    Wang, Zejing; Storb, Rainer; Halbert, Christine L.; Banks, Glen B.; Butts, Tiffany M.; Finn, Eric E.; Allen, James M.; Miller, A. Dusty; Jeffrey S. Chamberlain; Tapscott, Stephen J.

    2012-01-01

    Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a ...

  10. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

    Weir, Hazel M; Bradbury, Robert H; Lawson, Mandy; Rabow, Alfred A; Buttar, David; Callis, Rowena J; Curwen, Jon O; de Almeida, Camila; Ballard, Peter; Hulse, Michael; Donald, Craig S; Feron, Lyman J L; Karoutchi, Galith; MacFaul, Philip; Moss, Thomas; Norman, Richard A; Pearson, Stuart E; Tonge, Michael; Davies, Gareth; Walker, Graeme E; Wilson, Zena; Rowlinson, Rachel; Powell, Steve; Sadler, Claire; Richmond, Graham; Ladd, Brendon; Pazolli, Ermira; Mazzola, Anne Marie; D'Cruz, Celina; De Savi, Chris

    2016-06-01

    Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR. PMID:27020862

  11. 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

    2014-01-01

    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 disor...

  12. New Therapy of Skin Repair Combining Adipose-Derived Mesenchymal Stem Cells with Sodium Carboxymethylcellulose Scaffold in a Pre-Clinical Rat Model

    Cristiano Rodrigues; de Assis, Adriano M.; Moura, Dinara J.; Graziele Halmenschlager; Jenifer Saffi; Léder Leal Xavier; Marilda da Cruz Fernandes; Márcia Rosângela Wink

    2014-01-01

    Lesions with great loss of skin and extensive burns are usually treated with heterologous skin grafts, which may lead rejection. Cell therapy with mesenchymal stem cells is arising as a new proposal to accelerate the healing process. We tested a new therapy consisting of sodium carboxymethylcellulose (CMC) as a biomaterial, in combination with adipose-derived stem cells (ADSCs), to treat skin lesions in an in vivo rat model. This biomaterial did not affect membrane viability and induced a sma...

  13. Structured Illumination Microscopy and a Quantitative Image Analysis for the Detection of Positive Margins in a Pre-Clinical Genetically Engineered Mouse Model of Sarcoma.

    Fu, Henry L; Mueller, Jenna L; Whitley, Melodi J; Cardona, Diana M; Willett, Rebecca M; Kirsch, David G; Brown, J Quincy; Ramanujam, Nimmi

    2016-01-01

    Intraoperative assessment of surgical margins is critical to ensuring residual tumor does not remain in a patient. Previously, we developed a fluorescence structured illumination microscope (SIM) system with a single-shot field of view (FOV) of 2.1 × 1.6 mm (3.4 mm2) and sub-cellular resolution (4.4 μm). The goal of this study was to test the utility of this technology for the detection of residual disease in a genetically engineered mouse model of sarcoma. Primary soft tissue sarcomas were generated in the hindlimb and after the tumor was surgically removed, the relevant margin was stained with acridine orange (AO), a vital stain that brightly stains cell nuclei and fibrous tissues. The tissues were imaged with the SIM system with the primary goal of visualizing fluorescent features from tumor nuclei. Given the heterogeneity of the background tissue (presence of adipose tissue and muscle), an algorithm known as maximally stable extremal regions (MSER) was optimized and applied to the images to specifically segment nuclear features. A logistic regression model was used to classify a tissue site as positive or negative by calculating area fraction and shape of the segmented features that were present and the resulting receiver operator curve (ROC) was generated by varying the probability threshold. Based on the ROC curves, the model was able to classify tumor and normal tissue with 77% sensitivity and 81% specificity (Youden's index). For an unbiased measure of the model performance, it was applied to a separate validation dataset that resulted in 73% sensitivity and 80% specificity. When this approach was applied to representative whole margins, for a tumor probability threshold of 50%, only 1.2% of all regions from the negative margin exceeded this threshold, while over 14.8% of all regions from the positive margin exceeded this threshold. PMID:26799613

  14. Structured Illumination Microscopy and a Quantitative Image Analysis for the Detection of Positive Margins in a Pre-Clinical Genetically Engineered Mouse Model of Sarcoma.

    Henry L Fu

    Full Text Available Intraoperative assessment of surgical margins is critical to ensuring residual tumor does not remain in a patient. Previously, we developed a fluorescence structured illumination microscope (SIM system with a single-shot field of view (FOV of 2.1 × 1.6 mm (3.4 mm2 and sub-cellular resolution (4.4 μm. The goal of this study was to test the utility of this technology for the detection of residual disease in a genetically engineered mouse model of sarcoma. Primary soft tissue sarcomas were generated in the hindlimb and after the tumor was surgically removed, the relevant margin was stained with acridine orange (AO, a vital stain that brightly stains cell nuclei and fibrous tissues. The tissues were imaged with the SIM system with the primary goal of visualizing fluorescent features from tumor nuclei. Given the heterogeneity of the background tissue (presence of adipose tissue and muscle, an algorithm known as maximally stable extremal regions (MSER was optimized and applied to the images to specifically segment nuclear features. A logistic regression model was used to classify a tissue site as positive or negative by calculating area fraction and shape of the segmented features that were present and the resulting receiver operator curve (ROC was generated by varying the probability threshold. Based on the ROC curves, the model was able to classify tumor and normal tissue with 77% sensitivity and 81% specificity (Youden's index. For an unbiased measure of the model performance, it was applied to a separate validation dataset that resulted in 73% sensitivity and 80% specificity. When this approach was applied to representative whole margins, for a tumor probability threshold of 50%, only 1.2% of all regions from the negative margin exceeded this threshold, while over 14.8% of all regions from the positive margin exceeded this threshold.

  15. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

    Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations

  16. The utility of rhesus monkey (Macaca mulatta and other non-human primate models for preclinical testing of Leishmania candidate vaccines

    Gabriel Grimaldi Jr

    2008-11-01

    Full Text Available Leishmaniasis causes significant morbidity and mortality, constituting an important global health problem for which there are few effective drugs. Given the urgent need to identify a safe and effective Leishmania vaccine to help prevent the two million new cases of human leishmaniasis worldwide each year, all reasonable efforts to achieve this goal should be made. This includes the use of animal models that are as close to leishmanial infection in humans as is practical and feasible. Old world monkey species (macaques, baboons, mandrills etc. have the closest evolutionary relatedness to humans among the approachable animal models. The Asian rhesus macaques (Macaca mulatta are quite susceptible to leishmanial infection, develop a human-like disease, exhibit antibodies to Leishmania and parasite-specific T-cell mediated immune responses both in vivo and in vitro, and can be protected effectively by vaccination. Results from macaque vaccine studies could also prove useful in guiding the design of human vaccine trials. This review summarizes our current knowledge on this topic and proposes potential approaches that may result in the more effective use of the macaque model to maximize its potential to help the development of an effective vaccine for human leishmaniasis.

  17. Xeno-Free and Defined Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells Functionally Integrate in a Large-Eyed Preclinical Model

    Alvaro Plaza Reyes

    2016-01-01

    Full Text Available Human embryonic stem cell (hESC-derived retinal pigment epithelial (RPE cells could replace lost tissue in geographic atrophy (GA but efficacy has yet to be demonstrated in a large-eyed model. Also, production of hESC-RPE has not yet been achieved in a xeno-free and defined manner, which is critical for clinical compliance and reduced immunogenicity. Here we describe an effective differentiation methodology using human laminin-521 matrix with xeno-free and defined medium. Differentiated cells exhibited characteristics of native RPE including morphology, pigmentation, marker expression, monolayer integrity, and polarization together with phagocytic activity. Furthermore, we established a large-eyed GA model that allowed in vivo imaging of hESC-RPE and host retina. Cells transplanted in suspension showed long-term integration and formed polarized monolayers exhibiting phagocytic and photoreceptor rescue capacity. We have developed a xeno-free and defined hESC-RPE differentiation method and present evidence of functional integration of clinically compliant hESC-RPE in a large-eyed disease model.

  18. Pre-clinical evaluation of soybean-based wound dressings and dermal substitute formulations in pig healing and non-healing in vivo models

    Rostislav V Shevchenko

    2014-10-01

    Full Text Available In the last decade, a new class of natural biomaterials derived from de-fatted soybean flour processed by either thermoset or extraction procedures has been developed. These biomaterials uniquely combine adaptability to various clinical applications to proven tissue regeneration properties. In the present work, the biomaterials were formulated either as hydrogel or as paste formulation and their potential as wound dressing material or as dermal substitute was assessed by two in vivo models in pig skin: The healing full-thickness punch biopsy model and the non-healing full-thickness polytetrafluoroethylene (PTFE chamber model. The results clearly show that collagen deposition is induced by the presence of these biomaterials. A unique pattern of early inflammatory response, eliciting neutrophils and controlling macrophage infiltration, is followed by tissue cell colonization of the wound bed with a significant deposition of collagen fibers. The study also highlighted the importance in the use of optimal formulations and appropriate handling upon implantation. In large size, non-healing wounds, wound dermis was best obtained with the paste formulation as hydrogels appeared to be too loose to ensure lasting scaffolding properties. On the contrary, packing of the granules during the application of paste reduced biomaterial degradation rate and prevent the penetration of newly vascularized tissue, thus impeding grafting of split-thickness autologous skin grafts on the dermal substitute base.

