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Author Shahar, T.; Rozovski, U.; Hess, K.R.; Hossain, A.; Gumin, J.; Gao, F.; Fuller, G.N.; Goodman, L.; Sulman, E.P.; Lang, F.F.
Title Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival Type Journal Article
Year 2017 Publication Neuro-Oncology Abbreviated Journal Neuro Oncol
Volume 19 Issue 5 Pages 660-668
Keywords *glioblastoma; *mesenchymal stem cells; *microenvironment; *prognosis
Abstract Background: Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal cells in human gliomas as glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized that a higher percentage of GA-hMSCs in tumors predicts poor patient prognosis. Method: We determined the percentage of cells coexpressing GA-hMSC markers CD105+/CD73+/CD90+ from patients with newly diagnosed high-grade glioma and analyzed the association between this percentage and overall survival (OS) in 3 independent cohorts: fresh surgical glioblastoma specimens (cohort 1, N = 9), cultured tumor specimens at passage 3 (cohort 2, N = 28), and The Cancer Genome Atlas (TCGA) database. Results: In all cohorts, patient OS correlated with the percentages of GA-hMSCs in tumors. For cohort 1, the median OS of patients with tumors with a low percentage of triple-positive cells was 46 months, and for tumors with a high percentage of triple-positive cells, it was 12 months (hazard ratio [HR] = 0.24; 95% CI: 0.02-0.5, P = .02). For cohort 2, the median OS of patients with tumors with a low percentage of GA-hMSCs was 66 months, and for tumors with a high percentage, it was 11 months (HR = 0.38; 95% CI: 0.13-0.9, P = .04). In the database of TCGA, the median OS times in patients with high and low coexpression levels of CD105/CD73/CD90 were 8.4 months and 13.1 months (HR = 0.4; 95% CI: 0.1-0.88; P = .04), respectively. Conclusions: The percentage of GA-MSCs inversely correlates with OS, suggesting a role for GA-MSCs in promoting aggressive behavior of gliomas.
Address Brain Tumor Center, Unit 442, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (up) 1522-8517 ISBN Medium
Area Expedition Conference
Notes PMID:28453745 Approved no
Call Number ref @ user @ Serial 96589
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Author D'Alessandris, Q.G.; Biffoni, M.; Martini, M.; Runci, D.; Buccarelli, M.; Cenci, T.; Signore, M.; Stancato, L.; Olivi, A.; De Maria, R.; Larocca, L.M.; Ricci-Vitiani, L.; Pallini, R.
Title The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response Type Journal Article
Year 2017 Publication Neuro-Oncology Abbreviated Journal Neuro Oncol
Volume 19 Issue 8 Pages 1097-1108
Keywords cancer stem cells; glioblastoma; radiotherapy; temozolomide; treatment outcome
Abstract Background: Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods: The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 muM to 1 mM) was related with patients' survival. Results: Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 muM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions: Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.
Address Institute of Neurosurgery, Universita Cattolica del Sacro Cuore, Rome, Italy; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Institute of Pathology, Universita Cattolica del Sacro Cuore, Rome, Italy; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (up) 1522-8517 ISBN Medium
Area Expedition Conference
Notes PMID:28204560 Approved no
Call Number ref @ user @ Serial 96607
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Author Goffart, N.; Lombard, A.; Lallemand, F.; Kroonen, J.; Nassen, J.; Di Valentin, E.; Berendsen, S.; Dedobbeleer, M.; Willems, E.; Robe, P.; Bours, V.; Martin, D.; Martinive, P.; Maquet, P.; Rogister, B.
Title CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone Type Journal Article
Year 2017 Publication Neuro-Oncology Abbreviated Journal Neuro Oncol
Volume 19 Issue 1 Pages 66-77
Keywords Animals; Brain Neoplasms/metabolism/*pathology/radiotherapy; Chemokine CXCL12/*metabolism; Cranial Irradiation/*adverse effects; Gamma Rays/adverse effects; Glioblastoma/metabolism/*pathology/radiotherapy; Humans; Lateral Ventricles/metabolism/*pathology/radiation effects; Mice; Mice, Nude; Neoplastic Stem Cells/metabolism/*pathology/radiation effects; *Radiation Tolerance; Signal Transduction/radiation effects; Tumor Cells, Cultured; Cxcl12; glioblastoma; mesenchymal activation; radioresistance; subventricular zone
Abstract BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.
