Preclinical Therapeutic Testing Research Articles

Cryptopatches Are Essential for the Development of Human GALT

Abnormal gut-associated lymphoid tissue (GALT) in humans is associated with infectious and autoimmune diseases, which cause dysfunction of the gastrointestinal (GI) tract immune system. To aid in investigating GALT pathologies in vivo, we bioengineered a human-mouse chimeric model characterized by the development of human GALT structures originating in mouse cryptopatches. This observation expands our mechanistic understanding of the role of cryptopatches in human GALT genesis and emphasizes the evolutionary conservation of this developmental process. Immunoglobulin class switching to IgA occurs in these GALT structures, leading to numerous human IgA-producing plasma cells throughout the intestinal lamina propria. CD4+ T cell depletion within GALT structures results from HIV infection, as it does in humans. This human-mouse chimeric model represents the most comprehensive experimental platform currently available for the study and for the preclinical testing of therapeutics designed to repair disease-damaged GALT.

A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.

305 THE PGI2 AND IP RECEPTOR PATHWAY IN TUMOR ENDOTHELIAL CELLS PROMOTES ANGIOGENESIS IN AN AUTOCRINE MANNER

mice enabled establishment of a stable patient-derived model. This primary cancer model retains the ability to develop characteristic bone, liver, and lung metastases. Treatment with sunitinib resulted in significantly lower mean final graft weights and decreased graft MVD. CONCLUSIONS: Using a TSG model for RCC, large cohorts that maintain histologic, immunophenotypic, and genetic fidelity can be generated from a single parental tumor. Response to sunitinib in this model appears to be mediated by decreased MVD. This novel model has potential applications in examining pathways of response to current targeted therapies and as a platform for pre-clinical testing of new therapeutics.

304 A PATIENT-DERIVED TUMORGRAFT MODEL FOR RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research (II)1 Apr 2013304 A PATIENT-DERIVED TUMORGRAFT MODEL FOR RENAL CELL CARCINOMA Alan Thong, Alexandre Ingels, Maija Valta, Matthias Saar, Rosie Nolley, Jennifer Santos, Sarah Young, Hongjuan Zhao, and Donna Peehl Alan ThongAlan Thong Stanford, CA More articles by this author , Alexandre IngelsAlexandre Ingels Paris, France More articles by this author , Maija ValtaMaija Valta Stanford, CA More articles by this author , Matthias SaarMatthias Saar Homburg, Germany More articles by this author , Rosie NolleyRosie Nolley Stanford, CA More articles by this author , Jennifer SantosJennifer Santos Stanford, CA More articles by this author , Sarah YoungSarah Young Stanford, CA More articles by this author , Hongjuan ZhaoHongjuan Zhao Stanford, CA More articles by this author , and Donna PeehlDonna Peehl Stanford, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1688AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Current models of renal cell carcinoma (RCC) are limited to cell lines that offer poor genetic and histologic fidelity. A primary human tissue based model using orthotopic tissue slice grafts (TSG) may offer advantages by preserving tissue architecture, cellular interactions, and genetic fidelity. This pilot study aims to demonstrate the feasibility of a RCC TSG model, verify its fidelity, and assess responsiveness to a targeted therapeutic. METHODS Fresh RCC tissue was harvested from 13 nephrectomies. 8mm diameter tissue cores were obtained and precision sliced to 300um thickness for implantation under the renal capsule of immunodeficient mice. Histological, immunohistochemical, and Von Hippel-Lindau (VHL) gene sequencing analyses were performed at a minimum of 8 weeks post-implantation. A sub-cohort of 28 mice grafted from a single parental tumor was randomized to 4 weeks of treatment with sunitinib or control diluent, followed by sacrifice for assessment of histology, graft weight, and mean vessel density (MVD). RESULTS Primarily xenografted mice demonstrated an 88% engraftment rate in 191 mice, however variable tumor growth rates were observed between cases, depending on patient pathology. Histology, immunophenotype, and VHL status were preserved at 8 weeks post-implantation. Serial passaging into subsequent generations of mice enabled establishment of a stable patient-derived model. This primary cancer model retains the ability to develop characteristic bone, liver, and lung metastases. Treatment with sunitinib resulted in significantly lower mean final graft weights and decreased graft MVD. CONCLUSIONS Using a TSG model for RCC, large cohorts that maintain histologic, immunophenotypic, and genetic fidelity can be generated from a single parental tumor. Response to sunitinib in this model appears to be mediated by decreased MVD. This novel model has potential applications in examining pathways of response to current targeted therapies and as a platform for pre-clinical testing of new therapeutics. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e123-e124 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alan Thong Stanford, CA More articles by this author Alexandre Ingels Paris, France More articles by this author Maija Valta Stanford, CA More articles by this author Matthias Saar Homburg, Germany More articles by this author Rosie Nolley Stanford, CA More articles by this author Jennifer Santos Stanford, CA More articles by this author Sarah Young Stanford, CA More articles by this author Hongjuan Zhao Stanford, CA More articles by this author Donna Peehl Stanford, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer's disease.