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

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

    2016-01-01

    Objectives: To evaluate the effect of learning styles and study behaviors on preclinical medical students′ pharmacology exam scores in a non-Western setting. Materials and Methods: Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on ph...

  20. PRECLINICAL DRUG TRIALS IN THE mdx MOUSE: ASSESSMENT OF RELIABLE AND SENSITIVE OUTCOME MEASURES

    SPURNEY, CHRISTOPHER F.; Gordish-Dressman, Heather; Alfredo D Guerron; Sali, Arpana; Gouri S Pandey; Rawat, Rashmi; van der Meulen, Jack H; Cha, Hee-Jae; Pistilli, Emidio E.; Partridge, Terence A.; Hoffman, Eric P; Nagaraju, Kanneboyina

    2009-01-01

    The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trial...

  1. Preclinical Evaluation of Hepatoprotective Activity of Ocimum basilicum L. and Allium sativum L.

    Deodelsy Bermúdez Toledo:; María Boffill Cárdenas; Emoe Betancourt Morgado; Raylen Escobar Román; Ignacio Igualada Correa; Bennia Alonso Cárdenas

    2014-01-01

    Background: finding natural treatments designed to protect the liver from the damaging effects of hepatotoxins is an important topic in medical and pharmaceutical research. Objective: to pre-clinically evaluate the hepatoprotective activity of the species Ocimum basilicum L. and Allium sativum L. in an animal model of acetaminophen-induced toxicity. Methods: a preclinical pharmacological study was conducted to evaluate the hepatoprotective effect of the species Ocimum basilicum L. and Allium ...

  2. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Michael Halpern

    2010-08-01

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

  3. A neurocognitive model of borderline personality disorder: effects of childhood sexual abuse and relationship to adult social attachment disturbance.

    Minzenberg, Michael J; Poole, John H; Vinogradov, Sophia

    2008-01-01

    Borderline personality disorder (BPD) is a paradigmatic disorder of adult attachment, with high rates of antecedent childhood maltreatment. The neurocognitive correlates of both attachment disturbance and maltreatment are both presently unknown in BPD. This study evaluated whether dimensional adult attachment disturbance in BPD is related to specific neurocognitive deficits, and whether childhood maltreatment is related to these dysfunctions. An outpatient BPD group (n=43) performed nearly 1 SD below a control group (n=26) on short-term recall, executive, and intelligence functions. These deficits were not affected by emotionally charged stimuli. In the BPD group, impaired recall was related to attachment-anxiety, whereas executive dysfunction was related to attachment-avoidance. Abuse history was correlated significantly with executive dysfunction and at a trend level with impaired recall. Neurocognitive deficits and abuse history exhibited both independent and interactive effects on adult attachment disturbance. These results suggest that (a) BPD patients' reactivity in attachment relationships is related to temporal-limbic dysfunction, irrespective of the emotional content of stimuli, (b) BPD patients' avoidance within attachment relationships may be a relational strategy to compensate for the emotional consequences of frontal-executive dysregulation, and (c) childhood abuse may contribute to these neurocognitive deficits but may also exert effects on adult attachment disturbance that is both independent and interacting with neurocognitive dysfunction. PMID:18211741

  4. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.

    Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin P; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T; Zhang, Wentao; Marlowe, Charles K; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T; Dale, Stephanie; Yturralde, Olivia; Matthews, David J; Lamb, Peter; Laird, A Douglas

    2015-04-01

    Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. PMID:25637314

  5. Dual-energy computed tomography for the assessment of early treatment effects of regorafenib in a preclinical tumor model: comparison with dynamic contrast-enhanced CT and conventional contrast-enhanced single-energy CT

    Knobloch, Gesine; Hamm, Bernd [Charite - Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany); Jost, Gregor; Pietsch, Hubertus [Bayer Healthcare, MR and CT Contrast Media Research, Berlin (Germany); Huppertz, Alexander [Imaging Science Institute Charite - Siemens, Berlin (Germany)

    2014-08-15

    The potential diagnostic value of dual-energy computed tomography (DE-CT) compared to dynamic contrast-enhanced CT (DCE-CT) and conventional contrast-enhanced CT (CE-CT) in the assessment of early regorafenib treatment effects was evaluated in a preclinical setting. A rat GS9L glioma model was examined with contrast-enhanced dynamic DE-CT measurements (80 kV/140 kV) for 4 min before and on days 1 and 4 after the start of daily regorafenib or placebo treatment. Tumour time-density curves (0-240 s, 80 kV), DE-CT (60 s) derived iodine maps and the DCE-CT (0-30 s, 80 kV) based parameters blood flow (BF), blood volume (BV) and permeability (PMB) were calculated and compared to conventional CE-CT (60 s, 80 kV). The regorafenib group showed a marked decrease in the tumour time-density curve, a significantly lower iodine concentration and a significantly lower PMB on day 1 and 4 compared to baseline, which was not observed for the placebo group. CE-CT showed a significant decrease in tumour density on day 4 but not on day 1. The DE-CT-derived iodine concentrations correlated with PMB and BV but not with BF. DE-CT allows early treatment monitoring, which correlates with DCE-CT. Superior performance was observed compared to single-energy CE-CT. circle Regorafenib treatment response was evaluated by CT in a rat tumour model. (orig.)

  6. New therapy of skin repair combining adipose-derived mesenchymal stem cells with sodium carboxymethylcellulose scaffold in a pre-clinical rat model.

    Cristiano Rodrigues

    Full Text Available Lesions with great loss of skin and extensive burns are usually treated with heterologous skin grafts, which may lead rejection. Cell therapy with mesenchymal stem cells is arising as a new proposal to accelerate the healing process. We tested a new therapy consisting of sodium carboxymethylcellulose (CMC as a biomaterial, in combination with adipose-derived stem cells (ADSCs, to treat skin lesions in an in vivo rat model. This biomaterial did not affect membrane viability and induced a small and transient genotoxicity, only at the highest concentration tested (40 mg/mL. In a rat wound model, CMC at 10 mg/mL associated with ADSCs increased the rate of cell proliferation of the granulation tissue and epithelium thickness when compared to untreated lesions (Sham, but did not increase collagen fibers nor alter the overall speed of wound closure. Taken together, the results show that the CMC is capable to allow the growth of ADSCs and is safe for this biological application up to the concentration of 20 mg/mL. These findings suggest that CMC is a promising biomaterial to be used in cell therapy.

  7. The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research.

    Langston, Rebekah G; Rudenko, Iakov N; Cookson, Mark R

    2016-02-01

    In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD. PMID:26811536

  8. Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination.

    Jones, Christopher R; Hatley, Oliver J D; Ungell, Anna-Lena; Hilgendorf, Constanze; Peters, Sheila Annie; Rostami-Hodjegan, Amin

    2016-05-01

    Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5'-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination. PMID:26964996

  9. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma.

    Patwardhan, Parag P; Ivy, Kathryn S; Musi, Elgilda; de Stanchina, Elisa; Schwartz, Gary K

    2016-01-26

    Sarcomas are rare but highly aggressive mesenchymal tumors with a median survival of 10-18 months for metastatic disease. Mutation and/or overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. MGCD516 (Sitravatinib) is a novel small molecule inhibitor targeting multiple RTKs involved in driving sarcoma cell growth. In the present study, we evaluated the efficacy of MGCD516 both in vitro and in mouse xenograft models in vivo. MGCD516 treatment resulted in significant blockade of phosphorylation of potential driver RTKs and induced potent anti-proliferative effects in vitro. Furthermore, MGCD516 treatment of tumor xenografts in vivo resulted in significant suppression of tumor growth. Efficacy of MGCD516 was superior to imatinib and crizotinib, two other well-studied multi-kinase inhibitors with overlapping target specificities, both in vitro and in vivo. This is the first report describing MGCD516 as a potent multi-kinase inhibitor in different models of sarcoma, superior to imatinib and crizotinib. Results from this study showing blockade of multiple driver signaling pathways provides a rationale for further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma. PMID:26675259

  10. Inhalant Abuse and Dextromethorphan.

    Storck, Michael; Black, Laura; Liddell, Morgan

    2016-07-01

    Inhalant abuse is the intentional inhalation of a volatile substance for the purpose of achieving an altered mental state. As an important, yet underrecognized form of substance abuse, inhalant abuse crosses all demographic, ethnic, and socioeconomic boundaries, causing significant morbidity and mortality in school-aged and older children. This review presents current perspectives on epidemiology, detection, and clinical challenges of inhalant abuse and offers advice regarding the medical and mental health providers' roles in the prevention and management of this substance abuse problem. Also discussed is the misuse of a specific "over-the-counter" dissociative, dextromethorphan. PMID:27338970

  11. Child Abuse in India

    Mohammad Reza Iravani

    2011-01-01

    Child abuse is harm to, or neglect of, a child by another person, whether adult or child. Child abuse happens in all cultural, ethnic, and income groups. Child abuse can be physical, emotional - verbal, sexual or through neglect. Abuse may cause serious injury to the child and may even result in death. A problem that is only beginning to come into light in India rape, sexual abuse, and sexual harassment are worldwide issues of gender violence. There is very little research done in this area i...

