A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

PubMed

Macy, Margaret E; Kieran, Mark W; Chi, Susan N; Cohen, Kenneth J; MacDonald, Tobey J; Smith, Amy A; Etzl, Michael M; Kuei, Michele C; Donson, Andrew M; Gore, Lia; DiRenzo, Jennifer; Trippett, Tanya M; Ostrovnaya, Irina; Narendran, Aru; Foreman, Nicholas K; Dunkel, Ira J

2017-11-01

Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population. © 2017 Wiley Periodicals, Inc.

Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note.

PubMed

Coca, H A; Cebula, H; Benmekhbi, M; Chenard, M P; Entz-Werle, N; Proust, F

2016-12-01

Diffuse intrinsic pontine gliomas (DIPG) constitute 10-15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7-14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population. Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach. Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56minutes (range 45 to 67minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III). Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

PubMed Central

El-Khouly, Fatma E.; van Vuurden, Dannis G.; Stroink, Thom; Hulleman, Esther; Kaspers, Gertjan J. L.; Hendrikse, N. Harry; Veldhuijzen van Zanten, Sophie E. M.

2017-01-01

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG. PMID:29164054

State of affairs in use of steroids in diffuse intrinsic pontine glioma: an international survey and a review of the literature.

PubMed

Veldhuijzen van Zanten, Sophie E M; Cruz, Ofelia; Kaspers, Gertjan J L; Hargrave, Darren R; van Vuurden, Dannis G

2016-07-01

Children diagnosed with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with severe neurologic deterioration and inevitable death at a median of 9 months from diagnosis. Steroids are widely prescribed as supportive or palliative treatment although they are known to cause severe side effects that may reduce the quality of life. This study aims to review the current knowledge on, and use of, steroids in DIPG patients. A global questionnaire-study among health care professionals was performed to ascertain information on the current (multi-)institutional and (multi-)national use of steroids, the availability of clinical guidelines, and the need for improvements in prescribing steroids to DIPG patients. In addition, an extensive literature search was performed to review studies investigating steroids in pediatric brain tumor patients. From 150 responding health care professionals, only 7 % had clinical guidelines. The use of steroids was heterogeneous and over 85 % of respondents reported serious side effects. Fourteen articles, with low level of evidence, described the use of steroids in pediatric brain tumor patients. Clinical trials investigating optimal dose or regimen were lacking. This study is a first inventory of the availability of evidence-based information and clinical guidelines, and the current attitude towards the use of steroids in DIPG patients. To date, the risk-benefit ratio of steroids in this disease is yet to be determined. We emphasize the need for clinical trials resulting in guidelines on steroids, and possibly alternative drugs, to optimize the quality of care and quality of life of DIPG patients.

Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

DTIC Science & Technology

2014-11-01

LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 39 19b. TELEPHONE...for this mouse cohort was included in Figure 1. Out of 23 GFAP tv- a; p53 floxed mice infected with RCAS-PDGF-B and RCAS-Cre, 18 developed...being used as part of the DIPG preclinical consortium (together with several laboratories that are using human DIPG xenografts ) to help prioritize

HGG-22. TARGETING NEURONAL ACTIVITY-REGULATED NEUROLIGIN-3 DEPENDENCY FOR HIGH-GRADE GLIOMA THERAPY

PubMed Central

Venkatesh, Humsa S; Tam, Lydia T; Woo, Pamelyn J; Monje, Michelle

2017-01-01

Abstract Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. Here, we demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in Nlgn3 knockout mice. Using genetic mouse models, we illustrate that Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.

Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

PubMed

Hennika, Tammy; Hu, Guo; Olaciregui, Nagore G; Barton, Kelly L; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J; Tsoli, Maria; Ziegler, David S; Carcaboso, Angel M; Becher, Oren J

2017-01-01

Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

Diffuse intrinsic pontine glioma in children and adolescents: a single-center experience.

PubMed

Vallero, Stefano Gabriele; Bertin, Daniele; Basso, Maria Eleonora; Pittana, Laura Stefania; Mussano, Anna; Fagioli, Franca