IntroductionDespite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the AD-relevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models.MethodsFour different groups of mice ranging across the lifespan of this model (test groups: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze).ResultsThere were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed.ConclusionThis is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.

Lymphocytic choriomeningitis virus infection in FVB mouse produces hemorrhagic disease.

The viral family Arenaviridae includes a number of viruses that can cause hemorrhagic fever in humans. Arenavirus infection often involves multiple organs and can lead to capillary instability, impaired hemostasis, and death. Preclinical testing for development of antiviral or therapeutics is in part hampered due to a lack of an immunologically well-defined rodent model that exhibits similar acute hemorrhagic illness or sequelae compared to the human disease. We have identified the FVB mouse strain, which succumbs to a hemorrhagic fever-like illness when infected with lymphocytic choriomeningitis virus (LCMV). FVB mice infected with LCMV demonstrate high mortality associated with thrombocytopenia, hepatocellular and splenic necrosis, and cutaneous hemorrhage. Investigation of inflammatory mediators revealed increased IFN-γ, IL-6 and IL-17, along with increased chemokine production, at early times after LCMV infection, which suggests that a viral-induced host immune response is the cause of the pathology. Depletion of T cells at time of infection prevented mortality in all treated animals. Antisense-targeted reduction of IL-17 cytokine responsiveness provided significant protection from hemorrhagic pathology. F1 mice derived from FVB×C57BL/6 mating exhibit disease signs and mortality concomitant with the FVB challenged mice, extending this model to more widely available immunological tools. This report offers a novel animal model for arenavirus research and pre-clinical therapeutic testing.

Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis

ObjectiveEosinophilic oesophagitis (EoE) is a chronic inflammatory condition of the oesophagus with limited treatment options. No previous transgenic model has specifically targeted the oesophageal mucosa to induce oesophageal eosinophilia.DesignWe developed...

Quantitative Longitudinal Imaging of Vascular Inflammation and Treatment by Ezetimibe in apoE Mice by FMT Using New Optical Imaging Biomarkers of Cathepsin Activity and αvβ3 Integrin

Inflammation as a core pathological event of atherosclerotic lesions is associated with the secretion of cathepsin proteases and the expression of α v β 3 integrin. We employed fluorescence molecular tomographic (FMT) noninvasive imaging of these molecular activities using cathepsin sensing (ProSense, CatB FAST) and α v β 3 integrin (IntegriSense) near-infrared fluorescence (NIRF) agents. A statistically significant increase in the ProSense and IntegriSense signal was observed within the chest region of apoE−/− mice (P < 0.05) versus C57BL/6 mice starting 25 and 22 weeks on high cholesterol diet, respectively. In a treatment study using ezetimibe (7 mg/kg), there was a statistically significant reduction in the ProSense and CatB FAST chest signal of treated (P < 0.05) versus untreated apoE−/− mice at 31 and 21 weeks on high cholesterol diet, respectively. The signal of ProSense and CatB FAST correlated with macrophage counts and was found associated with inflammatory cells by fluorescence microscopy and flow cytometry of cells dissociated from aortas. This report demonstrates that cathepsin and α v β 3 integrin NIRF agents can be used as molecular imaging biomarkers for longitudinal detection of atherosclerosis, and cathepsin agents can monitor anti-inflammatory effects of ezetimibe with applications in preclinical testing of therapeutics and potentially for early diagnosis of atherosclerosis in patients.

Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma

Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4+ and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4+ T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8+ T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.

Long‐term organ culture of keloid disease tissue

Keloid disease (KD) is a common fibroproliferative disorder of unknown aetiopathogenesis, with highly unsatisfactory treatment. Therefore, it is crucial to have a robust and clinically relevant model for studying KD pathobiology as well as preclinical testing of potential KD therapeutics. However, the unique occurrence of KD in human skin and the corresponding lack of animal models pose a major challenge in KD research. Therefore, we developed a simplified assay for the serum-free, long-term organ culture of KD tissue that facilitates quantitative analyses of major KD read-out parameters. Four millimetre KD punches embedded in a collagen matrix and organ-cultured at the epidermis air-liquid interphase (ALI) in supplemented William's E medium showed optimal tissue, cell and RNA preservation for up to 6 weeks (as measured by H & E and Pyronin Y histochemistry as well as by MTT assay, lactate dehydrogenase release and quantitative Ki67/TUNEL immunohistomorphometry). The keloid phenotype persisted well during this period, as shown by collagen-I and -III synthesis (Herovici's histochemistry staining and ELISA), and analysis of the expression of significant KD markers (CD3, CD20, CD31, CD34, CD56, tryptase, Langerin, vimentin, neutrophil elastase, CTGF and Collagen). To functionally evaluate whether this assay can test the response to candidate therapeutics, dexamethasone, a glucocorticosteroid often used in KD therapy, was administered. Indeed, dexamethasone significantly reduced the keloid volume and cellularity plus induced epidermal shrinkage. Therefore, this novel assay provides a quantitative, clinically relevant model system for studying KD pathobiology and response to treatment.

Stemness of the CT-2A Immunocompetent Mouse Brain Tumor Model: Characterization In Vitro

Evidence has pointed to brain tumor stem cells (BTSC) as culprits behind human high-grade glioma (hHGG) resistance to standard therapy. Pre-clinical rodent models are the mainstay for testing of new therapeutic strategies. The typical model involves the intracranial injection of human glioma cells into immunocompromised hosts, hindering the evaluation of tumor-host responses and resulting in non-infiltrative tumors. The CT-2A model is an immunocompetent mouse model with potential to overcome these disadvantages. In this study, we confirmed the highly infiltrative nature of intracranial CT-2A tumors and optimized reproducible injection parameters. We then generated neurospheres and established, for the first time, the stemness of this model. CT-2A expression of the BTSC marker, CD133, increased from 2% in monolayer cells to 31% in fully-formed neurospheres. Investigation of three stem cell markers (Oct4, Nanog and Nestin) revealed a distinct stemness signature with monolayer cells expressing Oct4 and Nestin (no Nanog), and neurospheres expressing all three. Additionally, CT-2A cells were more proliferative and invasive than U87 cells, while CT-2A neurospheres were significantly more proliferative and invasive than either monolayer cells in vitro. Taken together, our results show that this model is a valuable tool for pre-clinical testing of novel therapeutics against hHGG and also affords the opportunity for investigation of BTSC in an immunocompetent setting.

Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by marked impairments in motor function caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Animal models of PD have traditionally been based on toxins, such as 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that selectively lesion dopaminergic neurons. Motor impairments from 6-OHDA lesions of SNc neurons are well characterized in rats, but much less work has been done in mice. In this study, we compare the effectiveness of a series of drug-free behavioral tests in assessing sensorimotor impairments in the unilateral 6-OHDA mouse model, including six tests used for the first time in this PD mouse model (the automated treadmill “DigiGait” test, the challenging beam test, the adhesive removal test, the pole test, the adjusting steps test, and the test of spontaneous activity) and two tests used previously in 6-OHDA-lesioned mice (the limb-use asymmetry “cylinder” test and the manual gait test). We demonstrate that the limb-use asymmetry, challenging beam, pole, adjusting steps, and spontaneous activity tests are all highly robust assays for detecting sensorimotor impairments in the 6-OHDA mouse model. We also discuss the use of the behavioral tests for specific experimental objectives, such as simple screening for well-lesioned mice in studies of PD cellular pathophysiology or comprehensive behavioral analysis in preclinical therapeutic testing using a battery of sensorimotor tests.