  12. Collaborative pre-competitive preclinical drug discovery with academics and pharma/biotech partners at Sanford|Burnham: infrastructure, capabilities & operational models.

    Chung, Thomas D Y

    2014-03-01

    There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> $1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core

  13. A 3-month preclinical trial to assess the performance of a new TVT-like mesh (TVTx) in a sheep model.

    Rezapour, Masoumeh; Novara, Giacomo; Meier, Peter A; Holste, Joerg; Landgrebe, Susanne; Artibani, Walter

    2007-02-01

    The objective of this study was to evaluate in a sheep model the performance of a new polypropylene mesh (TVTx), which is intended as a less invasive treatment for female stress urinary incontinence. Eight female sheep were used in this study, each one being implanted with eight TVTx samples. At each time-point (weeks 1, 2, 4, and 12) seven TVTx were pulled out, while one TVTx was carefully dissected for histological investigations. One TVTx and one TVT, moreover, were inserted and immediately pulled out for obtaining the initial pullout forces in all sheep. The initial pullout values of TVT and TVTx were overlapping. The pullout forces of TVTx were >5 N (500 g) and increasing from weeks 1 to 12 (p<0.001). Histology revealed good tissue integration of TVTx in the tissue within 12 weeks after implantation. No abnormal histological findings were observed. This data could support the realization of a clinical trial with the TVTx mesh. PMID:16628374

  14. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model.

    Ferreira, Adilson Kleber; Tavares, Maurício Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-Sá-Junior, Paulo Luiz; Barbuto, José Alexandre Marzagão; Figueiredo, Carlos Rogério; Cury, Yara; Damião, Mariana Celestina Frojuello Costa Bernstorff; Parise-Filho, Roberto

    2015-09-01

    Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analogue of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthetized, and molecular modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis, by flow cytometry, and Western blot analysis of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The production of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico analysis corroborated the biological findings, showing that RPF151 has physicochemical improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy. PMID:25894379

  15. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Chattopadhyay, Nibedita; Berger, Allison J; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition. PMID:26709701

  16. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Nibedita Chattopadhyay

    Full Text Available In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  17. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism

    Chattopadhyay, Nibedita; Berger, Allison J.; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition. PMID:26709701

  18. 188Re-HTDD-lipiodol solution as a new therapeutic agent for transhepatic arterial administration in liver cancer: a preclinical study using liver-cancer model in rabbit

    188Re-HTDD-lipiodol solution was developed and reported to be a new therapeutic material for transhepatic arterial embolization (TAE) of liver cancer. In this study we compared the tissue retention of 188Re-HTDD-lipiodol with that of 188Re-TDD-lipiodol using liver-cancer model in rabbit. Cancer cell line VX2 was inoculated into 7 rabbits and grown up to larger than 3 cm. TAE was performed with 188Re-TDD-lipiodol in 3 rabbits and with 188Re-HTDD-lipiodol in 4 rabbits. Conjugated planar scans were performed at 1, 2, 6, 24, 48 hours after TAE. From these images, the mean life of radioactivity retention in tumor was calculated, and the required dose for human application as also calculated from the mean life and MIRDOSE3 software. The mean lifes of radioactivity in liver were 10.2±1.0 hr in TDD group and 17.6±0.8 hr in HTDD group (p188Re-HTDD-lipiodol for 5.7 cm-sized tumor and 88 mCi for 9,7 cm-sized tumor. By the introduction of long chain alkyl group, 188Re-HTDD-lipiodol showed significantly better tumor retention than that of 188Re-TDD-lipiodol. And the required dose of radiation for human application was calculated to be 18 ∼ 88 mCi when using 188Re-HTDD-lipiodol

  19. The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer

    Ball Richard Y

    2010-07-01

    Full Text Available Abstract Background Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue. Results We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing. Conclusion To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.

  20. Vitamin D for combination photodynamic therapy of skin cancer in individuals with vitamin D deficiency: Insights from a preclinical study in a mouse model of squamous cell carcinoma

    Anand, Sanjay; Thomas, Erik; Hasan, Tayyaba; Maytin, Edward V.

    2016-03-01

    Combination photodynamic therapy (cPDT) in which vitamin D (VD) is given prior to aminolevulinate, a precursor (pro-drug) for protoporphyrin IX (PpIX), is an approach developed in our laboratory. We previously showed that 1α,25- dihydroxyvitamin D3 (calcitriol), given prior to PDT, enhances accumulation of PpIX and improves cell death post-PDT in a mouse skin cancer model. However, since calcitriol poses a risk for hypercalcemia, we replaced systemic calcitriol with oral cholecalciferol (D3), administered as a high (tenfold, "10K") diet over a ten-day period. Here, we ask whether VD deficiency might alter the response to cPDT. Nude mice were fed a VD-deficient diet for at least 4 weeks ("deficient"); controls were fed a normal 1,000 IU/kg diet ("1K"). Human A431 cells were implanted subcutaneously and mice were switched to the 10K diet or continued on their baseline diets (controls). In other experiments, mice received a human equivalent dose of 50,000 IU D3 by oral gavage, to simulate administration of a single, high-dose VD pill. At various times, tumors were harvested and serum was collected to measure levels of VD metabolic intermediates. A significant increase in PpIX levels and in the expression of differentiation and proliferation markers in tumor tissue was observed after VD supplementation of both the deficient and 1K mice. Further results describing mechanistic details of PpIX enhancement through alteration of heme- and VD-metabolic enzyme levels will be presented. Based on these results, a clinical study using oral vitamin D prior to PDT for human skin cancer should be performed.

  1. Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.

    Eberlein, Catherine A; Stetson, Daniel; Markovets, Aleksandra A; Al-Kadhimi, Katherine J; Lai, Zhongwu; Fisher, Paul R; Meador, Catherine B; Spitzler, Paula; Ichihara, Eiki; Ross, Sarah J; Ahdesmaki, Miika J; Ahmed, Ambar; Ratcliffe, Laura E; O'Brien, Elizabeth L Christey; Barnes, Claire H; Brown, Henry; Smith, Paul D; Dry, Jonathan R; Beran, Garry; Thress, Kenneth S; Dougherty, Brian; Pao, William; Cross, Darren A E

    2015-06-15

    Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. PMID:25870145

  2. Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models

    Eberlein, Catherine A.; Stetson, Daniel; Markovets, Aleksandra A.; Al-Kadhimi, Katherine J.; Lai, Zhongwu; Fisher, Paul R.; Meador, Catherine B.; Spitzler, Paula; Ichihara, Eiki; Ross, Sarah J.; Ahdesmaki, Miika J.; Ahmed, Ambar; Ratcliffe, Laura E.; Christey O’Brien, Elizabeth L.; Barnes, Claire H.; Brown, Henry; Smith, Paul D.; Dry, Jonathan R.; Beran, Garry; Thress, Kenneth S.; Dougherty, Brian; Pao, William; Cross, Darren A. E.

    2015-01-01

    Resistance to targeted EGFR inhibitors is likely to develop in EGFR mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR TKIs including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002 or AZD9291. Compared to parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumours in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumours. Further, these findings suggest that NRAS modifications in tumour samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. PMID:25870145

  3. Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model.

    Bousserouel, Souad; Le Grandois, Julie; Gossé, Francine; Werner, Dalal; Barth, Stephan W; Marchioni, Eric; Marescaux, Jacques; Raul, Francis

    2013-08-01

    Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 µg/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 µg/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp-treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death‑receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID:23754197

  4. Psychological Sequelae of Childhood Sexual Abuse: Abuse-Related Characteristics, Coping Strategies, and Attributional Style

    Steel, Jennifer; Sanna, Lawrence; Hammond, Barbara; Whipple, James; Cross, Herbert

    2004-01-01

    Objective: The aim of this study was to test a model predicting the contribution of abuse-related characteristics and mediating variables such as coping and attributional style in the development of psychological sequelae in adults reporting a history of child sexual abuse (CSA). Methodology: Two hundred and eighty-five males and females from…

  5. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

    Ferrari Stefano

    2009-12-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

  6. Multi-disciplinary data organization and visualization models for clinical and pre-clinical studies: A case study in the application of proton beam radiosurgery for treating spinal cord injury related pain

    Verma, Sneha K.; Liu, Brent J.

