Evaluating the Effectiveness of an Alternating Pressure Overlay in Patients Undergoing Cardiothoracic Surgery.

LOCAL PROBLEM: In 2019 and the first half of 2020, our facility experienced an increase in the number and severity of hospital-acquired pressure injuries (HAPIs) among our cardiothoracic surgery population. Fifty percent of these HAPIs occurred within 72 hours of surgery. A review of the literature revealed that alternating pressure overlays (APOs) have been successfully used to prevent HAPIs in surgical patients. PURPOSE: The primary purpose of our quality improvement (QI) project was to measure perioperative HAPI rates in cardiothoracic surgery patients after the addition of APOs to our HAPI prevention protocol. Our secondary purpose was to identify common factors among those patients who developed HAPIs. METHODS: This QI project collected both pre- and postintervention data and compared the findings. A nurse-led team was responsible for measuring HAPI rates during the intervention-from July through October 2020-which involved placing an APO under cardiothoracic surgery patients during the 72-hour perioperative period. APOs were placed on all operating room (OR) tables and remained with the patients following surgery. Bed linens and skin care products were standardized for consistency. Lifts were used to reduce friction during repositioning. RESULTS: During preintervention data collection, we identified 10 patients who developed HAPIs (seven out of 1,174 cardiothoracic surgery patients in 2019, for a HAPI rate of 0.6%, and three out of 333 patients in the first half of 2020, for a HAPI rate of 0.9%). During the four-month intervention period, in which APOs were used in 331 patients undergoing cardiothoracic surgery, no HAPIs developed. CONCLUSION: Use of an APO in cardiothoracic ORs and critical care units may help reduce HAPI rates.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk.

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

Tandem detergent-extraction and immunoprecipitation of proteinopathy: Scalable enrichment of ALS-associated TDP-43 aggregates.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved, ubiquitously expressed nucleic acid-binding protein that regulates DNA/RNA metabolism. Genetics and neuropathology studies have linked TDP-43 to several neuromuscular and neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under pathological conditions, TDP-43 mislocalizes to the cytoplasm where it forms insoluble, hyper-phosphorylated aggregates during disease progression. Here, we optimized a scalable in vitro immuno-purification strategy referred to as tandem detergent-extraction and immunoprecipitation of proteinopathy (TDiP) to isolate TDP-43 aggregates that recapitulate those identified in postmortem ALS tissue. Moreover, we demonstrate that these purified aggregates can be utilized in biochemical, proteomics, and live-cell assays. This platform offers a rapid, accessible, and streamlined approach to study ALS disease mechanisms, while overcoming many limitations that have hampered TDP-43 disease modeling and therapeutic drug discovery efforts.

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4 - expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk. Summary: Windham et al . discover that APOE in astrocytes can traffic to lipid droplets (LDs), where it modulates LD composition and size. Astrocytes expressing the Alzheimer's risk variant APOE4 form large LDs with impaired turnover and increased peroxidation sensitivity.

Work-place cancer and palliative care interprofessional education: experiences of students and staff.

Workplace-based interprofessional education (IPE) offers opportunities for pre-registration students to interact with patients in authentic settings. Senior dietetic, medical, nursing, physiotherapy and radiation therapy students took part in a workplace IPE initiative on cancer and palliative care informed by experiential learning theory and run by clinical tutors. Research was undertaken to gauge students and tutors' experiences of the initiative. The mixed methods approach included: Pre and post-administration of the University of West England Interprofessional questionnaire 'Communication and Teamwork Scale, 'Interprofessional Learning Scale,' 'Interprofessional Interaction Scale.' Two questions were added relating to cancer and palliative care. Separate focus group interviews were held with students and tutors. There was a positive shift in the Communication and Teamwork scale based on students' pre and post questionnaires, but no change in the other two scales. Analysis of student and tutor focus group data showed that both affirmed the IPE initiative for a range of reasons. A brief experiential, theory-informed IPE initiative with a focus on cancer and palliative care was well received by both students and clinical tutors. The mixed method approach highlighted some discrepancies between quantitative and qualitative results but when synthesized were explicable, demonstrating the value of using a mixed methods approach to research.

Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis.

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion-inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.