2014-06-01

Patients with diffuse intrinsic pontine glioma (DIPG) have a very poor prognosis. Only radiotherapy (XRT) has proven to be effective in delaying the disease progression. Several chemotherapy schedules have been applied so far, but none demonstrated significant improvements in progression and survival. We retrospectively analyzed the clinical data of children diagnosed with DIPG at our center (Pediatric Hospital "Regina Margherita," Turin, Italy) between 1999 and 2013. Progression-free survival (PFS) and overall survival (OS) were used to describe the outcomes. Twenty-four children were included in our report. Patients diagnosed before March 2003 (n = 12) were treated with XRT and vincristine (VCR); the remaining 12 patients received XRT and temozolomide (TMZ). Progression-free survival was 18.8 % at 1 year (SE = 7.6 %), while overall survival was 44.1 % at 1 year (SE = 9.9 %). Median PFS was 8.1 months, whereas median OS was 11.2 months. No statistically significant difference in PFS or OS was evidenced between the two treatment groups. Radiotherapy followed by VCR or TMZ allows obtaining results that are in line with previous reports, with no advantages over other similar treatment schedules. DIPGs are challenging tumors with a dismal outcome. Further research and newer therapies are urgently needed in order to achieve improvements in survival.

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

PubMed

Janssens, Geert O; Gandola, Lorenza; Bolle, Stephanie; Mandeville, Henry; Ramos-Albiac, Monica; van Beek, Karen; Benghiat, Helen; Hoeben, Bianca; Morales La Madrid, Andres; Kortmann, Rolf-Dieter; Hargrave, Darren; Menten, Johan; Pecori, Emilia; Biassoni, Veronica; von Bueren, Andre O; van Vuurden, Dannis G; Massimino, Maura; Sturm, Dominik; Peters, Max; Kramm, Christof M

2017-03-01

Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

End-of-life care of children with diffuse intrinsic pontine glioma.

PubMed

Hasan, Fyeza; Weingarten, Kevin; Rapoport, Adam; Bouffet, Eric; Bartels, Ute

2018-05-01

The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010. All patients died of disease progression, experiencing a significant symptom burden prior to death. Despite this, the majority of patient days at the end of life were spent at home. However, 60% of patients were hospitalized at least once in their final 3 months, often close to the time of death. A wide range of healthcare professionals were involved, providing a range of medicinal/non-medicinal interventions. Chemotherapy was given to 30% of patients in their final month. Thirty of 33 families approached (91%) agreed to a "Do not resuscitate" order. A small subset of families opted for intensive treatment towards the end of life including cardiopulmonary resuscitation, intensive care admission and mechanical ventilation. Children with DIPG have complex needs and require intensive multidisciplinary support. This paper describes the end-of-life choices made for these children and discusses how these choices influence our institutional model for palliative care. We believe this approach will be useful to clinicians caring for similar patients.

Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.

PubMed

Lober, Robert M; Cho, Yoon-Jae; Tang, Yujie; Barnes, Patrick D; Edwards, Michael S; Vogel, Hannes; Fisher, Paul G; Monje, Michelle; Yeom, Kristen W

2014-03-01

While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.

Clinicopathological features and treatment outcomes of brain stem gliomas in Saudi population

PubMed Central

Bayoumi, Yasser; Sabbagh, Abdulrahman J; Mohamed, Reham; ElShokhaiby, Usama M; Maklad, Ahmed Marzouk; Tunio, Mutahir A; Balbaid, Ali Abdullah O

2014-01-01

AIM: To analyze experiences to identify treatment outcomes and prognostic factors in a Saudi population. METHODS: Medical records of patients with brainstem gliomas treated from July 2001 to December 2012 were reviewed to identify treatment outcomes of surgery, radiation therapy and chemotherapy and associated prognostic factors in a Saudi population. RESULTS: We analyzed 49 brain stem glioma (BSG) patients from July 2001 to December 2012; 31 of them were males (63.3%) with a median age of 12.6 years (range: 8-64 mo). Twenty-two patients (44.9%) had diffuse intrinsic pontine gliomas (DIPG) and 15 (30.6%) presented with focal/tectal BSG. Histopathology was available in 30 patients (61.2%). Median survival time for the whole cohort was 1.5 years. One and two year OS rates were 51.1% and 41.9% respectively. Two year OS rates for focal/tectal, dorsally exophytic, cervicomedullary and DIPG tumors were 60%, 33.3%, 33.3% and 13.6% respectively (P < 0.0001). Significant prognostic factors related to OS were age at diagnosis (worse for > 18 years) P = 0.01, KPS < 70 P = 0.02, duration of symptoms (< 60 d) P = 0.002, histology (better for favorable) P = 0.002, surgery (maximal resection) P = 0.002, and concurrent chemotherapy with radiation therapy in DIPG (better if given) P = 0.01. CONCLUSION: BSG, especially the DIPG subgroup, had a dismal prognosis, needing more aggressive neurosurgical, radiation and chemotherapy techniques, while focal and tectal tumors were found to have a better prognosis. PMID:25493242