    2016-03-01

    An increasing adoption of electronic medical records has made information more accessible to clinicians and researchers through dedicated systems such as HIS, RIS and PACS. The speed and the amount at which information are generated in a multi-institutional clinical study make the problem complicated compared to day-to-day hospital workflow. Often, increased access to the information does not translate into the efficient use of that information. Therefore, it becomes crucial to establish models which can be used to organize and visualize multi-disciplinary data. Good visualization in turn makes it easy for clinical decision-makers to reach a conclusion within a small span of time. In a clinical study involving multi-disciplinary data and multiple user groups who need access to the same data and presentation states based on the stage of the clinical trial or the task are crucial within the workflow. Therefore, in order to demonstrate the conceptual system design and system workflow, we will be presenting a clinical trial based on application of proton beam for radiosurgery which will utilize our proposed system. For demonstrating user role and visualization design purposes, we will be focusing on three different user groups which are researchers involved in patient enrollment and recruitment, clinicians involved in treatment and imaging review and lastly the principle investigators involved in monitoring progress of clinical study. Also datasets for each phase of the clinical study including preclinical and clinical data as it related to subject enrollment, subject recruitment (classifier), treatment (DICOM), imaging, and pathological analysis (protein staining) of outcomes.

  7. Relationships between preclinical course grades and standardized exam performance.

    Hu, Yinin; Martindale, James R; LeGallo, Robin D; White, Casey B; McGahren, Eugene D; Schroen, Anneke T

    2016-05-01

    Success in residency matching is largely contingent upon standardized exam scores. Identifying predictors of standardized exam performance could promote primary intervention and lead to design insights for preclinical courses. We hypothesized that clinically relevant courses with an emphasis on higher-order cognitive understanding are most strongly associated with performance on United States Medical Licensing Examination Step exams and National Board of Medical Examiners clinical subject exams. Academic data from students between 2007 and 2012 were collected. Preclinical course scores and standardized exam scores were used for statistical modeling with multiple linear regression. Preclinical courses were categorized as having either a basic science or a clinical knowledge focus. Medical College Admissions Test scores were included as an additional predictive variable. The study sample comprised 795 graduating medical students. Median score on Step 1 was 234 (interquartile range 219-245.5), and 10.2 % (81/795) scored lower than one standard deviation below the national average (205). Pathology course score was the strongest predictor of performance on all clinical subject exams and Step exams, outperforming the Medical College Admissions Test in strength of association. Using Pathology score risk stratifiers. PMID:26363626

  8. Personal constructs, childhood sexual abuse and revictimization.

    Freshwater, Kate; Leach, Chris; Aldridge, Jan

    2001-09-01

    Within the theoretical framework of Ryle's Procedural Sequence Object Relations Model and Kelly's Personal Construct Theory, this study investigates sex-role polarization of incest survivors and the centrality of abuse within survivors' constructs of men that may contribute to revictimization. Repertory grid methodology was used with 40 female survivors of childhood sexual abuse and 28 non-abused women. Grid measures and psychometric measures were compared between groups of women who had and had not experienced childhood sexual abuse, revictimized and non-revictimized survivors, and survivors who had and had not experienced incestuous abuse. Results showed significant differences between survivors and non-abused women, with survivors having higher levels of depression and perceived distress, lower self-esteem and higher self/ideal self discrepancy. Hypothesized differences in sex-role polarization were not found. There were few differences between revictimized and non-revictimized survivors, although revictimized survivors rated 'self now' as more powerful than non-revictimized survivors. No differences were found between survivors who had and had not experienced incestuous abuse. In addition to the value of exploring personal constructs, a range of models need to be considered in understanding revictimization and women's construal of men. The implications of using repertory grid methodology for research and clinical work are discussed. PMID:11802849

  9. Preclinical Models of Encephalopathy of Prematurity

    Jantzie, Lauren L.; Robinson, Shenandoah

    2015-01-01

    Encephalopathy of prematurity (EoP) encompasses the central nervous system (CNS) abnormalities associated with injury from preterm birth. Although rapid progress is being made, limited understanding exists of how the cellular and molecular CNS injury from early birth manifests as the myriad of neurological deficits in children who are born preterm. More importantly, this lack of direct insight into the pathogenesis of these deficits hinders both our ability to diagnose those infants who are a...

  10. Preclinical and human surrogate models of itch

    Hoeck, Emil August; Marker, Jens Broch; Gazerani, Parisa;

    2016-01-01

    Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch, are...

  11. Pharmacological enhancement of fear reduction: preclinical models

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

    2011-01-01

    Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit...

  12. The Economics of Reproducibility in Preclinical Research.

    Leonard P Freedman

    2015-06-01

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

  13. Maltreated and abused children

    HOUFOVÁ, Jana

    2011-01-01

    According to the statistics there are forty thousand of battered and abused children in the Czech Republic. Maltreatment and abuse are not revealed in most cases and thus they accompany the children during their whole childhood. The reason is that children cannot defend themselves. The maltreatment or the abuse of a child is revealed only if somebody from the child?s neighbourhood observes anything suspicious and decides to report it, which is both a moral and a legal obligation. A person, wh...

  14. Who Owns Child Abuse?

    Gerald Cradock

    2014-01-01

    Expectations of contemporary child protection apparatuses are strongly influenced by beliefs inherited from the nineteenth century child rescue movement. In particular, the belief that child abuse determination is obvious. However, this assumption fails to make a distinction between nineteenth century’s emphasis on impoverished environments and the twentieth century introduction of the pathological child abuser. Moreover, the proliferation of kinds of child abuse, and the need to distinguis...

  15. Child abuse and neglect

    Kiran, K

    2011-01-01

    Child abuse and neglect are important public health problems and recent estimates of their prevalence suggest that they are considerably more common than had hitherto been realized. Intervening to change parenting practices may, however, be important in their treatment. Despite their frequent occurrence among dental patients, neglect is the least known and identified type of abuse. The present case reports a 3-year-old girl suffering from abuse and neglect. The girl had dental neglect and als...

  16. SUBSTANCE ABUSE IN INDIA

    Bano Rubeena

    2009-12-01

    Full Text Available The epidemic of substance abuse in young generation has assumed alarming dimensions in India. Changing cultural values, increasing economic stress and dwindling supportive bonds are leading to initiation into substance use. Cannabis, heroin, and Indian-produced pharmaceutical drugs are the most frequently abused drugs in India. Drug use, misuse or abuse is also primarily due to the nature of the drug abused, the personality of the individual and the addict’s immediate environment. The processes of industrialization, urbanization and migration have led to loosening of the traditional methods of social control rendering an individual vulnerable to the stresses and strains of modern life.

  17. Child Sexual Abuse

    HROBAŘOVÁ, Petra

    2008-01-01

    My thesis deals with the problems of sexual abuse of children. It is divided into nine chapters, each of which has a subhead. In the first part, I focused on the term of child sexual abuse. In the second part, I focused on the problem of sexual abuse of children by family members. In the third part, I explained the term of commercial sexual violence committed against children. In the fourth part, I focused on the victims of sexual abuse and in the following part, I focused on the perpetrators...

  18. Elder Abuse and Neglect

    Muge Gulen

    2013-06-01

    Full Text Available Abuse and neglect are preventable societal problems that influence elderly individuals physically, spiritually and socially. Elder abuse is neglected for many years and is a growing problem all over the world. The aim of this article is to review the evaluation of elderly individuals who are exposed to abuse and neglect with systematic detailed history and physical examination and to describe individual, familial, and social measures that should be taken to prevent these abuses. [Archives Medical Review Journal 2013; 22(3.000: 393-407

  19. Substance Abuse in the Military

    ... DrugFacts » Substance Abuse in the Military DrugFacts: Substance Abuse in the Military Email Facebook Twitter Revised March ... alcohol and tobacco use, and especially prescription drug abuse, are much more prevalent and are on the ...

  20. The Idealized Cultural Identities Model on Help-Seeking and Child Sexual Abuse: A Conceptual Model for Contextualizing Perceptions and Experiences of South Asian Americans

    Kanukollu, Shanta N.; Mahalingam, Ramaswami

    2011-01-01

    In this paper, we propose an interdisciplinary framework to study perceptions of child sexual abuse and help-seeking among South Asians living in the United States. We integrate research on social marginality, intersectionality, and cultural psychology to understand how marginalized social experience accentuates South Asian immigrants' desire to…

  1. Preclinical Studies for Cartilage Repair

    Hurtig, Mark B.; Buschmann, Michael D; Fortier, Lisa A; Hoemann, Caroline D; Hunziker, Ernst B.; Jurvelin, Jukka S.; Mainil-Varlet, Pierre; McIlwraith, C. Wayne; Sah, Robert L.; Whiteside, Robert A.

    2011-01-01

    Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral...

  2. Ethical Considerations of Preclinical Testing

    Goldenthal, Allen

    2015-01-01

    The numbers of animal tests being conducted are on a sharp incline. Much of this increase is directly due to our ability to generate transgenic models and knock-outs, thereby increasing the validity of the animal model but not necessarily correlating directly with any translational medical benefits to the human counterpart. In spite of our best efforts, there still exist species differences that prevent the application directly from animal to human, and in some examples having a completely di...

  3. Sexual abuse in children - what to know

    Sexual abuse - children ... boys are sexually abused before they turn 18. Sexual abuse of children is any activity that the abuser ... anus or vagina Tongue kissing Oral sex Intercourse Sexual abuse can also happen without physical contact, such as: ...