Preclinical Testing of PI3K/AKT/mTOR Signaling Inhibitors in a Mouse Model of Ovarian Endometrioid Adenocarcinoma

Genetically engineered mouse (GEM) models of ovarian cancer that closely recapitulate their human tumor counterparts may be invaluable tools for preclinical testing of novel therapeutics. We studied murine ovarian endometrioid adenocarcinomas (OEA) arising from conditional dysregulation of canonical WNT and PI3K/AKT/mTOR pathway signaling to investigate their response to conventional chemotherapeutic drugs and mTOR or AKT inhibitors. OEAs were induced by injection of adenovirus expressing Cre recombinase (AdCre) into the ovarian bursae of Apc(flox/flox); Pten(flox/flox) mice. Tumor-bearing mice or murine OEA-derived cell lines were treated with cisplatin and paclitaxel, mTOR inhibitor rapamycin, or AKT inhibitors API-2 or perifosine. Treatment effects were monitored in vivo by tumor volume and bioluminescence imaging, in vitro by WST-1 proliferation assays, and in OEA tissues and cells by immunoblotting and immunostaining for levels and phosphorylation status of PI3K/AKT/mTOR signaling pathway components. Murine OEAs developed within 3 weeks of AdCre injection and were not preceded by endometriosis. OEAs responded to cisplatin + paclitaxel, rapamycin, and AKT inhibitors in vivo. In vitro studies showed that response to mTOR and AKT inhibitors, but not conventional cytotoxic drugs, was dependent on the status of PI3K/AKT/mTOR signaling. AKT inhibition in APC(-)/Pten(-) tumor cells resulted in compensatory upregulation of ERK signaling. The studies show the utility of this GEM model of ovarian cancer for preclinical testing of novel PI3K/AKT/mTOR signaling inhibitors and provide evidence for compensatory signaling, suggesting that multiple rather than single agent targeted therapy will be more efficacious for treating ovarian cancers with activated PI3K/AKT/mTOR signaling.

Of dogs and men: Comparative biology as a tool for the discovery of novel biomarkers and drug development targets in osteosarcoma

The similarities between human and canine osteosarcoma with regard to histology, biological behavior and molecular genetic alterations suggest that the dog provides a supplementary model for the development and preclinical testing of novel therapeutics. Counter intuitively, careful examination of the differences between OS in the two species may also be rewarding in terms of increasing our understanding of the pathogenesis of this cancer. This review will discuss the arguments in favor of the "dog model" and outline how the evaluation of treatment strategies in dogs has indicated avenues for improvement of protocols for human patients.

An In Silico Modeling Approach to Understanding the Dynamics of Sarcoidosis

BackgroundSarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis.Methodology/ResultsBased upon the literature, we developed a computational model of known interactions between essential immune cells (antigen-presenting macrophages, effector and regulatory T cells) and cytokine mediators (IL-2, TNFα, IFNγ) of granulomatous inflammation during sarcoidosis. The dynamics of these interactions are described by a set of ordinary differential equations. The model predicts bistable switching behavior which is consistent with normal (self-limited) and “sarcoidosis-like” (sustained) activation of the inflammatory components of the system following a single antigen challenge. By perturbing the influence of model components using inhibitors of the cytokine mediators, distinct clinically relevant disease phenotypes were represented. Finally, the model was shown to be useful for pre-clinical testing of therapies based upon molecular targets and dose-effect relationships.Conclusions/SignificanceOur work illustrates a dynamic computer simulation of granulomatous inflammation scenarios that is useful for the investigation of disease mechanisms and for pre-clinical therapeutic testing. In lieu of relevant in vitro or animal surrogates, our model may provide for the screening of potential therapies for specific sarcoidosis disease phenotypes in advance of expensive clinical trials.

