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2. Molecular and translational advances in meningiomas

Author

Suppiah S., Nassiri F., Bi W. L., Dunn I. F., Hanemann C. O., Horbinski C. M., Hashizume R., James C. D., Mawrin C., Noushmehr H., Perry A., Sahm F., Sloan A., Von Deimling A., Wen P. Y., Aldape K., Zadeh G., Au K., Barnhartz-Sloan J., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Griffith B., Herold-Mende C., Huang R. Y., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., McDermott M., Munoz D., Ng H. -K., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Suppiah S., Nassiri F., Bi W.L., Dunn I.F., Hanemann C.O., Horbinski C.M., Hashizume R., James C.D., Mawrin C., Noushmehr H., Perry A., Sahm F., Sloan A., Von Deimling A., Wen P.Y., Aldape K., Zadeh G., Au K., Barnhartz-Sloan J., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Griffith B., Herold-Mende C., Huang R.Y., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., McDermott M., Munoz D., Ng H.-K., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Cancer Research, Supplement Articles, Genomics, Intracranial Neoplasm, sporadic meningioma, Bioinformatics, World health, Translational Research, Biomedical, Meningioma, 03 medical and health sciences, biomolecular, 0302 clinical medicine, Meningeal Neoplasms, otorhinolaryngologic diseases, medicine, Recurrent disease, Humans, Meningeal Neoplasm, Molecular Targeted Therapy, xenograft, Stage (cooking), neoplasms, MENINGIOMA, business.industry, cell line, Prognosis, medicine.disease, Combined Modality Therapy, nervous system diseases, 3. Good health, Clinical trial, Oncology, 030220 oncology & carcinogenesis, Neurology (clinical), genetic, business, epigenetic, 030217 neurology & neurosurgery
Abstract

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Published
2019
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3. Life after surgical resection of a meningioma: a prospective cross-sectional study evaluating health-related quality of life

Author

Nassiri F., Price B., Shehab A., Au K., Cusimano M. D., Jenkinson M. D., Jungk C., Mansouri A., Santarius T., Suppiah S., Teng K. X., Toor G. S., Zadeh G., Walbert T., Drummond K. J., Aldape K., Barnhartz-Sloan J., Bi W. L., Brastianos P. K., Butowski N., Carlotti C., Dimeco F., Dunn I. F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C. O., Herold-Mende C., Horbinski C., Huang R. Y., James D., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Sahm F., Saladino A., Schichor C., Schultz D., Schmidt N. O., Selman W., Sloan A., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Deimling A. V., Wen P. Y., Westphal M., Workewych A. M., Nassiri F., Price B., Shehab A., Au K., Cusimano M.D., Jenkinson M.D., Jungk C., Mansouri A., Santarius T., Suppiah S., Teng K.X., Toor G.S., Zadeh G., Walbert T., Drummond K.J., Aldape K., Barnhartz-Sloan J., Bi W.L., Brastianos P.K., Butowski N., Carlotti C., Dimeco F., Dunn I.F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C.O., Herold-Mende C., Horbinski C., Huang R.Y., James D., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Sahm F., Saladino A., Schichor C., Schultz D., Schmidt N.O., Selman W., Sloan A., Spears J., Snyder J., Tabatabai G., Tatagiba M., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Deimling A.V., Wen P.Y., Westphal M., and Workewych A.M.

Subjects
Male, cognition, Cancer Research, medicine.medical_specialty, Cross-sectional study, insomnia, Population, Neurosurgery, Supplement Articles, meningioma, surgery, Meningioma, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Internal medicine, Meningeal Neoplasms, otorhinolaryngologic diseases, medicine, Humans, Longitudinal Studies, Prospective Studies, Prospective cohort study, education, education.field_of_study, business.industry, COGNIÇÃO, Cognition, Middle Aged, Prognosis, medicine.disease, humanities, 3. Good health, health-related quality of life, Cross-Sectional Studies, Oncology, 030220 oncology & carcinogenesis, Quality of Life, Female, fatigue, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies, Cohort study
Abstract

Background Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection. Results A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P < 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P < 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30. Conclusions Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy.