  4. Adolescent Substance Abuse.

    Thorne, Craig R.; DeBlassie, Richard R.

    1985-01-01

    Cummings (1979), citing evidence from the National Institute of Drug Abuse, reports that one of every eleven adult Americans suffers from a severe addictive problem. Drug addiction is epidemic among teenagers; one of every six teenagers suffers from a severe addictive problem. This paper focuses on adolescent drug/substance abuse. (Author)

  5. Special Issue: Substance Abuse.

    Fuhrmann, Barbara S., Ed.; Washington, Craig S., Ed.

    1984-01-01

    Presents ten articles about substance abuse: its effects, consequences, and strategies for intervention. Describes specific group therapy techniques and presents both a court service designed for assisting juveniles with drug/alcohol offenses, and a school-based substance abuse prevention program. Looks at strategies for counseling special…

  6. Battling Sexual Abuse

    Dessoff, Alan

    2010-01-01

    From costly lawsuits on behalf of victims to negative media coverage, districts can face potentially devastating consequences as a result of sexual abuse of their students by district employees. This article offers a few tips on how to battle sexual abuse particularly in school districts. The author stresses that by adopting strong policies that…

  7. Child Sexual Abuse

    ... example, by a friend, neighbor, child care person, teacher, or stranger. When sexual abuse has occurred, a child can develop many distressing ... t tell children to 'always do everything the teacher or baby-sitter tells you to ... of guilt about the abuse, and begin the process of overcoming the trauma. ...

  8. Preclinical research in cardiac repair

    Jansen of Lorkeers, S.J.

    2015-01-01

    In medical research, animal models serve as surrogates for human disease which has both advantages and disadvantages. Importantly, it prevents human suffering. Further advantages are mainly financial, since animal studies are cheaper and less time consuming than clinical research and logistical, sin

  9. The Role of Domestic Abuse in Labor and Marriage Markets

    Bowlus, Audra J.; Shannon N. Seitz

    1998-01-01

    In this paper we study the effects of abusive behavior on the labor force andmarital status decisions of women. Using a unique Canadian data set on domestic violence, we estimate the effects of abuse on the marital history as well as current employment using a sequential, multi-state model. In our model, spousal abuse affects labor supply through decreases in utility from leisure as well as through reductions in productivity at work and hence the market wage. Inaddition, abuse is treated as a...

  10. Preclinical research in cardiac repair

    Jansen of Lorkeers, S. J.

    2015-01-01

    In medical research, animal models serve as surrogates for human disease which has both advantages and disadvantages. Importantly, it prevents human suffering. Further advantages are mainly financial, since animal studies are cheaper and less time consuming than clinical research and logistical, since animals are more easily accessible compared to healthy volunteers or patients. Also, the (genetic) propinquity of animals, diminishes the ‘noise’ within one study leading to a decline in the num...

  11. Optimized design and analysis of preclinical intervention studies in vivo.

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

    2016-01-01

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

  12. Preclinical tools in PET-tracer development : automatisation and biopharmaceutical evaluation with special emphasis on the adenosine A3 receptor

    Positron Emission Tomography (PET) is the first choice technology for the visualization and quantification of receptors and transporters, enabling examination of e.g. neurological, psychiatric and oncological diseases on a molecular level. Therefore, new and innovative PET-radiopharmaceuticals need to be developed to get further insights into the biochemical mechanisms involved in pathological changes. PET-tracer development starts with the idea or modelling of the chemical structure of a (new) molecule with (hopefully) good binding characteristics to the desired target site. As next steps, the compound needs to be synthesized and radiolabelled with a suitable PET-nuclide. Then it has to be evaluated regarding its parameters in various preclinical experimental settings. Hence, two major tools are crucial in the development-process of new PET-tracers: 1) a fast and reliable production method, most desirable and optimal in an automated set-up, and 2) proof of tracer suitability (high affinity, high selectivity and specificity, beside low unspecific binding) through preclinical evaluation in an animal model, prior to human application. Both aspects, the radiochemical preparation and automatisation, as well as the biopharmaceutical evaluation are presented in the thesis in 5 different manuscripts. In detail, the development and preclinical evaluation of 4 different PET-tracers ([11C]DASB, [18F]FE SUPPY, [18F]FE SUPPY:2, and [18F]FE CIT) for 3 targets, the serotonin transporter (SERT), the adenosine A3 receptor (A3R) and the dopamine transporter (DAT), respectively, are covered in the present thesis. The first manuscript presents a method for a fast, reliable and fully-automated radiosynthesis of [11C]DASB (a tracer for the imaging of the SERT in human brain in e.g. depression patients) will facilitate further clinical investigations (e.g. for the department of psychiatry and psychotherapy of the medical university of Vienna) with this tracer. [18F]FE SUPPY was

  13. Genetic and biological markers in drug abuse and alcoholism

    Braude, M.C.; Chao, H.M.

    1986-01-01

    This book contains 11 selections. Some of the titles are: Polymorphic Gene Marker Studies; Pharmacogenetic Approaches to the Prediction of Drug Response; Genetic Markers of Drug Abuse in Mouse Models; Genetics as a Tool for Identifying Biological Markers of Drug Abuse; and Studies of an Animal Model of Alcoholism.

  14. A general perspective of alcohol abuse among elderly

    Karanja, Joseph; Lindroos, Linda

    2011-01-01

    This subject was chosen because alcohol abuse among elderly is a growing problem which is hidden and hasn’t been given enough attention. The purpose is to provide essential information about alcohol problems amongst the elderly, theories about causes and based best practices in alcohol problem treatment and rehabilitation. The study is intended to be of help in highlighting a practical help model of treatment for alcohol abusers. Research questions were: Why do elderly abuse alcohol? What are...

  15. Risk and Protection in the Perpetration of Child Abuse

    Dodge, Kenneth A.

    2005-01-01

    Michelle Hughes and her colleagues provide a comprehensive and accurate summary of the literature on predictors of child abuse in this issue of the North Carolina Medical Journal.1 Their review is organized in layers that conform to an ecological model of the factors that lead someone to engage in abuse or neglect of a child. The factors are further organized into risk factors (those that increase the likelihood of abuse) and protective factors (those that buffer a parent from engaging in abu...

  16. Invisible Abuse: Utah's Response to Emotional Child Abuse

    Sirrine, Janae

    2010-01-01

    The very nature of emotional child abuse makes it difficult to detect and report. Nevertheless, scholars and professionals in the field of child welfare have identified emotional abuse as being equally detrimental to children as physical abuse and neglect. Many states, including Utah, have unclear definitions of emotional child abuse. The purpose of this study is to interpret how Utah has used its statute on emotional abuse in the court system and whether the current definition of emotional c...

  17. Child Abuse in India

    Mohammad Reza Iravani

    2011-02-01

    Full Text Available Child abuse is harm to, or neglect of, a child by another person, whether adult or child. Child abuse happens in all cultural, ethnic, and income groups. Child abuse can be physical, emotional - verbal, sexual or through neglect. Abuse may cause serious injury to the child and may even result in death. A problem that is only beginning to come into light in India rape, sexual abuse, and sexual harassment are worldwide issues of gender violence. There is very little research done in this area in India and only a few books have been written, keeping the subject even further from the consciousness of the country. However, the problem persists with staggering incidence, and Indians unique profile adds to the complexity of an already difficult subject. Fortunately, the issue of child sexual abuse is slowly becoming a more recognized issue, and for this reason, this paper will focus much on sexual abuse against minor children: the laws, victims, and perpetrators. Finally, an analysis of the aspects of Indian culture that make this issue particularly difficult to understand and cope with will be presented.

  18. Encountering Child Abuse at Camp.

    Durall, John K.

    1997-01-01

    Defines child abuse, including the three categories: physical, sexual, and psychological. Presents characteristics and behaviors of each type of abuse, and long-term effects. Discusses how to handle abuse that occurs at camp, and the effects on the camp. Sidebars present abuse statistics, 15 activities that promote psychological wellness, and 8…

  19. Child Abuse and Mandated Reporting

    Woika, Shirley; Bowersox, Carissa

    2013-01-01

    Teachers and teachers-in-training are mandated reporters; they are legally required to report any suspected child abuse or neglect. This article describes: (1) How to file a report; (2) How prevalent child abuse is; (3) What abuse is; (4) What it means to be a mandated reporter; (5) When the report should be made; and (6) What to do if abuse is…

  20. Educators, Schools, and Child Abuse.

    Broadhurst, Diane D.

    The booklet provides an overview on the school-related issues involved in child abuse and neglect. Definitions, causes, and effects of abuse and neglect are reviewed in the first chapter; guidelines for identifying physical and sexual abuse, neglect, and emotional maltreatment are offered in chapter 2. Aspects of reporting abuse are noted as are…

  1. Pain and depression comorbidity: a preclinical perspective

    Li, Jun-Xu

    2014-01-01

    Pain and depression are two highly prevalent and deleterious disorders with significant socioeconomic impact to society. Clinical observations have long recognized the co-existence and interactions of pain and depression. However, the underlying mechanisms of pain-depression comorbidity and their dynamic interactions remain largely unknown. Preclinical animal studies may provide critical information for the understanding of this important comorbidity. This review analyzed the current preclini...