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

PubMed

Hoffman, Lindsey M; Veldhuijzen van Zanten, Sophie E M; Colditz, Niclas; Baugh, Joshua; Chaney, Brooklyn; Hoffmann, Marion; Lane, Adam; Fuller, Christine; Miles, Lili; Hawkins, Cynthia; Bartels, Ute; Bouffet, Eric; Goldman, Stewart; Leary, Sarah; Foreman, Nicholas K; Packer, Roger; Warren, Katherine E; Broniscer, Alberto; Kieran, Mark W; Minturn, Jane; Comito, Melanie; Broxson, Emmett; Shih, Chie-Schin; Khatua, Soumen; Chintagumpala, Murali; Carret, Anne Sophie; Escorza, Nancy Yanez; Hassall, Timothy; Ziegler, David S; Gottardo, Nicholas; Dholaria, Hetal; Doughman, Renee; Benesch, Martin; Drissi, Rachid; Nazarian, Javad; Jabado, Nada; Boddaert, Nathalie; Varlet, Pascale; Giraud, Géraldine; Castel, David; Puget, Stephanie; Jones, Chris; Hulleman, Esther; Modena, Piergiorgio; Giagnacovo, Marzia; Antonelli, Manila; Pietsch, Torsten; Gielen, Gerrit H; Jones, David T W; Sturm, Dominik; Pfister, Stefan M; Gerber, Nicolas U; Grotzer, Michael A; Pfaff, Elke; von Bueren, André O; Hargrave, Darren; Solanki, Guirish A; Jadrijevic Cvrlje, Filip; Kaspers, Gertjan J L; Vandertop, William P; Grill, Jacques; Bailey, Simon; Biassoni, Veronica; Massimino, Maura; Calmon, Raphaël; Sanchez, Esther; Bison, Brigitte; Warmuth-Metz, Monika; Leach, James; Jones, Blaise; van Vuurden, Dannis G; Kramm, Christof M; Fouladi, Maryam

2018-05-10

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume.

PubMed

Singh, Ranjodh; Zhou, Zhiping; Tisnado, Jamie; Haque, Sofia; Peck, Kyung K; Young, Robert J; Tsiouris, Apostolos John; Thakur, Sunitha B; Souweidane, Mark M

2016-11-01

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post-radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin's concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders.

Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium

PubMed Central

Poussaint, Tina Young; Vajapeyam, Sridhar; Ricci, Kelsey I.; Panigrahy, Ashok; Kocak, Mehmet; Kun, Larry E.; Boyett, James M.; Pollack, Ian F.; Fouladi, Maryam

2016-01-01

Background Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). Methods Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. Results Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. Conclusions ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials. PMID:26487690

A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method.

PubMed

Walker, David A; Liu, JoFen; Kieran, Mark; Jabado, Nada; Picton, Susan; Packer, Roger; St Rose, Christian

2013-04-01

Astrocytic tumors account for 42% of childhood brain tumors, arising in all anatomical regions and associated with neurofibromatosis type 1 (NF1) in 15%. Anatomical site determines the degree and risk of resectability; the more complete resection, the better the survival rates. New biological markers and modern radiotherapy techniques are altering the risk assessments of clinical decisions for tumor resection and biopsy. The increasingly distinct pediatric neuro-oncology multidisciplinary team (PNMDT) is developing a distinct evidence base. A multidisciplinary consensus conference on pediatric neurosurgery was held in February 2011, where 92 invited participants reviewed evidence for clinical management of hypothalamic chiasmatic glioma (HCLGG), diffuse intrinsic pontine glioma (DIPG), and high-grade glioma (HGG). Twenty-seven statements were drafted and subjected to online Delphi consensus voting by participants, seeking >70% agreement from >60% of respondents; where <70% consensus occurred, the statement was modified and resubmitted for voting. Twenty-seven statements meeting consensus criteria are reported. For HCLGG, statements describing overall therapeutic purpose and indications for biopsy, observation, or treatment aimed at limiting the risk of visual damage and the need for on-going clinical trials were made. Primary surgical resection was not recommended. For DIPG, biopsy was recommended to ascertain biological characteristics to enhance understanding and targeting of treatments, especially in clinical trials. For HGG, biopsy is essential, the World Health Organization classification was recommended; selection of surgical strategy to achieve gross total resection in a single or multistep process should be discussed with the PNMDT and integrated with trials based drug strategies for adjuvant therapies.

Hypofractionation vs Conventional Radiation Therapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Matched-Cohort Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, Geert O., E-mail: g.janssens@rther.umcn.nl; Jansen, Marc H.; Lauwers, Selmer J.