Published
2019
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6. DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Author

Nassiri F., Mamatjan Y., Suppiah S., Badhiwala J. H., Mansouri S., Karimi S., Saarela O., Poisson L., Gepfner-Tuma I., Schittenhelm J., Ng H. -K., Noushmehr H., Harter P., Baumgarten P., Weller M., Preusser M., Herold-Mende C., Tatagiba M., Tabatabai G., Sahm F., Von Deimling A., Aldape K., Au K., Barnhartz-Sloan J., Bi W. L., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Dunn I. F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C. O., Horbinski C., Huang R. Y., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Malta T. M., Mawrin C., McDermott M., Munoz D., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Sloan A., Spears J., Snyder J., Tirapelli D., Tonn J. C., Tsang D., Vogelbaum M. A., Wen P. Y., Walbert T., Westphal M., Workewych A. M., Zadeh G., Aldape K. D., Nassiri F., Mamatjan Y., Suppiah S., Badhiwala J.H., Mansouri S., Karimi S., Saarela O., Poisson L., Gepfner-Tuma I., Schittenhelm J., Ng H.-K., Noushmehr H., Harter P., Baumgarten P., Weller M., Preusser M., Herold-Mende C., Tatagiba M., Tabatabai G., Sahm F., Von Deimling A., Aldape K., Au K., Barnhartz-Sloan J., Bi W.L., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Dunn I.F., Galanis E., Giannini C., Goldbrunner R., Griffith B., Hashizume R., Hanemann C.O., Horbinski C., Huang R.Y., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Malta T.M., Mawrin C., McDermott M., Munoz D., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Sloan A., Spears J., Snyder J., Tirapelli D., Tonn J.C., Tsang D., Vogelbaum M.A., Wen P.Y., Walbert T., Westphal M., Workewych A.M., Zadeh G., and Aldape K.D.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, recurrence, predictor, ESTUDOS DE VALIDAÇÃO, Meningioma, nomogram, Internal medicine, medicine, Biomarkers, Tumor, Meningeal Neoplasms, Humans, Survival rate, Retrospective Studies, Oncotype DX Breast Cancer Assay, business.industry, Hazard ratio, Cancer, Disease Management, Retrospective cohort study, Nomogram, DNA Methylation, medicine.disease, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, Clinical research, Basic and Translational Investigations, Neurology (clinical), methylation, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Published
2019

7. Advances in multidisciplinary therapy for meningiomas

Author

Brastianos P. K., Galanis E., Butowski N., Chan J. W., Dunn I. F., Goldbrunner R., Herold-Mende C., Ippen F. M., Mawrin C., McDermott M. W., Sloan A., Snyder J., Tabatabai G., Tatagiba M., Tonn J. C., Wen P. Y., Aldape K., Nassiri F., Zadeh G., Jenkinson M. D., Raleigh D. R., Au K., Barnhartz-Sloan J., Bi W. L., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Giannini C., Griffith B., Hashizume R., Hanemann C. O., Horbinski C., Huang R. Y., James D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N. O., Selman W., Spears J., Suppiah S., Tirapelli D., Tsang D., Vogelbaum M. A., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Brastianos P.K., Galanis E., Butowski N., Chan J.W., Dunn I.F., Goldbrunner R., Herold-Mende C., Ippen F.M., Mawrin C., McDermott M.W., Sloan A., Snyder J., Tabatabai G., Tatagiba M., Tonn J.C., Wen P.Y., Aldape K., Nassiri F., Zadeh G., Jenkinson M.D., Raleigh D.R., Au K., Barnhartz-Sloan J., Bi W.L., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Giannini C., Griffith B., Hashizume R., Hanemann C.O., Horbinski C., Huang R.Y., James D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Schmidt N.O., Selman W., Spears J., Suppiah S., Tirapelli D., Tsang D., Vogelbaum M.A., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Oncology, Cancer Research, medicine.medical_treatment, Supplement Articles, meningioma, Systemic therapy, surgery, 0302 clinical medicine, Meningeal Neoplasms, Trabectedin, Cancer, clinical trial, targeted therapy, Prognosis, Combined Modality Therapy, 3. Good health, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, International Consortium on Meningiomas, Patient Safety, Meningioma, medicine.drug, medicine.medical_specialty, Oncology and Carcinogenesis, Antineoplastic Agents, Radiosurgery, 03 medical and health sciences, Internal medicine, medicine, otorhinolaryngologic diseases, Humans, Meningeal Neoplasm, Oncology & Carcinogenesis, neoplasms, business.industry, Neurosciences, Evaluation of treatments and therapeutic interventions, medicine.disease, RADIOTERAPIA, Brain Disorders, nervous system diseases, Clinical trial, Radiation therapy, radiation, Neurology (clinical), Cranial Irradiation, business, 030217 neurology & neurosurgery
Abstract

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.