  2. Behavioral pharmacology of designer cathinones: a review of the preclinical literature.

    Gregg, Ryan A; Rawls, Scott M

    2014-02-27

    "Bath salts" is one street name for a family of synthetic cathinones that display pharmacological effects resembling cocaine and commonly abused amphetamines. Despite extensive legislation aimed at the criminalization of bath salts, several designer cathinones are gaining a foothold in the illicit drug scene; for example, in the United Kingdom, mephedrone (4-methylmethcathinone, MEPH) is highly popular among drug abusers whereas, in the United States, MDPV (methylenedioxypyrovalerone) and methylone are highly prevalent. To date, knowledge about the hazards of designer cathinones is based mostly on hospital reports and anecdotal evidence derived from online surveys. Despite the paucity of preclinical studies directed toward designer cathinones, a number of invaluable findings arising from those studies are enabling scientists to develop their neuropharmacological profiles. Despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce different behavioral effects, including unique effects on locomotor activity, learning, anxiety, thermoregulation, and abuse liability. The present review will discuss the behavioral effects of MEPH, MDPV, and methylone and compare those effects to established psychostimulant drugs. The rise in the use of designer cathinones in the United States and abroad justifies further investigations into these compounds, both for a greater understanding of the danger that "bath salts" pose to the public, and to provide insight into replacement cathinones as they emerge onto the market. PMID:24231450

  3. Infantile abuse: Radiological diagnosis

    Ana Teresa Araujo Reyes

    2006-08-01

    Full Text Available Infantile abuse is a frequent problem, that must be suspected to bediagnosed, the children victims of infantile abuse can present anytype of injury, nevertheless there are associated injuries common toan inferred trauma that constitute radiological patterns highly specific for abuse, among them are the metafisial injuries, posterior costal fractures and first costal arc fractures, fractures of the toracolumbar region, fractures without apparent explanation, fractures in different stage of evolution, subdural hematoma, subarachnoid hemorrhage, intraparenquimatose contusion and diffuse axonal injury, which combined with the history of the trauma, the age, the development of mental abilities, as well as the mechanism guides the injury diagnose.

  4. Radiosynoviorthesis. Clinical and preclinical dosimetry

    Accurate calculation of internal dose estimates in the Radiosynoviorthesis treatment requires several steps of analysis. The use of animal models (rabbits) to predict human kinetics and dosimetry is an essential first step in the evaluation of new radiocolloids, but involves many uncertainties. There is no gold standard method for extrapolating animal data to humans. Nonetheless, human dose estimates based on animal data are considered to be reasonable approximations to be used for proceeding with dose estimates based on human data, which are ultimately used to assess the safety and efficacy evaluations of radiopharmaceuticals, and continues to be an important element in the radiopharmaceutical approval process. The obtained absorbed dose profiles versus synovial tissue, bone and articular cartilage depth will permit the specialist to prescribe the adequate dose of radionuclide to treat rheumatoid arthritis in medium and large joints without expose the healthy structures of the synovial joint to an excessive and unnecessary irradiation risk, eliminating the fixed dose and fixed radionuclides for each joints (Author)

  5. Animal models of alcohol and drug dependence

    Cleopatra S. Planeta

    2013-01-01

    Full Text Available Drug addiction has serious health and social consequences. In the last 50 years, a wide range of techniques have been developed to model specific aspects of drug-taking behaviors and have greatly contributed to the understanding of the neurobiological basis of drug abuse and addiction. In the last two decades, new models have been proposed in an attempt to capture the more genuine aspects of addiction-like behaviors in laboratory animals. The goal of the present review is to provide an overview of the preclinical procedures used to study drug abuse and dependence and describe recent progress that has been made in studying more specific aspects of addictive behavior in animals.

  6. An integral approach to substance abuse.

    Amodia, Diana S; Cano, Carol; Eliason, Michele J

    2005-12-01

    There is a pressing need in the substance abuse field for more comprehensive models of etiology and treatment that address the complex issues of addiction, including the biological, social, cultural, spiritual and developmental needs of individuals and groups. This article presents a theoretical framework for an integral approach to substance abuse that expands on the existing biopsychosocial model. One contribution of the model is an integrated approach to spirituality from a cross-cultural perspective. This integral approach examines substance abuse etiology and treatment from a four-quadrant perspective adapted from the work of Ken Wilber, and incorporates concepts from integrative medicine and transpersonal psychology/psychiatry. Implications of the model are explored. PMID:16480163

  7. Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer’s disease

    Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K.; Martin, Paul T.

    2013-01-01

    Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting Aβ amyloid may have clinical benefit in Alzheimer’s disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native Aβ amyloid-specific binding peptide, lowers brain Aβ amyloid plaque burden and brain Aβ1-40 and Aβ1-42 peptide levels, improves cognitive learning and memory in Morris Water maze tests and increases the expression of synaptic ...

  8. Domestic Abuse and Child Health

    Rawlings, Samantha; Siddique, Zahra

    2014-01-01

    We examine the effects of different kinds of domestic abuse (physical violence, emotional abuse, sexual abuse and physical violence while the victim is pregnant) on health outcomes of children born to victims. We use data on approximately 0.6 million children born between 1975 and 2013 across thirty different developing countries to investigate this relationship. Comparing children of abused mothers with otherwise similar children whose mothers were not victims of abuse, we find these childre...

  9. Children, contact and domestic abuse

    Morrison, Fiona

    2014-01-01

    In recent years the issue of children’s contact with non-resident parents has been increasingly debated. The policy gaze has focused on contested contact when there are allegations of domestic abuse. Some commentators argue that in circumstances of domestic abuse, contact with an abusive father may not be in the ‘best interests’ of the child. To support these claims they point to evidence that domestic abuse adversely affects children, and domestic abuse often continues followi...

  10. Linking child maltreatment history with child abuse potential: Relative roles of maltreatment types

    Mitkovic-Voncina Marija

    2014-01-01

    Full Text Available The independent roles of each childhood maltreatment type on child abuse potential in adults have been insufficiently explored and are inconsistent, with dissociation as one of the possible suggested mediators of intergenerational child abuse. We investigated these effects among 164 non-clinical adult parents, who filled in general questionnaires: Childhood Trauma Questionnaire (CTQ, Child Abuse Potential Inventory (CAPI and Dissociative Experience Scale (DES. Among all maltreatment types (emotional, physical and sexual abuse, emotional and physical neglect, emotional abuse was the only independent predictor in the regression model of child abuse potential. The relationship between emotional abuse history and child abuse potential was partially mediated by dissociation. The findings could speak in favor of the potentially unique detrimental role of emotional abuse in intergenerational maltreatment, with dissociation as one of the possible mechanisms.

  11. Toxic Knowledge: Self-Alteration Through Child Abuse Work.

    Sigad, Laura I; Davidov, Jonathan; Lev-Wiesel, Rachel; Eisikovits, Zvi

    2016-02-01

    The purpose of the present article is to examine the multiple ways in which the private lives of professionals are affected by involvement with child abuse intervention and prevention. Using a descriptive-phenomenological perspective and 40 in-depth interviews with professionals to present a model based on qualitative data, we studied the ways in which child abuse professionals conceptualize, understand, and integrate their experiences into their personal and family lives. We find that the process of internalizing child abuse knowledge occurs in two domains: One affirms or denies the existence of the phenomenon; the other concerns the strategies used to contend with the effects of working in abuse. Knowledge of child abuse is toxic, in the sense that it serves as a catalyst leading to the alteration of one's self-perception and parental identity. We present a typology of self-alteration resulting from child abuse knowledge and describe the mechanism of this change. PMID:25381277

  12. Sexual Abuse of Children.

    Csapo, Marg

    1988-01-01

    Canadian reports and legislation are reviewed to highlight the school's role in prevention and reporting of suspicions of child sexual abuse. The vulnerability of handicapped children and child pornography are two areas of victimization emphasized. (Author/DB)

  13. Alcoholism and Alcohol Abuse

    ... drinking once you've started Physical dependence - withdrawal symptoms Tolerance - the need to drink more alcohol to feel the same effect With alcohol abuse, you are not physically dependent, but you still ...

  14. Effects of Drug Abuse

    ... Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking ...

  15. Other Drugs of Abuse

    ... Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking ...

  16. Drug abuse first aid

    ... medlineplus.gov/ency/article/000016.htm Drug abuse first aid To use the sharing features on this page, ... Diarrhea Hallucinations Nausea and vomiting Restlessness Shaking Death First Aid 1. Check the patient's airway, breathing, and pulse. ...

