Immunotherapy of High-Grade Gliomas: Preclinical In Vivo Experiments in Animal Models

2012 ◽  
pp. 245-273
Author(s):  
Kristen A. Batich ◽  
Bryan D. Choi ◽  
Duane A. Mitchell
Keyword(s):  
Animal Models ◽  
High Grade ◽  
In Vivo Experiments ◽  
High Grade Gliomas

scholarly journals The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Jian Teng ◽  
Ghazal Lashgari ◽  
Elie I Tabet ◽  
Bakhos A Tannous
Keyword(s):  
Er Stress ◽  
Cell Survival ◽  
Natural Compound ◽  
Therapeutic Option ◽  
High Grade ◽  
Intrinsic Resistance ◽  
Clinical Prognosis ◽  
Cancer Cell Survival ◽  
High Grade Gliomas

Abstract Background Pediatric high-grade gliomas (pHGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis. Treatment of pHGGs is particularly challenging given the intrinsic resistance to chemotherapy, an absence of novel therapeutics, and the difficulty of drugs to reach the tumor beds. Accumulating evidence suggests that production of reactive oxygen species (ROS) and misfolded proteins, which typically leads to endoplasmic reticulum (ER) stress, is an essential mechanism in cancer cell survival. Methods Several cell viability assays were used in 6 patient-derived pHGG cultures to evaluate the effect of the natural compound obtusaquinone (OBT) on cytotoxicity. Orthotopic mouse models were used to determine OBT effects in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Results OBT significantly inhibited cell survival of patient-derived pHGG cells in culture. OBT inhibited tumor growth and extended survival in 2 different orthotopic xenograft models. Mechanistically, OBT induced ER stress through abnormal ROS accumulation. Conclusion Our data demonstrate the utility and feasibility of OBT as a potential therapeutic option for improving the clinical treatment of pHGGs.

scholarly journals Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas

2019 ◽  
Vol 22 (1) ◽  
pp. 139-151 ◽  
Author(s):  
Han Shen ◽  
Man Yu ◽  
Maria Tsoli ◽  
Cecilia Chang ◽  
Swapna Joshi ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Glucose Metabolism ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Grade ◽  
Mtdna Copy Number ◽  
Mitochondrial Oxidation ◽  
High Grade Gliomas

Abstract Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.

scholarly journals Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance

2015 ◽  
Vol 122 (6) ◽  
pp. 1360-1369 ◽  
Author(s):  
Roberto Jose Diaz ◽  
Roberto Rey Dios ◽  
Eyas M. Hattab ◽  
Kelly Burrell ◽  
Patricia Rakopoulos ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Low Dose ◽  
Glioma Cells ◽  
High Grade ◽  
Fluorescein Sodium ◽  
Tumor Margins ◽  
Histopathological Correlation ◽  
High Grade Gliomas

OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.

scholarly journals Applications of Radiomics and Radiogenomics in High-Grade Gliomas in the Era of Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5921
Author(s):  
Anahita Fathi Kazerooni ◽  
Stephen J. Bagley ◽  
Hamed Akbari ◽  
Sanjay Saxena ◽  
Sina Bagheri ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
Extent Of Resection ◽  
Target Area ◽  
High Grade ◽  
Future Directions ◽  
Mri Scans ◽  
High Grade Gliomas ◽  
Changes Over Time

Machine learning (ML) integrated with medical imaging has introduced new perspectives in precision diagnostics of high-grade gliomas, through radiomics and radiogenomics. This has raised hopes for characterizing noninvasive and in vivo biomarkers for prediction of patient survival, tumor recurrence, and genomics and therefore encouraging treatments tailored to individualized needs. Characterization of tumor infiltration based on pre-operative multi-parametric magnetic resonance imaging (MP-MRI) scans may allow prediction of the loci of future tumor recurrence and thereby aid in planning the course of treatment for the patients, such as optimizing the extent of resection and the dose and target area of radiation. Imaging signatures of tumor genomics can help in identifying the patients who benefit from certain targeted therapies. Specifying molecular properties of gliomas and prediction of their changes over time and with treatment would allow optimization of treatment. In this article, we provide neuro-oncology, neuropathology, and computational perspectives on the promise of radiomics and radiogenomics for allowing personalized treatments of patients with gliomas and discuss the challenges and limitations of these methods in multi-institutional clinical trials and suggestions to mitigate the issues and the future directions.

scholarly journals In vivo animal models in periodontal research - focus on rodents

2021 ◽  
Vol 24 (2) ◽  
pp. 167-175
Author(s):  
E. I. Firkova
Keyword(s):  
Animal Models ◽  
Cellular Level ◽  
In Vitro Tests ◽  
Large Species ◽  
In Vivo Experiments ◽  
Data Translation ◽  
In Vivo Animal Models ◽  
Periodontal Research