Published
2019

8. Imaging and diagnostic advances for intracranial meningiomas

Author

Huang R. Y., Bi W. L., Griffith B., Kaufmann T. J., La Fougere C., Schmidt N. O., Tonn J. C., Vogelbaum M. A., Wen P. Y., Aldape K., Nassiri F., Zadeh G., Dunn I. F., Au K., Barnhartz-Sloan J., Brastianos P. K., Butowski N., Carlotti C., Cusimano M. D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Hashizume R., Hanemann C. O., Herold-Mende C., Horbinski C., James D., Jenkinson M. D., Jungk C., Kaufman T. J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J. C., Mamatjan Y., Mansouri A., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H. -K., Perry A., Pirouzmand F., Poisson L. M., Pollo B., Raleigh D., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Selman W., Sloan A., Spears J., Snyder J., Suppiah S., Tabatabai G., Tatagiba M., Tirapelli D., Tsang D., Deimling A. V., Walbert T., Westphal M., Workewych A. M., Huang R.Y., Bi W.L., Griffith B., Kaufmann T.J., La Fougere C., Schmidt N.O., Tonn J.C., Vogelbaum M.A., Wen P.Y., Aldape K., Nassiri F., Zadeh G., Dunn I.F., Au K., Barnhartz-Sloan J., Brastianos P.K., Butowski N., Carlotti C., Cusimano M.D., Dimeco F., Drummond K., Galanis E., Giannini C., Goldbrunner R., Hashizume R., Hanemann C.O., Herold-Mende C., Horbinski C., James D., Jenkinson M.D., Jungk C., Kaufman T.J., Krischek B., Lachance D., Lafougere C., Lee I., Liu J.C., Mamatjan Y., Mansouri A., Mawrin C., McDermott M., Munoz D., Noushmehr H., Ng H.-K., Perry A., Pirouzmand F., Poisson L.M., Pollo B., Raleigh D., Sahm F., Saladino A., Santarius T., Schichor C., Schultz D., Selman W., Sloan A., Spears J., Snyder J., Suppiah S., Tabatabai G., Tatagiba M., Tirapelli D., Tsang D., Deimling A.V., Walbert T., Westphal M., and Workewych A.M.

Subjects
Cancer Research, medicine.medical_specialty, Neuroimaging, Supplement Articles, Multimodal Imaging, perfusion, Meningioma, 03 medical and health sciences, 0302 clinical medicine, Medical imaging, medicine, Meningeal Neoplasms, Humans, Meningeal Neoplasm, Radiation treatment planning, medicine.diagnostic_test, business.industry, imaging, Magnetic resonance imaging, medicine.disease, radiology, 3. Good health, Tumor detection, RADIOLOGIA, PET, Oncology, 030220 oncology & carcinogenesis, Radiological weapon, Neurology (clinical), Radiology, business, 030217 neurology & neurosurgery, CT, MRI
Abstract

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.

Published
2019

10. OS08.3 Genomic landscape of meningiomas

Author

Bi, W. L., primary, Greenwald, N. F., additional, Abedalthagafi, M., additional, Agarwalla, P., additional, Horowitz, P., additional, Santagata, S., additional, Al-Mefty, O., additional, Beroukhim, R., additional, and Dunn, I. F., additional

Published
2017
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12. Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma

Author

Aizer, A. A., primary, Arvold, N. D., additional, Catalano, P., additional, Claus, E. B., additional, Golby, A. J., additional, Johnson, M. D., additional, Al-Mefty, O., additional, Wen, P. Y., additional, Reardon, D. A., additional, Lee, E. Q., additional, Nayak, L., additional, Rinne, M. L., additional, Beroukhim, R., additional, Weiss, S. E., additional, Ramkissoon, S. H., additional, Abedalthagafi, M., additional, Santagata, S., additional, Dunn, I. F., additional, and Alexander, B. M., additional

Published
2014
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13. Mass spectrometry imaging as a tool for surgical decision-making

Author

Calligaris, D., primary, Norton, I., additional, Feldman, D. R., additional, Ide, J. L., additional, Dunn, I. F., additional, Eberlin, L. S., additional, Cooks, R. G., additional, Jolesz, F. A., additional, Golby, A. J., additional, Santagata, S., additional, and Agar, N. Y., additional

Published
2013
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17. TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice.