  17. Developing Treatments for Stimulant Abuse: A Brief Overview.

    Davidson, C

    2016-06-01

    The abuse of stimulants such as cocaine, amphetamine, and methamphetamine is a huge problem in many parts of the world. Abuse of these drugs does not ruin just the user's life, but also adversely affects those around them. Despite many years of research, there are no approved medications for stimulant dependence, and treatment is focused on psychotherapy and abstinence. Over the last 10 to 20 years, there have been some major changes in approach to medication development for stimulant dependence. These include assessing ligands for non-dopaminergic sites, atypical dopamine transporter ligands, blocking long-term potentiation and / or memory reconsolidation, vaccines against the stimulant, and molecular approaches including pharmacogenomics and gene silencing. Also included in this overview are non-drug treatments such as deep brain stimulation and psychosurgery. This overview highlights recent preclinical and clinical studies of treatment development for stimulant dependence. PMID:27377486

  18. Drug abuse in athletes

    Reardon CL; Creado S

    2014-01-01

    Claudia L Reardon, Shane Creado Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Drug abuse occurs in all sports and at most levels of competition. Athletic life may lead to drug abuse for a number of reasons, including for performance enhancement, to self-treat otherwise untreated mental illness, and to deal with stressors, such as pressure to perform, injuries, physical pain, and retirement from sport. This review examines t...

  19. Detecting Medicare Abuse

    David Becker; Daniel Kessler; Mark McClellan

    2004-01-01

    This paper identifies which types of patients and hospitals have abusive Medicare billings that are responsive to law enforcement. For a 20 percent random sample of elderly Medicare beneficiaries hospitalized from 1994-98 with one or more of six illnesses that are prone to abuse, we obtain longitudinal claims data linked with Social Security death records, hospital characteristics, and state/year-level anti-fraud enforcement efforts. We show that increased enforcement leads certain types of t...

  20. Sexual abuse and incest

    Şahin, Figen; Taşar, Medine Ayşin

    2012-01-01

    Incest which is the severest form of child sexual abuse is defined as the sexual behaviours between close relatives whose marriage is illegal or describes inappropriate sexual behaviours within a family relation framework Incestous relation is accepted as a taboo therefore it is frequently a secret within the family and is a chronic process which is hard to recognize It is important to recognize and prevent incest because it is more difficult to be revealed compared to other forms of abuse an...

  1. Sexual abuse and incest

    Medine Ayşin Taşar; Figen Şahin

    2012-01-01

    Incest, which is the severest form of child sexual abuse is defined as the sexual behaviours between close relatives whose marriage is illegal or describes inappropriate sexual behaviours within a family relation framework. Incestous relation is accepted as a taboo, therefore it is frequently a secret within the family and is a chronic process which is hard to recognize. It is important to recognize and prevent incest because it is more difficult to be revealed compared to other forms of abus...

  2. The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence.

    Sani, Gabriele; Serra, Giulia; Kotzalidis, Giorgio D; Romano, Silvia; Tamorri, Stefano M; Manfredi, Giovanni; Caloro, Matteo; Telesforo, C Ludovica; Caltagirone, Saverio S; Panaccione, Isabella; Simonetti, Alessio; Demontis, Francesca; Serra, Gino; Girardi, Paolo

    2012-08-01

    Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder. PMID:22784018

  3. Preclinical safety and antitumor efficacy of insulin combined with irradiation

    Background and purpose: We have previously reported that insulin significantly enhances tumor oxygenation (pO2) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials. Material and methods: Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO2 (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose-response study on mice bearing FSaII fibrosarcoma. Results: The effect on regrowth delay was directly correlated with the effect on the tumor pO2, with a maximal effect using 400 mU kg-1 insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy. Conclusion: Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic

  4. Contextual Effects on Kindergarten Teachers' Intention to Report Child Abuse

    Feng, Jui-Ying; Wu, Yow-Wu B.; Fetzer, Susan; Chang, Hsin-Yi

    2012-01-01

    Child abuse is underreported for children with socioeconomic inequalities. The impact of geographic location combined with sociocultural characteristics on teachers' reports of child abuse remains unclear. A national survey of 572 kindergarten teachers from 79 schools in Taiwan used hierarchical linear modeling to investigate the contribution of…

  5. A Multilevel Evaluation of a Comprehensive Child Abuse Prevention Program

    Lawson, Michael A.; Alameda-Lawson, Tania; Byrnes, Edward C.

    2012-01-01

    Objectives: The purpose of this study is to examine the extent to which participation in a county-wide prevention program leads to improvements in protective factors associated with child abuse prevention (CAP) and whether improvements in measured protective factors relate to decreased odds of child abuse. Method: Using multilevel growth modeling,…

  6. A Theoretical Foundation for Understanding Clergy-Perpetrated Sexual Abuse

    Fogler, Jason M.; Shipherd, Jillian C.; Rowe, Erin; Jensen, Jennifer; Clarke, Stephanie

    2008-01-01

    Incorporating elements from broadband theories of psychological adaptation to extreme adversity, including Summit's (1983) Child Sexual Abuse Accommodation Syndrome, Finkelhor and Browne's (1986) Traumagenic Dynamics Model of sexual abuse, and Pyszczynski and colleagues' (1997) Terror Management Theory, this paper proposes a unified theoretical…

  7. Substance Abuse: Implications for Counseling African American Men.

    Wade, Jay C.

    1994-01-01

    Examines factors--such as unemployment, economic deprivation, racism, issues pertaining to gender roles--and their contribution to substance abuse in African American men. Specifically reviews the use of alcohol, opiates, crack, and cocaine. Argues that a biopsychosocial model offers the best framework in conceptualizing substance abuse and…

  8. Preclinical testing for teratogenicity and developmental toxicity: methods and limitations.

    Barrow, P C

    2002-01-01

    With regard to the risk of reproductive or developmental toxicity, the regulatory decisions to allow clinical trials in humans or the marketing of a new drug are based almost entirely on animal data. This is not the case for other types of toxicity for which the preclinical data are supported by data from clinical trials. Whilst animal studies have been remarkably successful in the detection of reproductive toxicology over the last 40 years, they are not infallible. The efficacy of animal experimentation is largely dependent on the selection of appropriate animal models. Progress in the study of teratogenic mechanisms, comparative physiology, developmental biology and pharmacokinetics will hopefully continue to bring about more economical and effective uses of animals. Nevertheless, owing to the limitations of animal models, the monitoring of human births unfortunately remains an essential defence in the detection and early prevention of chemical-induced birth defects. PMID:12185956

  9. Preclinical animal anxiety research - flaws and prejudices.

    Ennaceur, A.; Chazot, P L

    2016-01-01

    Abstract The current tests of anxiety in mice and rats used in preclinical research include the elevated plus‐maze (EPM) or zero‐maze (EZM), the light/dark box (LDB), and the open‐field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a sourc...

  10. Childhood Experiences of Sexual Abuse and Later Parenting Practices among Non-Offending Mothers of Sexually Abused and Comparison Girls

    Kim, Kihyun; Trickett, Penelope K.; Putnam, Frank W.

    2010-01-01

    Objective: The primary goal of this study was to explore the relationship between childhood sexual abuse and parenting practices among non-offending mothers of sexually abused girls. Guided by a developmental-ecological perspective of parenting, several models with different potential pathways starting from the mothers' childhood experiences of…

  11. Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations

    Fisher, Marc; Feuerstein, Giora; Howells, David W.; Hurn, Patricia D.; Kent, Thomas A.; Savitz, Sean I.; Lo, Eng H

    2009-01-01

    The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical r...

  12. The basics of preclinical drug development for neurodegenerative disease indications

    Spack Edward G; Steinmetz Karen L

    2009-01-01

    Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have...

  13. Information-Processing Correlates of Reported Sexual Abuse in Eating-Disordered and Comparison Women.

    Waller, Glenn; Ruddock, Angela

    1995-01-01

    An adaptation of the Stroop Test (using colored words related to sexual abuse) impaired color-naming in eating-disordered women (n=50) and in comparison women reporting sexual abuse. The interference effect was related to abuse characteristics, degree of bulimic psychopathology, and frequency of binging. A two-stage model of cognitive reaction to…

  14. Changing the Culture of Alcohol Abuse on Campus: Lessons Learned from Secondhand Smoke

    Misch, Donald A.

    2010-01-01

    Alcohol abuse is the single greatest public health hazard on American college and university campuses, but the culture of abusive alcohol consumption continues to be highly resistant to change. The author argues that secondhand smoke campaigns can be used as models to change the culture of alcohol abuse on campus. He proposes the implementation of…

  15. Forty Years of Forensic Interviewing of Children Suspected of Sexual Abuse, 1974–2014: Historical Benchmarks

    Kathleen Coulborn Faller

    2014-01-01

    This article describes the evolution of forensic interviewing as a method to determine whether or not a child has been sexually abused, focusing primarily on the United States. It notes that forensic interviewing practices are challenged to successfully identify children who have been sexually abused and successfully exclude children who have not been sexually abused. It describes models for child sexual abuse investigation, early writings and practices related to child interviews, and the de...

  16. Abuse and neglect of seniors in British Columbia: an empirical and theoretical analysis

    McMullen, Jennifer Elizabeth

    2008-01-01

    This thesis provides a description of elder abuse in British Columbia by profiling the parties involved in elder abuse situations and empirically testing Gordon and Brill?s (2001) Integrated Theoretical Model of Elder Abuse as an explanation of the relevant risk factors. The data were collected from a purposive sample of cases reported to the British Columbia Coalition for the Elimination of Abuse to Seniors from January 1, 2000 to December 31, 2004. The sample (N=392) was comprised of cases ...