2013-02-01

Purpose: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. Methods and Materials: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptomsmore » for {<=}3 months, {>=}2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. Results: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. Conclusions: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.« less

A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume

PubMed Central

Singh, Ranjodh; Zhou, Zhiping; Tisnado, Jamie; Haque, Sofia; Peck, Kyung K.; Young, Robert J.; Tsiouris, Apostolos John; Thakur, Sunitha B.; Souweidane, Mark M.

2017-01-01

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post–radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin’s concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods high-lighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interob-server agreement and produced tumor volumes with delineated borders. PMID:27391980

Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem.

PubMed

Zhou, Zhiping; Ho, Sharon L; Singh, Ranjodh; Pisapia, David J; Souweidane, Mark M

2015-04-01

Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application. Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion. No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity. Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study.

PubMed

Sewing, A Charlotte P; Caretti, Viola; Lagerweij, Tonny; Schellen, Pepijn; Jansen, Marc H A; van Vuurden, Dannis G; Idema, Sander; Molthoff, Carla F M; Vandertop, W Peter; Kaspers, Gertjan J L; Noske, David P; Hulleman, Esther

2014-12-30

Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models. Copyright © 2014 Elsevier B.V. All rights reserved.

T2-weighted images are superior to other MR image types for the determination of diffuse intrinsic pontine glioma intratumoral heterogeneity.

PubMed

Harward, Stephen; Harrison Farber, S; Malinzak, Michael; Becher, Oren; Thompson, Eric M

2018-03-01

Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SD Tumor ) normalized to the genu of the corpus callosum (SD Corpus Callosum ). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p < 0.01) and ADC (p < 0.0001). Following radiotherapy, T2-weighted and contrast-enhanced T1-weighted image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical trials.

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma.

PubMed

Venkatesh, Humsa S; Tam, Lydia T; Woo, Pamelyn J; Lennon, James; Nagaraja, Surya; Gillespie, Shawn M; Ni, Jing; Duveau, Damien Y; Morris, Patrick J; Zhao, Jean J; Thomas, Craig J; Monje, Michelle

2017-09-28

High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

PubMed Central

Venkatesh, Humsa S.; Tam, Lydia T.; Woo, Pamelyn J.; Lennon, James; Nagaraja, Surya; Gillespie, Shawn M.; Ni, Jing; Duveau, Damien Y.; Morris, Patrick J.; Zhao, Jean J.; Thomas, Craig J.; Monje, Michelle

2017-01-01

Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy. PMID:28959975

IMMU-22. ADOPTIVE CELL THERAPY AGAINST DIPG USING DEVELOPMENTALLY REGULATED ANTIGENS

PubMed Central

Flores, Catherine; Gil, Jorge; Abraham, Rebecca; Pham, Christina; Wildes, Tyler; Moore, Ginger; Drake, Jeffrey; Dyson, Kyle; Mitchell, Duane

2017-01-01

Abstract INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) survival has remained static over decades and DIPG is now the main cause of brain tumor-related deaths in children. Immunotherapy has emerged as a treatment modality with the highest curative potential in patients with refractory malignancies. Our group has pioneered an adoptive cell therapy platform employing total tumor RNA pulsed dendritic cells to generate large amounts of polyclonal antigen-specific T cells in both human and murine systems. As DIPGs are embryonal tumors, our objective in this proposal is to identify a set of developmentally regulated antigens that are overexpressed during oncogenesis of DIPG in order to cause immunological rejection of this tumor without the need for tumor tissue. METHODS: We employ RNA-pulsed bone marrow-derived dendritic cells to ex vivo activate tumor-reactive T cells for use in adoptive cell therapy. Here we use either total RNA isolated from tumor tissue, (TTRNA) or developmental antigens (DevAg) RNA isolated from postnatal day 4 murine brain stem. Either TTRNA-T cells or DevAg-T cells were used in adoptive cell therapy against a preclinical model of DIPG. RESULTS: Pediatric brain tumors are bland relative to peripheral tumors in terms of high expression of immunogenic antigens. Since DIPG antigens remain largely uncharacterized, we used total RNA isolated from tumor cells to generate tumor-specific T cells to use for our therapeutic approach to first demonstrate that immune responses can be generated against this tumor. We also successfully generated immunity against DIPG in a preclinical model using DevAg-T cells for adoptive cell therapy. CONCLUSION: The region- and age- specific nature of DIPG suggests that the underlying pathophysiology likely involves dysregulation of a postnatal neurodevelopmental process which occurs in embryonal tumors. Here we leverage this and demonstrate that DIPG can be effectively treated using adoptive cell therapy against overexpressed developmentally regulated antigens.