Periodontal research has developed very fast in the last two decades. Although at this stage of science a lot of genetic and molecular-based trials are performed in order to elucidate the complex etiology, pathophysiology, biofilm-host interactions and responses on genetic and cellular level, in vivo animal models are still used. In many ways, in vivo experiments are superior to in vitro tests when the dynamics of the immune-inflammatory nature of the periodontal disease and peri-implantitis and the specific healing of soft and hard tissues is concerned. Screening the efficacy, mechanisms of action and application of different biomaterials requires in vivo experiments, be-fore the data translation to clinical settings. A number of small animals like rodents and large species like dogs and nonhuman primates are involved in periodontal research. As live creatures are used, the design of the studies must be well defined, with regard to the type of the animals, most suitable for the tested hypothesis, observation period, sample size, study power, critical size defects, and specific testing sites.

Ga-68 PSMA PET/CT in recurrent high-grade gliomas: evaluating PSMA expression in vivo

2021 ◽  
Author(s):  
Arunav Kumar ◽  
Sreedharan Thankarajan ArunRaj ◽  
Khush Bhullar ◽  
K. P. Haresh ◽  
Subhash Gupta ◽  
...  
Keyword(s):  
High Grade ◽  
Psma Pet ◽  
Pet Ct ◽  
High Grade Gliomas ◽  
Psma Expression

scholarly journals HGG-02. NEUROPHYSIOLOGICAL SMALL MOLECULE SCREEN TO TARGET NEURON-GLIOMA INTERACTIONS IN PEDIATRIC HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i17-i17
Author(s):  
David Rogawski ◽  
Sara Mulinyawe ◽  
Craig Thomas ◽  
Michelle Monje
Keyword(s):  
Ion Channels ◽  
Small Molecule ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
In Vivo Experiments ◽  
Target Neuron ◽  
Glioma Cell Proliferation ◽  
Glioma Growth

Abstract Neurons stimulate glioma growth via synaptic and paracrine signaling mechanisms. We recently demonstrated that neurons form AMPA receptor-dependent synapses with glioma cells, and that neuronal activity also induces potassium-evoked currents that are amplified by gap junctions coupling glioma cells. However, our understanding of the neurotransmitters, receptors, and ion channels participating in neuron-glioma signaling remains incomplete. We have recently developed a high-throughput neuron-glioma co-culture strategy to screen small molecules for agents that may disrupt neuron-glioma signaling. Glioma cell proliferation is increased tenfold when cultured together with neurons; this robust biological effect can be probed in a targeted screen of compounds influencing neurotransmitter receptors and ion channels. The neurophysiological small molecule library used was curated to include approved anti-epileptics, neuroleptics, and antidepressants, as well as a variety of other compounds acting on different neurotransmitter types and ion channels. Hits from the primary screen were run through a counter-screen using glioma cells grown alone without neurons, to identify compounds that specifically affect neuron-glioma interactions. Correlation of the screening results with drug mechanisms of action will allow us to map out the key neurotransmitter pathways regulating glioma growth, which can be further validated using genetic and in vivo experiments. Drugs identified in this glioma neuroscience screen may be readily translated into much-needed therapeutics for children with high-grade glioma.

scholarly journals Quality of reporting of otorhinolaryngology articles using animal models with the ARRIVE statement

2017 ◽  
Vol 52 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Aren Bezdjian ◽  
Sjaak F L Klis ◽  
Jeroen P M Peters ◽  
Wilko Grolman ◽  
Inge Stegeman
Keyword(s):  
Animal Models ◽  
Animal Studies ◽  
Quality Of Reporting ◽  
Research Reporting ◽  
In Vivo Experiments ◽  
Funding Agencies ◽  
Pubmed Database ◽  
In Vivo Animal Models

Research involving animal models is crucial for the advancement of science, provided that experiments are designed, performed, interpreted, and reported well. In order to investigate the quality of reporting of articles in otorhinolaryngology research using animal models, a PubMed database search was conducted to retrieve eligible articles. The checklist of the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines was used to assess the quality of reporting of articles published in ear, nose and throat (ENT) and multidisciplinary journals. Two authors screened titles, abstracts, and full texts to select articles reporting otorhinolaryngology research using in vivo animal models. ENT journals ( n = 35) reported a mean of 57.1% adequately scored ARRIVE items (median: 58.3%; 95% confidence interval [CI; 53.4–60.9%]), while articles published in multidisciplinary journals ( n = 36) reported a mean of 49.1% adequately scored items (median: 50.0; 95% CI [46.2–52.0%]). Articles published in ENT journals showed better quality of reporting of animal studies based on the ARRIVE guidelines ( P < 0.05). However, adherence to the ARRIVE guidelines is generally poor in otorhinolaryngology research using in vivo animal models. The endorsement of the ARRIVE guidelines by authors, research and academic institutes, editorial offices and funding agencies is recommended for improved reporting of scientific research using animal models.

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