Address Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liege, Liege, Belgium (N.G., A.L., J.N., M.D., E.W., B.R.); Department of Neurosurgery, CHU and University of Liege, Liege, Belgium (A.L., D.M.); Department of Radiotherapy and Oncology, CHU and University of Liege, Liege, Belgium (F.L., P.M.); Laboratory of Tumor and Development Biology, GIGA-Cancer Research Center, University of Liege, Liege, Belgium (F.L.); Cyclotron Research Centre, University of Liege, Liege, Belgium (F.L.); Human Genetics, CHU and University of Liege, Liege, Belgium (N.G., J.K., V.B.); Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands (N.G., J.K., S.B., P.R.); GIGA-Viral Vector Plateform, University of Liege, Liege, Belgium (E.D.V.); Department of Neurology, CHU and University of Liege, Liege, Belgium (P.M., B.R.)
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (up) 1522-8517 ISBN Medium
Area Expedition Conference
Notes PMID:27370398 Approved no
Call Number ref @ user @ Serial 96647
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Author Rocha, G. da S.; Mello Jorge, M.H.P. de; Grembek, O.
Title After-effects and disabilities in traffic crash victims in northern Brazil Type Journal Article
Year 2017 Publication Traffic Injury Prevention Abbreviated Journal Traffic Inj Prev
Volume 18 Issue 4 Pages 412-419
Keywords Accidents, Traffic/*statistics & numerical data; Adolescent; Adult; Aged; Brazil/epidemiology; Child; Cities; Cross-Sectional Studies; *Disabled Persons; Facial Injuries/epidemiology/mortality/pathology; Female; Humans; Injury Severity Score; Logistic Models; Male; Middle Aged; Motorcycles; Odds Ratio; Risk Factors; Wounds and Injuries/*epidemiology/mortality/pathology; Young Adult; Crashes; after-effects; severity of trauma; traffic; victims
Abstract OBJECTIVES: The objective of this study was to identify the characteristics related to crash and victim, as well as the after-effects/disabilities and consequences arising from traffic crashes occurring in the city of Rio Branco-Acre. METHODS: This is an analytical descriptive cross-sectional study conducted in the City of Rio Branco-Acre. The study population consisted of 405 residents of the city who were victims of traffic crashes, of all age groups and genders, who were hospitalized for the first time as a result of the crash in public hospitals and the health system network, as recorded in the Hospital Information System, and who were discharged between January 1 and December 31, 2010. The data sources included hospital record consultations and active searches for the victims. Hierarchical logistic regression was performed to evaluate the factors associated with the after-effects. RESULTS: The majority of the study population was motorcycle victims (68.6%), male, and young (20-39 years). Concerning the after-effects, the following were significantly associated: factors related to the presence of a postcrash activity limitation (odds ratio [OR] = 2.39; 95% confidence interval [CI], 2.39-6.76), length of hospital stay in days (OR = 1 03; 95% CI, 1.01-1.06), and surgical treatment (OR = 1.82; 95% CI, 1.03-3.21). Those who suffered damage to soft tissue and nerves or facial injury showed an odds ratio of 2 to 4 times of having an after-effect/disability, independent of the victim's personal attributes. CONCLUSION: The mechanism, such as the origin of the pattern of injuries, explains the exposure factors shown by each attribute of the victim and their characteristics. Many of the injuries were precursors to after-effects/disabilities, which, due to their nature and extent, result in the modification of the apparently healthy living standards of young victims who are routinely injured in traffic crashes. Therefore, public policies for prevention should be formulated, reformulated, and implemented, taking into account each attribute of the victims and their social conditions, because these are closely related to their habits and customs. This is a starting point for promoting changes to the current reality that traffic crashes present in the morbidity and mortality of the population.
Address c University of California , Berkeley , Safe Transportation Research and Education Center , Berkeley , California
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (up) 1538-9588 ISBN Medium
Area Expedition Conference
Notes PMID:27575383 Approved no
Call Number ref @ user @ Serial 97666
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Author Hu, B.; Emdad, L.; Kegelman, T.P.; Shen, X.-N.; Das, S.K.; Sarkar, D.; Fisher, P.B.
Title Astrocyte Elevated Gene-1 Regulates beta-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal Type Journal Article
Year 2017 Publication Molecular Cancer Research : MCR Abbreviated Journal Mol Cancer Res
Volume 15 Issue 2 Pages 225-233
Keywords Brain Neoplasms/genetics/metabolism/*pathology; Cell Adhesion Molecules/genetics/*metabolism; Cell Line, Tumor; Glioblastoma/genetics/metabolism/*pathology; Humans; Neoplastic Stem Cells/*pathology; Signal Transduction; Tumor Cells, Cultured; beta Catenin/genetics/*metabolism
Abstract Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein-protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated beta-catenin translocation into the nucleus by forming a complex with LEF1 and beta-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3beta signaling axis, AEG-1 controlled phosphorylation levels of beta-catenin that stabilized the protein. IMPLICATIONS: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225-33. (c)2016 AACR.
Address VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN (up) 1541-7786 ISBN Medium
Area Expedition Conference
Notes PMID:27903708 Approved no
Call Number ref @ user @ Serial 96619
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