Author

Tsitsikov EN, Laouini D, Dunn IF, Sannikova TY, Davidson L, Alt FW, and Geha RS

Subjects
Animals, Antibodies, Monoclonal immunology, Apoptosis, B-Lymphocytes immunology, CD3 Complex immunology, Cells, Cultured, Immunoglobulins biosynthesis, Kinetics, Lymphocyte Activation, Mice, Mice, Knockout, Necrosis, Skin Diseases etiology, Skin Diseases pathology, Superantigens immunology, TNF Receptor-Associated Factor 1, Tumor Necrosis Factor-alpha pharmacology, Proteins genetics, Proteins physiology, Signal Transduction, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha antagonists & inhibitors
Abstract

TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because it lacks a RING finger domain and is predominantly expressed in activated lymphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. TRAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 antibodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappa B and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling.

Published
2001
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18. Assessment of alterations in gene expression in recurrent malignant glioma after radiotherapy using complementary deoxyribonucleic acid microarrays.

Author

Joki T, Carroll RS, Dunn IF, Zhang J, Abe T, and Black PM

Subjects
Aged, Blood Vessels pathology, Blotting, Northern, Brain Neoplasms blood supply, DNA, Complementary genetics, Female, Glioblastoma blood supply, Humans, Male, Microcirculation, Middle Aged, Neoplasm Recurrence, Local, Brain Neoplasms genetics, Brain Neoplasms radiotherapy, Gene Expression, Glioblastoma genetics, Glioblastoma radiotherapy, Oligonucleotide Array Sequence Analysis
Abstract

Objective: We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen., Methods: Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis., Results: Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor beta, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor alpha, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients' recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens., Conclusion: After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.

Published
2001
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19. Continuous release of endostatin from microencapsulated engineered cells for tumor therapy.

Author

Joki T, Machluf M, Atala A, Zhu J, Seyfried NT, Dunn IF, Abe T, Carroll RS, and Black PM

Subjects
Alginates, Angiogenesis Inhibitors therapeutic use, Angiogenesis Inhibitors toxicity, Animals, Biocompatible Materials, Capillaries, Capsules, Cattle, Cell Transplantation, Cells, Cultured, Collagen therapeutic use, Cricetinae, Endostatins, Endothelium, Vascular cytology, Endothelium, Vascular drug effects, Genetic Vectors, Humans, Mice, Mice, Nude, Peptide Fragments therapeutic use, Polylysine analogs & derivatives, Recombinant Proteins administration & dosage, Recombinant Proteins metabolism, Swine, Transfection, Transplantation, Heterologous, Angiogenesis Inhibitors administration & dosage, Brain Neoplasms therapy, Collagen administration & dosage, Collagen genetics, Glioma therapy, Peptide Fragments administration & dosage, Peptide Fragments genetics
Abstract

Research studies suggest that tumor-related angiogenesis contributes to the phenotype of malignant gliomas. We assessed the effect of local delivery of the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG) xenografts. Baby hamster kidney (BHK) cells were stably transfected with a human endostatin (hES) expression vector and were encapsulated in alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES. The release of biologically active endostatin was confirmed using assays of bovine capillary endothelial (BCE) proliferation and of tube formation. Human endostatin released from the microcapsules brought about a 67. 2% inhibition of BCE proliferation. Furthermore, secreted hES was able to inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells stably transfected with KDR, a tyrosine kinase) treated with conditioned U-87MG medium. A single local injection of encapsulated endostatin-secreting cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous U87 xenografts' weight 21 days post treatment. This inhibition was achieved by only 150.8 ng/ml human endostatin secreted from 2 x 10(5) encapsulated cells. Encapsulated endostatin-secreting cells are effective for the treatment of human glioblastoma xenografts. Continuous local delivery of endostatin may offer an effective therapeutic approach to the treatment of a variety of tumor types.

Published
2001
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20. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs.