Role of Early Postradiation Magnetic Resonance Imaging Scans in Children With Diffuse Intrinsic Pontine Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ko, Christine; Kaushal, Aradhana, E-mail: kaushala@mail.nih.gov; Hammoud, Dima A.

2012-07-15

Purpose: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG). Methods and Materials: Patients were treated on a prospective study at the National Cancer Institute (Protocol no. 06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6-8 weeks. Results: Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4-13 years). Patients were treated with external-beam RT to 55.8 Gy (n = 10) or 54 Gy (nmore » = 1), with a gross tumor volume to planning target volume expansion of 1.8-2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6-8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6-8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6-8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction. Conclusions: There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6-8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6-8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best of our knowledge, this is the first documentation of this phenomenon in this cohort of patients.« less

A case report of adult cerebellar high-grade glioma with H3.1 K27M mutation: a rare example of an H3 K27M mutant cerebellar tumor.

PubMed

Funata, Nobuaki; Nobusawa, Sumihito; Nakata, Satoshi; Yamazaki, Tatsuya; Takabagake, Kazuhiko; Koike, Tsukasa; Maegawa, Tatsuya; Yamada, Ryoji; Shinoura, Nobusada; Mine, Yutaka

2018-01-01

Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

PubMed

Manley, Peter E; Trippett, Tanya; Smith, Amy A; Macy, Margaret E; Leary, Sarah E S; Boklan, Jessica; Cohen, Kenneth J; Goldman, Stewart; Kilburn, Lindsay B; Dhall, Girish; Devin, Jeanne; Herzog, Cynthia E; Partap, Sonia; Fauchet, Floris; Badreddine, Emmy; Bernard, John P; Chi, Susan N

2018-05-11

This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m 2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m 2 ; the MTD was 30 mg/m 2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m 2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG. © 2018 Wiley Periodicals, Inc.

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

ClinicalTrials.gov

2018-06-28

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.

PubMed

Zukotynski, Katherine A; Vajapeyam, Sridhar; Fahey, Frederic H; Kocak, Mehmet; Brown, Douglas; Ricci, Kelsey I; Onar-Thomas, Arzu; Fouladi, Maryam; Poussaint, Tina Young

2017-08-01

The purpose of this study was to describe baseline 18 F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18 F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18 F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18 F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [ P = 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [ P = 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [ P = 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [ P = 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [ P = 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion: 18 F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jalali, Rakesh, E-mail: rjalali@tmc.gov.i; Raut, Nirmal; Arora, Brijesh

Purpose: To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs). Methods and Materials: Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m{sup 2}, Days 1-42). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m{sup 2}, Days 1-5) was given every 28 days to a maximum of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron emission tomographymore » scans. Results: Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen patients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respectively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leucopenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients. During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly better survival than those who did not (p = 0.048). Conclusions: TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone. Further clinical trials should explore novel treatment modalities.« less

Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

ClinicalTrials.gov

2018-03-09

Central Nervous System Embryonal Tumor, Not Otherwise Specified; Malignant Glioma; Recurrent Atypical Teratoid/Rhabdoid Tumor; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Diffuse Intrinsic Pontine Glioma

WEE1 Inhibitor AZD1775 and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

ClinicalTrials.gov

2018-06-11

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

Children with minimal chance for cure: parent proxy of the child's health-related quality of life and the effect on parental physical and mental health during treatment.

PubMed

Mandrell, Belinda N; Baker, Justin; Levine, Deena; Gattuso, Jami; West, Nancy; Sykes, April; Gajjar, Amar; Broniscer, Alberto

2016-09-01

To assess health-related quality of life (HRQOL) from the time of diagnosis until disease progression in a cohort of children with diffuse intrinsic pontine glioma (DIPG). The assessment was collected from the perspectives of the child and their parents and evaluated the effect of the child's HRQOL on their parents' physical and mental well-being, thus providing insight into the optimal timing of palliative consultation, including anticipatory grief and bereavement services. This longitudinal study assessed 25 parents and their children, ages 2-17 years of age with DIPG across five time-points, baseline and weeks 2, 4, 6, 16, 24. Assessments included the PedsQL 4.0 Core Scales, PedsQL 3.0 Brain Tumor Scale, and Short-Form 36. HRQOL instruments were completed by the child (age ≥5 years) and parent-proxy (ages 2-17 years), with the parent completing the SF-36. Children's reports and parents' proxy of their child's HRQOL indicated poor physical functioning and increased anxiety at the initiation of therapy. A trending improvement in the children's HRQOL was reported by children and parents from baseline to week 6, with a decline at week 16. The childs' parent proxy reported cognitive problems, procedural anxiety and lower overall brain tumor HRQOL were assoicated with poorer self-reported parental mental status. Palliative care consultation should be initiated at the time of diagnosis and is supported in the high physical and emotional symptom burden reported by our patients, with heightened involvement initiated at 16 weeks. Prompt palliative care involvement, mitigating anxiety associated with clinic visits and procedures, management of brain tumor specific symptoms, advanced care planning, anticipatory grief and bereavement services, and care coordination may maximize HRQOL for patients and ensure positive long-term outcomes for parents of children with DIPG.