A novel mouse model for arenavirus hemorrhagic fever (67.20)

Abstract The viral family Arenaviridae includes a number of viruses that can cause hemorrhagic fever. Arenavirus infection often involves multiple organs and can lead to capillary instability, impaired hemostasis, and death. There is a lack of treatment options available to those suffering from arenaviral hemorrhagic fever and a well established mouse model of arenaviral hemorrhagic fever would benefit preclinical testing for arenavirus antivirals or therapeutics. We have identified the FVB mouse strain, which succumbs to a hemorrhagic fever like illness when infected with lymphocytic choriomeningitis virus (LCMV). FVB mice infected with LCMV demonstrate high mortality associated with thrombocytopenia, hepatocellular and splenic necrosis, and cutaneous hemorrhage whereas C57BL/6 mice survive. Investigation of possible inflammatory mediators revealed increased IFN-g and IL-6, along with increased chemokine production, at early times after LCMV infection as compared to C57BL/6 mice. Removal of CD4+ or CD8+ cells from FVB mice at time of infection prevented mortality in all treated animals and treatment with FK506 early during infection delayed disease onset. This report offers a novel animal model for arenavirus research and pre-clinical therapeutic testing.

The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.

Environmental enrichment induces optimistic cognitive bias in rats

People’s affective or emotional state can alter their cognitive processing, biasing interpretation of ambiguous stimuli. Those in a more positive state interpret such stimuli in a more optimistic manner than those in a negative state. Recently this research has extended to animals, and has shown that manipulations associated with negative affect cause animals to interpret ambiguous stimuli more pessimistically. We investigated whether exposure to environmental enrichment engenders optimistic responses to ambiguous stimuli. Rats, Rattus norvegicus , were trained on a novel conditional discrimination task whereby they learned the correct response necessary to obtain a food reward given the stimulus present during approach (rough or smooth sandpaper). One stimulus was associated with a higher-value reward than the other. Once the rats were trained, cognitive bias was probed by exploring their responses to an ambiguous stimulus (intermediate grade of sandpaper); a rat was defined as optimistic if it chose the response appropriate to the stimulus associated with the better reward. Animals transferred from unenriched to enriched cages showed more optimistic responses following the change. A control group maintained in unenriched cages showed pessimistic responses throughout. These results demonstrate for the first time that environmental enrichment can induce an optimistic cognitive bias in rats previously housed in standard caging, possibly indicative of a more positive affective state. These results add support to the suggestion that measuring cognitive biases can give an insight into animal emotional states; this has implications for animal welfare and preclinical testing of potential therapeutics for mood disorders.

Transgenic Mouse Models of Tauopathy in Drug Discovery

Tauopathies, including Alzheimer's disease, are neurodegenerative diseases characterized by the deposition of hyperphosphorylated tau protein in the central nervous system, and are the major cause of dementia in later life. Considerable advances have been made in developing mouse models that recapitulate, to varying extents, the development of human tau pathology, and the learning and memory deficits characteristic of some tauopathies. Furthermore, such models have been used to show promising disease-modifying effects in pre-clinical testing of new therapeutics. Various strategies have been utilised to generate mouse models of tauopathies. Some of the most enlightening models developed to date either constitutively or inducibly express pathogenic tau mutations. These animals have been instrumental in defining critical disease-related mechanisms, including the observation that tangles are not the toxic form of tau in disease. Here, we discuss the strengths and weaknesses of well characterised transgenic models that emulate human tauopathy, and include a comprehensive listing of the main phenotypic characteristics of all reported tau transgenic rodents. We summarise the use of tau mice for the development and evaluation of new therapeutic approaches, and their utility in identifying novel drug targets. In addition, we review the parameters to be considered in the development of the next generation of mouse models of tauopathy, aimed at further increasing our understanding of disease aetiology and in evaluating novel treatments.

Non-germline genetically engineered mouse models for translational cancer research

Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models.