  17. Ramucirumab: preclinical research and clinical development

    Aprile G

    2014-10-01

    Full Text Available Giuseppe Aprile,1 Erika Rijavec,2 Caterina Fontanella,1 Karim Rihawi,1 Francesco Grossi21Department of Oncology, University Hospital of Udine, Udine, Italy; 2Lung Cancer Unit, National Cancer Institut “San Martino”, Genoa, ItalyAbstract: Ramucirumab (IMC-1121B, LY3009806, a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2, is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramucirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer. Keywords: ramucirumab, gastric cancer, lung cancer, breast cancer, antiangiogenic

  18. Clinical simulation in teaching preclinical dentistry.

    Suvinen, T I; Messer, L B; Franco, E

    1998-02-01

    Current and projected approaches to dental education have created a wide interest in clinical simulation, and recently there has been a considerable expansion in the availability of experiential learning tools which imitate "real life" clinical conditions in dentistry. These include patient simulation devices such as heads, jaws, teeth and clinical environments, standardized patients, interactive video-discs and computer-based instruction. This paper reviews some of the equipment currently available for simulation of clinical procedures, and assesses the initial experiences and responses of 2nd, 3rd and 4th year undergraduate dental students at The University of Melbourne to case-based simulations in a patient simulator in comparison with preclinical exercises in a traditional bench and manikin laboratory. Student response to teaching and learning in the simulator over a 3-year evaluation period, collected via a student questionnaire was uniformly positive. Students were very enthusiastic about the learning environment and educational approach, preferring it to traditional preclinical laboratory instruction. PMID:9588960

  19. How Do People with Intellectual Disabilities View Abuse and Abusers?

    Northway, Ruth; Melsome, Melissa; Flood, Samantha; Bennett, Davey; Howarth, Joyce; Thomas, Becki

    2013-01-01

    People with intellectual disabilities have a higher risk of being abused than other people, but to date research has not explored their views regarding abuse. This article reports the findings relating to one question within a participatory research study concerning the abuse of people with intellectual disabilities. This question asked what…

  20. Alienation and Domestic Abuse: How Abused Women Cope with Loneliness

    Arokach, Ami

    2006-01-01

    This study explored the manner in which abused women cope with loneliness. Eighty women, victims of domestic abuse, were compared to 84 women from the general population who have had no history of abusive relationships. A 34-item yes/no loneliness questionnaire was utilized in order to compare the "beneficial" ways of coping with loneliness in the…

  1. Development and Testing of Intervention Model for Child Sexual Abuse Prevention on Primary School Children in Padang City, 2014

    Meri Neherta

    2015-12-01

    Full Text Available Background: Sexual violence against children increased in many regions in Indonesia, both in cities and in desa. Keadaan is also happening in the city of Padang, where cases of sexual violence against children is increasing from year to year. Therefore, necessary one model to be able to do primary prevention. Aims & Objectives: The aim of this study is to establish a model of promotion and prevention interventions that can be used as primary prevention of sexual violence against primary school children in Padang City. Material & Methods: The method was combining qualitative and quantitative research. The population of this study was the teachers and students within amount of ten elementary schools in the Padang City with 170 sample of people. Result: The model of intervention through Minangkabau language songs can enhance children's knowledge and assertiveness toward primary prevention of sexual violence. Conclusion: "Neherta" Model is a promotion and prevention interventions model of sexual violence against primary school children in Padang City.

  2. Substance abuse in later life.

    D'Archangelo, E.

    1993-01-01

    Substance abuse affects an appreciable portion of the elderly population. Elderly people have characteristics that could hinder identification, diagnosis, intervention, and treatment of substance abuse. If physicians use strategies specific to the elderly, management is often successful.

  3. Medical Consequences of Drug Abuse

    ... Home » Related Topics » Medical Consequences Medical Consequences of Drug Abuse Email Facebook Twitter Drug addiction is a brain ... and lung disease can all be affected by drug abuse. Some of these effects occur when drugs are ...

  4. Child neglect and psychological abuse

    ... or neglect, call 911. Call the Childhelp National Child Abuse Hotline (1-800-4-A-CHILD). Know that ... can/identifying/. Accessed November 21, 2014. Read More Child abuse - physical Update Date 11/20/2014 Updated by: ...

  5. Child Abuse: The Hidden Bruises

    ... AACAP Facts for Families Guide Skip breadcrumb navigation Child Abuse - The Hidden Bruises Quick Links Facts For Families ... 5; Updated November 2014 The statistics on physical child abuse are alarming. It is estimated hundreds of thousands ...

  6. Childhood Sexual Abuse and Suicide

    ... abused and controlling for other adversities. 1 o Victims of child sexual abuse were more likely to report having a psychiatric disorder in the last 12 months, which puts victims at a higher risk of a suicide attempt ...

  7. Substance Abuse and Mental Health

    ... More Drugs and Alcohol Tobacco Learn More Substance Abuse and Mental Health Drugs and Alcohol Did you ... related topics from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Free Resources for parents and ...

  8. Adolescent Relationship Abuse (ARA) Toolkit

    U.S. Department of Health & Human Services — The Adolescent Relationship Abuse (ARA) Toolkit provides information and strategies on how to: incorporate abuse prevention into programming; conduct staff...

  9. Substance Abuse Treatment Facilities Locator

    U.S. Department of Health & Human Services — The Substance Abuse and Mental Health Services Administration (SAMHSA) provides on-line resource for locating drug and alcohol abuse treatment programs. The...

  10. Resveratrol: A review of preclinical studies for human cancer prevention

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations

  11. Preclinical effects of melanocortins in male sexual dysfunction.

    Shadiack, A M; Althof, S

    2008-07-01

    The neurobiology of sexual behavior involves the interrelationships between sex steroids and neurotransmitters that result in both central nervous system (CNS) effects and effects in the genitalia. Tools such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scanning can help determine what areas of the brain are activated under sexual stimulation. Our understanding of the role of various neurotransmitters, neurosteroids and other CNS-acting compounds is improving. The role of CNS-acting compounds such as dopamine agonists in the treatment of male sexual dysfunction is under active investigation. Melanocortins have CNS and peripheral roles in a wide variety of bodily functions. The melanocortin agonist bremelanotide appears to act in the CNS to promote erections in preclinical models, and may also stimulate behaviors that facilitate sexual activity beyond their erectogenic effects. PMID:18552829

  12. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings.

    Gogos, Andrea; Sbisa, Alyssa M; Sun, Jeehae; Gibbons, Andrew; Udawela, Madhara; Dean, Brian

    2015-01-01

    Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17β-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems. PMID:26491441

  13. Distinguishing between exploratory and confirmatory preclinical research will improve translation.

    Jonathan Kimmelman

    2014-05-01

    Full Text Available Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation, researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation, researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.

  14. Preclinical Characterization of the FAAH Inhibitor JNJ-42165279.

    Keith, John M; Jones, William M; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A; Webb, Michael; Karbarz, Mark; Scott, Brian P; Wilson, Sandy J; Luo, Lin; Wennerholm, Michelle L; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R; Breitenbucher, J Guy

    2015-12-10

    The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio. PMID:26713105

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

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

    2016-02-01

    Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market. PMID:26612506

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

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

    2016-03-01

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

  17. Working with the Abused Camper.

    Johnson, Rebecca Cowan

    1990-01-01

    Describes forms of and reasons behind child abuse. Describes camp staff's role as reporters of suspected abuse. Describes techniques for identifying and dealing with abuse victims. Recommends offering victims respect, support, advocacy, and unconditional love. Describes steps staff might take to maximize camp's effectiveness in helping abuse…

  18. Israeli Perspectives on Elder Abuse

    Rabi, Keren

    2006-01-01

    Despite the prevailing agreement among researchers that the increasing rate of elder abuse in Israel is relatively understudied, not sufficiently identified, and not appropriately addressed, literature on elderly abuse in the Israeli society remains limited. The common discourse on aging, eldercare, and elder abuse and neglect, mainly revolves…

  19. Commentary: Gender, Disability, and Abuse.

    Goldson, Edward J.

    1997-01-01

    This commentary discusses the research article "Gender Differences in Abused Children with and without Disabilities" (Sobsey and others) that follows, which found that children with disabilities are at greater risk for being maltreated, that boys are more frequently abused, and that boys with disabilities are sexually abused more frequently than…

  20. Cognitive and Emotional Differences between Abusive and Non-Abusive Fathers

    Francis, Karen J.; Wolfe, David A.

    2008-01-01

    Objective: Abusive fathers perpetrate a substantial portion of child physical abuse. Despite this, little is known about how they differ from non-abusive fathers. This study compared a broad range of cognitive and affective factors between physically abusive and non-abusive fathers. Methods: Abusive (n = 24) and non-abusive (n = 25) fathers…