Computation of reliable textural indices from multimodal brain MRI: suggestions based on a study of patients with diffuse intrinsic pontine glioma

NASA Astrophysics Data System (ADS)

Goya-Outi, Jessica; Orlhac, Fanny; Calmon, Raphael; Alentorn, Agusti; Nioche, Christophe; Philippe, Cathy; Puget, Stéphanie; Boddaert, Nathalie; Buvat, Irène; Grill, Jacques; Frouin, Vincent; Frouin, Frederique

2018-05-01

Few methodological studies regarding widely used textural indices robustness in MRI have been reported. In this context, this study aims to propose some rules to compute reliable textural indices from multimodal 3D brain MRI. Diagnosis and post-biopsy MR scans including T1, post-contrast T1, T2 and FLAIR images from thirty children with diffuse intrinsic pontine glioma (DIPG) were considered. The hybrid white stripe method was adapted to standardize MR intensities. Sixty textural indices were then computed for each modality in different regions of interest (ROI), including tumor and white matter (WM). Three types of intensity binning were compared : constant bin width and relative bounds; constant number of bins and relative bounds; constant number of bins and absolute bounds. The impact of the volume of the region was also tested within the WM. First, the mean Hellinger distance between patient-based intensity distributions decreased by a factor greater than 10 in WM and greater than 2.5 in gray matter after standardization. Regarding the binning strategy, the ranking of patients was highly correlated for 188/240 features when comparing with , but for only 20 when comparing with , and nine when comparing with . Furthermore, when using or texture indices reflected tumor heterogeneity as assessed visually by experts. Last, 41 features presented statistically significant differences between contralateral WM regions when ROI size slightly varies across patients, and none when using ROI of the same size. For regions with similar size, 224 features were significantly different between WM and tumor. Valuable information from texture indices can be biased by methodological choices. Recommendations are to standardize intensities in MR brain volumes, to use intensity binning with constant bin width, and to define regions with the same volumes to get reliable textural indices.

Bevacizumab as Therapy for Radiation Necrosis in Four Children With Pontine Gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Arthur K., E-mail: arthur.liu@ucdenver.ed; Macy, Margaret E.; Foreman, Nicholas K.

Purpose: Diffuse pontine gliomas are a pediatric brain tumor that is fatal in nearly all patients. Given the poor prognosis for patients with this tumor, their quality of life is very important. Radiation therapy provides some palliation, but can result in radiation necrosis and associated neurologic decline. The typical treatment for this necrosis is steroid therapy. Although the steroids are effective, they have numerous side effects that can often significantly compromise quality of life. Bevacizumab, an antibody against vascular endothelial growth factor, has been suggested as a treatment for radiation necrosis. We report on our initial experience with bevacizumab therapymore » for radiation necrosis in pediatric pontine gliomas. Materials and Methods: Four children with pontine gliomas treated at the Children's Hospital in Denver and the University of Colorado Denver developed evidence of radiation necrosis both clinically and on imaging. Those 4 children then received bevacizumab as a treatment for the radiation necrosis. We reviewed the clinical outcome and imaging findings. Results: After bevacizumab therapy, 3 children had significant clinical improvement and were able to discontinue steroid use. One child continued to decline, and, in retrospect, had disease progression, not radiation necrosis. In all cases, bevacizumab was well tolerated. Conclusions: In children with pontine gliomas, bevacizumab may provide both therapeutic benefit and diagnostic information. More formal evaluation of bevacizumab in these children is needed.« less

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.

PubMed

Alli, Saira; Figueiredo, Carlyn A; Golbourn, Brian; Sabha, Nesrin; Wu, Megan Yijun; Bondoc, Andrew; Luck, Amanda; Coluccia, Daniel; Maslink, Colin; Smith, Christian; Wurdak, Heiko; Hynynen, Kullervo; O'Reilly, Meaghan; Rutka, James T

2018-05-15

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

ClinicalTrials.gov

2018-01-26

Glioblastoma Multiforme; Fibrillary Astrocytoma of Brain; Glioma of Brainstem; Anaplastic Astrocytoma; Pilomyxoid Astrocytoma; Mixed Oligodendroglioma-Astrocytoma; Brain Stem Glioma; Diffuse Intrinsic Pontine Glioma

Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma.