Evaluative Attitudes May Explain the Link Between Injunctive Norms and Sexual Aggression.

The current study examined the extent to which evaluative attitudes toward sexual aggression (i.e., positive or negative evaluative judgments about sexually aggressive behavior) mediate the association between injunctive norms (i.e., extent to which peers approve or disapprove of sexually aggressive behavior) and self-reported sexual aggression against women. Participants were 200 male undergraduate students. Approximately one in four males reported engaging in at least one sexually aggressive act since the age of 16. Participants with a history of sexual aggression also reported the highest likelihood of engaging in sexually aggressive behavior in the future. We tested two separate mediation models to examine the extent to which evaluative attitudes account for the link between injunctive norms and sexual aggression: one model with self-reported history of sexual aggression as the outcome and the other with likelihood of engaging in sexually aggressive behavior as the outcome. Results showed that more positive evaluative attitudes toward sexual aggression accounted for the association between injunctive norms and self-reported history of sexual aggression. Similarly, evaluative attitudes accounted for the link between injunctive norms and self-reported likelihood of engaging in sexually aggressive behavior in the future. Overall, these findings are consistent with theoretical and empirical explanations of sexual offending and general criminal behavior; however, this is the first study to explore the relationship between injunctive norms and evaluative attitudes in the context of explaining sexually aggressive behavior. If more rigorous research establishes a causal relationship between injunctive norms, evaluative attitudes, and sexually aggressive behavior, this would suggest that targeting these factors in prevention programs may reduce sexual aggression by male undergraduate students.

How well do indirect measures assess sexual interest in children? A meta-analysis.

OBJECTIVE: We quantitatively reviewed the construct validity evidence for all cognitively based indirect measures of sexual interest in prepubescent children (pedophilic interest) and pubescent children (hebephilic interest) using meta-analysis. METHOD: Studies were included if they presented scores on a cognitively based indirect measure of pedohebephilic interest for a sample of adolescent or adult males who had committed a sexual offense against a child 16 years of age or younger, or who reported sexual interest in children, and for a comparison group. Studies were also included if they reported on the strength of association between scores on an indirect measure and an independent indicator of pedohebephilic interest in a sample of males. We used meta-analysis with robust variance estimation to summarize effect sizes and metaregression to test potential moderators. RESULTS: Cognitively based indirect measures of pedohebephilic interest showed a moderate difference between pedohebephilic (n = 2,552) and nonpedohebephilic males (n = 2,434), d = 0.61, 95% CI [0.46, 0.76], k = 39. A small-to-moderate correlation was also observed between indirect measures and independent indicators of pedohebephilic interest, r = .23, 95% CI [0.17, 0.28], k = 23, n = 3,623. These effects were qualified by substantial heterogeneity; however, most moderators we tested did not account for a significant amount of heterogeneity. CONCLUSIONS: Findings suggest that publication bias did not substantially distort the results. However, the lack of significant moderators suggests more research is needed to understand the conditions under which indirect measures best reflect pedohebephilic interest. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801.

All coronaviruses known to have recently emerged as human pathogens probably originated in bats1. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801-an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials-markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.

Acute SARS-CoV-2 Infection is Highly Cytopathic, Elicits a Robust Innate Immune Response and is Efficiently Prevented by EIDD-2801.

All known recently emerged human coronaviruses likely originated in bats. Here, we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbor endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained Type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a pre-exposure prophylaxis strategy for coronavirus infection. Our results show that prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II clinical trials for the treatment of COVID-19, dramatically prevented SARS-CoV-2 infection in vivo and thus has significant potential for the prevention and treatment of COVID-19.

Potassium starvation induces autophagy in yeast.

Autophagy is a conserved process that recycles cellular contents to promote survival. Although nitrogen limitation is the canonical inducer of autophagy, recent studies have revealed several other nutrients important to this process. In this study, we used a quantitative, high-throughput assay to identify potassium starvation as a new and potent inducer of autophagy in the yeast Saccharomyces cerevisiae We found that potassium-dependent autophagy requires the core pathway kinases Atg1, Atg5, and Vps34, and other components of the phosphatidylinositol 3-kinase complex. Transmission EM revealed abundant autophagosome formation in response to both stimuli. RNA-Seq indicated distinct transcriptional responses: nitrogen affects transport of ions such as copper, whereas potassium targets the organization of other cellular components. Thus, nitrogen and potassium share the ability to influence molecular supply and demand but do so in different ways. Both inputs promote catabolism through bulk autophagy, but result in distinct mechanisms of cellular remodeling and synthesis.