Author

Dunn IF, Heese O, and Black PM

Subjects
Animals, Brain Neoplasms metabolism, Endopeptidases physiology, Endothelium, Vascular pathology, Epidermal Growth Factor physiology, Fibroblast Growth Factors physiology, Gene Expression Regulation, Neoplastic, Glioma metabolism, Growth Substances genetics, Humans, Mice, Models, Biological, Neoplasm Proteins genetics, Platelet-Derived Growth Factor physiology, Receptors, Growth Factor drug effects, Receptors, Growth Factor genetics, Receptors, Growth Factor physiology, Transforming Growth Factors physiology, Brain Neoplasms blood supply, Glioma blood supply, Growth Substances physiology, Neoplasm Proteins physiology, Neovascularization, Pathologic metabolism
Abstract

It has become well accepted that solid tumors must create a vascular system for nutrient delivery and waste removal in order to grow appreciably. This process, angiogenesis, is critical to the progression of gliomas, with vascular changes accompanying the advancement of these tumors. The cascade of events in this process of blood vessel formation involves a complex interplay between tumor cells, endothelial cells, and their surrounding basement membranes in which enzymatic degradation of surrounding ground substance and subsequent endothelial cell migration, proliferation, and tube formation occurs. It is likely that a host of growth factors is responsible for mediating these key events. To date, a role for Vascular Endothelial Growth Factor (VEGF) in glioma angiogenesis has been convincingly demonstrated. This review explores the contribution of other growth factors--Fibroblast Growth Factors (FGFs), Platelet-Derived Growth Factor (PDGF), Epidermal Growth Factor (EGF), and Transforming Growth Factors (TGFs)--to glioma angiogenesis. These growth factors may influence glioma angiogenesis by directly stimulating endothelial cell proliferation, by mediating the expression of key proteases on endothelial cells necessary for angiogenesis, or by regulating the expression of VEGF and of each other.

Published
2000
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21. A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo.

Author

Tsai EY, Falvo JV, Tsytsykova AV, Barczak AK, Reimold AM, Glimcher LH, Fenton MJ, Gordon DC, Dunn IF, and Goldfeld AE

Subjects
Animals, Base Sequence, CREB-Binding Protein, Cell Line, Enhancer Elements, Genetic, Gene Expression Regulation drug effects, Lipopolysaccharides pharmacology, Molecular Sequence Data, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-ets, Signal Transduction genetics, ets-Domain Protein Elk-1, DNA-Binding Proteins, Nuclear Proteins genetics, Proto-Oncogene Proteins genetics, Sp1 Transcription Factor genetics, Trans-Activators genetics, Transcription Factors genetics, Tumor Necrosis Factor-alpha genetics
Abstract

The tumor necrosis factor alpha (TNF-alpha) gene is rapidly activated by lipopolysaccharide (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-alpha gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-alpha promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-alpha nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-alpha gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-alpha promoter in vivo, and the binding sites for each of these activators are required for LPS-stimulated TNF-alpha gene expression. Furthermore, assembly of the LPS-stimulated TNF-alpha enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300. The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-alpha promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved.

Published
2000
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22. Structure of the murine TRAF1 gene.

Author

Dunn IF, Geha RS, and Tsitsikov EN

Subjects
Animals, B-Lymphocytes, Base Sequence, Cloning, Molecular, Exons, Gene Expression, Gene Expression Regulation, Introns, Lymphocyte Activation, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Restriction Mapping, T-Lymphocytes, TNF Receptor-Associated Factor 1, Tissue Distribution, Transcription, Genetic, Proteins genetics, Receptors, Tumor Necrosis Factor
Abstract

We have cloned, characterized and sequenced the murine TNF Receptor Associated Factor 1 (TRAF1) gene. Restriction mapping and Southern blotting analysis revealed that the TRAF1 gene comprises 10 exons and 9 intervening introns and spreads over 18 kb of genomic DNA. 5'-RACE analysis of the TRAF1 transcript using mRNA from activated spleen B cells revealed several transcription start sites between positions -42 to +4 relative to the 5'end of the murine TRAF1 cDNA sequence. We also isolated and sequenced the 5'-upstream promoter region, which lacks TATA-like and CAAT-like sites but contains GC-rich sequences. Taken together, these results suggest that the TRAF1 gene promoter is a member of the class of Sp-1-dependent promoters. Near the transcription initiation start site we identified three identical decanucleotide repeats (CCAGCCCAGC) which may play a role in the transcriptional regulation of TRAF1 expression. In addition we show that TRAF1 mRNA is not expressed in non-stimulated lymphocytes but can be induced upon activation with different stimuli, including anti-CD3, anti-IgM, anti-CD40 antibodies, LPS, or a combination of phorbol-12-myristate-13-acetate and ionomycin.

Published
1999
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