PubMed

Huang, Tina Y; Piunti, Andrea; Lulla, Rishi R; Qi, Jin; Horbinski, Craig M; Tomita, Tadanori; James, C David; Shilatifard, Ali; Saratsis, Amanda M

2017-04-17

Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable. These tumors are characterized by a high rate of histone H3 mutation, resulting in replacement of lysine 27 with methionine (K27M) in genes encoding H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B). Detection of these gain-of-function mutations has clinical utility, as they are associated with distinct tumor biology and clinical outcomes. Given the paucity of tumor tissue available for molecular analysis and relative morbidity of midline tumor biopsy, CSF-derived tumor DNA from patients with diffuse midline glioma may serve as a viable alternative for clinical detection of histone H3 mutation. We demonstrate the feasibility of two strategies to detect H3 mutations in CSF-derived tumor DNA from children with brain tumors (n = 11) via either targeted Sanger sequencing of H3F3A and HIST1H3B, or H3F3A c.83 A > T detection via nested PCR with mutation-specific primers. Of the six CSF specimens from children with diffuse midline glioma in our cohort, tumor DNA sufficient in quantity and quality for analysis was isolated from five (83%), with H3.3K27M detected in four (66.7%). In addition, H3.3G34V was identified in tumor DNA from a patient with supratentorial glioblastoma. Test sensitivity (87.5%) and specificity (100%) was validated via immunohistochemical staining and Sanger sequencing in available matched tumor tissue specimens (n = 8). Our results indicate that histone H3 gene mutation is detectable in CSF-derived tumor DNA from children with brain tumors, including diffuse midline glioma, and suggest the feasibility of "liquid biopsy" in lieu of, or to complement, tissue diagnosis, which may prove valuable for stratification to targeted therapies and monitoring treatment response.

Computation of reliable textural indices from multimodal brain MRI: suggestions based on a study of patients with diffuse intrinsic pontine glioma.

PubMed

Goya-Outi, Jessica; Orlhac, Fanny; Calmon, Raphael; Alentorn, Agusti; Nioche, Christophe; Philippe, Cathy; Puget, Stéphanie; Boddaert, Nathalie; Buvat, Irène; Grill, Jacques; Frouin, Vincent; Frouin, Frederique

2018-05-10

Few methodological studies regarding widely used textural indices robustness in MRI have been reported. In this context, this study aims to propose some rules to compute reliable textural indices from multimodal 3D brain MRI. Diagnosis and post-biopsy MR scans including T1, post-contrast T1, T2 and FLAIR images from thirty children with diffuse intrinsic pontine glioma (DIPG) were considered. The hybrid white stripe method was adapted to standardize MR intensities. Sixty textural indices were then computed for each modality in different regions of interest (ROI), including tumor and white matter (WM). Three types of intensity binning were compared [Formula: see text]: constant bin width and relative bounds; [Formula: see text] constant number of bins and relative bounds; [Formula: see text] constant number of bins and absolute bounds. The impact of the volume of the region was also tested within the WM. First, the mean Hellinger distance between patient-based intensity distributions decreased by a factor greater than 10 in WM and greater than 2.5 in gray matter after standardization. Regarding the binning strategy, the ranking of patients was highly correlated for 188/240 features when comparing [Formula: see text] with [Formula: see text], but for only 20 when comparing [Formula: see text] with [Formula: see text], and nine when comparing [Formula: see text] with [Formula: see text]. Furthermore, when using [Formula: see text] or [Formula: see text] texture indices reflected tumor heterogeneity as assessed visually by experts. Last, 41 features presented statistically significant differences between contralateral WM regions when ROI size slightly varies across patients, and none when using ROI of the same size. For regions with similar size, 224 features were significantly different between WM and tumor. Valuable information from texture indices can be biased by methodological choices. Recommendations are to standardize intensities in MR brain volumes, to use intensity binning with constant bin width, and to define regions with the same volumes to get reliable textural indices.

Motexafin-Gadolinium and Involved Field Radiation Therapy for Intrinsic Pontine Glioma of Childhood: A Children's Oncology Group Phase 2 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, Kristin A., E-mail: bradley@humonc.wisc.edu; Zhou Tianni; McNall-Knapp, Rene Y.