Acute Cerebellitis and Atypical Posterior Reversible Encephalopathy Syndrome Associated with Methadone Intoxication.

We report a case of a 9-year-old boy who presented with altered mental status and ataxia following 3 days of vomiting. Shortly after arrival to our emergency department, he declined and required intubation. The following day, he recovered and was successfully extubated. He was found to be positive for methadone on his urine drug screen. Brain imaging demonstrated a pattern of acute cerebellitis. Following extubation, the patient returned to his normal mental status; however, he began to have consistently elevated blood pressure and bradycardia and subsequent brain imaging showed supratentorial changes that were related to atypical posterior reversible encephalopathy syndrome. Through medical management including high-dose steroids and antihypertensive medications, the patient's blood pressure normalized, and he was eventually discharged home without further complications.

Identifying Challenges and Risks Associated with the Analysis of Major Mycotoxins in Feed and Botanicals.

Changing weather conditions have heightened the risk of growth of mycotoxigenic molds on crops and various agricultural commodities. Mycotoxins, which are linked to carcinogenic and nephrotoxic effects in animals and humans, have been traditionally analyzed by immunoassays, gas, and LC techniques with spectrophotometric detectors. This review discusses the current techniques and challenges in commercial settings associated with the analysis of mycotoxins in unique matrices such as animal feeds, herbal products, and dietary supplements containing botanicals. Because of the advantages and growing acceptance of LC-tandem MS (MS/MS) over traditional approaches, discussion is mainly based on LC-MS/MS-based approaches. Considering the impact of sample preparation on accuracy of quantitative results, discussion about pros and cons of recently introduced sample preparation techniques is integrated with analytical methods. A section of the review explains the importance and availability of reference materials for mycotoxins. The present discussion provides good insight into the current challenges and developments during mycotoxin analysis of feed and botanicals and addresses the need for researchers in terms of an official MS-based method.

Interprofessional Education for Cancer Care.

BACKGROUND: Cancer care is typically delivered by a range of health professionals, and is frequently a uniprofessional pre-registration clinical placement. A workplace-based, 6-hour interprofessional education (IPE) pilot on cancer care, led by clinical tutors, was undertaken in a New Zealand hospital, accompanied by an external evaluation. The pilot involved a cohort of 21 dietetic, medicine, pharmacy, physiotherapy and radiation therapy students. The aim of the evaluation was to determine student and tutor reactions to IPE, and any changes in perceptions and attitudes. METHODS: The evaluation used focus groups to collect data: two student groups and one tutor group. Focus groups were audio-recorded, transcribed; the content was coded and then analysed. RESULTS: Both students and tutors reported benefits from having IPE in the workplace environment, with cancer care seen as a suitable topic. Students reported a better understanding of professional roles, skills and the provision of collaborative care, and suggested other professions should be included in future IPE. Patient selection needed to be better tailored for physiotherapy students to ensure uniform relevance. As a result of competing demands, tutors found that they needed an 18-month lead time to establish the IPE programme. Tutors felt that the programme had gone relatively smoothly and that they had benefitted from forming closer interpersonal relationships, but noted considerable unanticipated and unremunerated preparation time. DISCUSSION: This short workplace-based IPE programme elicited a positive student and tutor response, but highlighted the need for improvements: broadening the topic area, targeted patient selection, including more professions and providing administrative support for tutors. Cancer care was generally seen as a suitable topic.

Phase 2 study of everolimus for relapsed or refractory classical Hodgkin lymphoma.

BACKGROUND: The current standard of care for classical Hodgkin lymphoma (HL) is multiagent chemotherapy with or without radiation. In patients who relapse or fail to respond, additional high-dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT) can improve progression-free survival (PFS). Novel therapies are required for patients refractory to chemotherapy and AHSCT. The mammalian target of rapamycin inhibitor everolimus has shown preliminary activity in preclinical models of HL and promising efficacy in patients with relapsed or refractory HL. METHODS: This was an open-label, two-stage, phase 2 study that enrolled 57 patients aged ≥ 18 years with classic HL that had progressed after standard therapy. Patients received everolimus 10 mg daily until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was overall response rate; secondary endpoints included PFS, overall survival, time to response, duration of response, and safety. RESULTS: Overall response rate was 45.6% (95% confidence interval [CI] 32.4-59.3%); five patients (8.8%) experienced a complete response and 21 patients had a partial response (36.8%). Median PFS was 8.0 months (95% CI 5.1-11.0 months). Seven patients (12%) were long-term responders (≥ 12 months). The most common study drug-related adverse events were thrombocytopenia (45.6%), fatigue (31.6%), anemia (26.3%), rash (24.6%), and stomatitis (22.8%). CONCLUSIONS: Everolimus 10 mg/day demonstrated favorable results in patients with heavily pretreated, relapsed, or refractory classical HL. These findings support the further evaluation of everolimus in this indication.Trial registration ClinicalTrials.gov NCT01022996. Registered November 25, 2009.

Attitude May Be Everything, But Is Everything an Attitude? Cognitive Distortions May Not Be Evaluations of Rape.

Cognitive distortions are often referred to as attitudes toward rape in theory, research, and clinical practice pertaining to sexual aggression. In the social-psychological literature, however, attitudes are typically defined as evaluations; thus, in this context, attitudes toward rape are considered evaluations of rape (e.g., rape is negative vs. positive). The purpose of the current study was to explore whether a widely used measure of cognitive distortions (RAPE Scale; Bumby, 1996) assesses evaluation of rape, and, if not, whether evaluation of rape and the cognitions assessed by the RAPE Scale are independently associated with sexually aggressive behavior. Participants (660 male undergraduate students) completed the RAPE Scale as well as measures of evaluation of rape and sexually aggressive behavior. An exploratory factor analysis revealed that the RAPE Scale items formed a correlated but distinct factor from the Evaluation of Rape Scale items. Regression analyses indicated that the Evaluation of Rape Scale and the RAPE Scale had small to moderate independent associations with self-report measures of sexually aggressive behavior. Our results suggest that evaluation of rape may be distinct from cognitive distortions regarding rape, and both evaluation and cognitive distortions may be relevant for understanding sexual violence.

Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide.

BACKGROUND: Glioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype. METHODS: To model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling. RESULTS: Cultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal. CONCLUSION: A defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.

Modeling astrocytoma pathogenesis in vitro and in vivo using cortical astrocytes or neural stem cells from conditional, genetically engineered mice.

Current astrocytoma models are limited in their ability to define the roles of oncogenic mutations in specific brain cell types during disease pathogenesis and their utility for preclinical drug development. In order to design a better model system for these applications, phenotypically wild-type cortical astrocytes and neural stem cells (NSC) from conditional, genetically engineered mice (GEM) that harbor various combinations of floxed oncogenic alleles were harvested and grown in culture. Genetic recombination was induced in vitro using adenoviral Cre-mediated recombination, resulting in expression of mutated oncogenes and deletion of tumor suppressor genes. The phenotypic consequences of these mutations were defined by measuring proliferation, transformation, and drug response in vitro. Orthotopic allograft models, whereby transformed cells are stereotactically injected into the brains of immune-competent, syngeneic littermates, were developed to define the role of oncogenic mutations and cell type on tumorigenesis in vivo. Unlike most established human glioblastoma cell line xenografts, injection of transformed GEM-derived cortical astrocytes into the brains of immune-competent littermates produced astrocytomas, including the most aggressive subtype, glioblastoma, that recapitulated the histopathological hallmarks of human astrocytomas, including diffuse invasion of normal brain parenchyma. Bioluminescence imaging of orthotopic allografts from transformed astrocytes engineered to express luciferase was utilized to monitor in vivo tumor growth over time. Thus, astrocytoma models using astrocytes and NSC harvested from GEM with conditional oncogenic alleles provide an integrated system to study the genetics and cell biology of astrocytoma pathogenesis in vitro and in vivo and may be useful in preclinical drug development for these devastating diseases.