2013-01-01

Purpose: To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas. Methods and Materials: Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments overmore » 6 weeks. The total dose was 54 Gy. Results: Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18% {+-} 5%, and the estimated 1-year OS was 53% {+-} 6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension. Conclusions: Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas.« less

Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

ClinicalTrials.gov

2018-03-30

Anaplastic Astrocytoma; Brain Stem Glioma; Childhood Mixed Glioma; Fibrillary Astrocytoma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

MRI Evaluation of Non-Necrotic T2-Hyperintense Foci in Pediatric Diffuse Intrinsic Pontine Glioma.

PubMed

Clerk-Lamalice, O; Reddick, W E; Li, X; Li, Y; Edwards, A; Glass, J O; Patay, Z

2016-05-19

The conventional MR imaging appearance of diffuse intrinsic pontine glioma suggests intralesional histopathologic heterogeneity, and various distinct lesion components, including T2-hypointense foci, have been described. Here we report the prevalence, conventional MR imaging semiology, and advanced MR imaging features of non-necrotic T2-hyperintense foci in diffuse intrinsic pontine glioma. Twenty-five patients with diffuse intrinsic pontine gliomas were included in this study. MR imaging was performed at 3T by using conventional and advanced MR imaging sequences. Perfusion (CBV), vascular permeability (v e , K trans ), and diffusion (ADC) metrics were calculated and used to characterize non-necrotic T2-hyperintense foci in comparison with other lesion components, namely necrotic T2-hyperintense foci, T2-hypointense foci, peritumoral edema, and normal brain stem. Statistical analysis was performed by using Kruskal-Wallis and Wilcoxon rank sum tests. Sixteen non-necrotic T2-hyperintense foci were found in 12 tumors. In these foci, ADC values were significantly higher than those in either T2-hypointense foci (P = .002) or normal parenchyma (P = .0002), and relative CBV values were significantly lower than those in either T2-hypointense (P = .0002) or necrotic T2-hyperintense (P = .006) foci. Volume transfer coefficient values in T2-hyperintense foci were lower than those in T2-hypointense (P = .0005) or necrotic T2-hyperintense (P = .0348) foci. Non-necrotic T2-hyperintense foci are common, distinct lesion components within diffuse intrinsic pontine gliomas. Advanced MR imaging data suggest low cellularity and an early stage of angioneogenesis with leaky vessels resulting in expansion of the extracellular space. Because of the lack of biopsy validation, the underlying histoarchitectural and pathophysiologic changes remain unclear; therefore, these foci may correspond to a poorly understood biologic event in tumor evolution. © 2016 American Society of Neuroradiology.

Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen : Acute toxicity in pediatric high-grade glioma patients.

PubMed

Seidel, Clemens; von Bueren, André O; Bojko, Sabrina; Hoffmann, Marion; Pietsch, Torsten; Gielen, Gerrit H; Warmuth-Metz, Monika; Bison, Brigitte; Kortmann, Rolf-D; Kramm, Christof M

2018-03-01

As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3-18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol. Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3-4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3-4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3-4 leukopenia appeared more often in children aged 3-7 years (n = 38/85, 45%) than in children aged 8-12 years (n = 39/120, 33%) and 13-18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1-2: 44%, grade 3-4: 6% vs. grade 1-2: 28%, grade 3-4: 1%; P <0.001). Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.

Vorinostat and Radiation Therapy Followed by Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ClinicalTrials.gov

2018-06-19

Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Brain Stem Glioma; Childhood Glioblastoma; Giant Cell Glioblastoma; Gliosarcoma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Gliosarcoma

A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas.

PubMed

Guisado, D I; Singh, R; Minkowitz, S; Zhou, Z; Haque, S; Peck, K K; Young, R J; Tsiouris, A J; Souweidane, M M; Thakur, S B

2016-07-01

Diffuse intrinsic pontine gliomas are inoperable high-grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel (1)H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. We prospectively analyzed 3D multivoxel (1)H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel (1)H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment. © 2016 by American Journal of Neuroradiology.

Chronic, intermittent convection-enhanced delivery devices.

PubMed

Lewis, Owen; Woolley, Max; Johnson, David; Rosser, Anne; Barua, Neil U; Bienemann, Alison S; Gill, Steven S; Evans, Sam

2016-02-01

Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features. While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.). Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field. At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists. Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Wild-Type Reovirus in Combination With Sargramostim in Treating Younger Patients With High-Grade Relapsed or Refractory Brain Tumors

ClinicalTrials.gov

2018-03-16

Childhood Astrocytoma; Childhood Atypical Teratoid/Rhabdoid Tumor; Diffuse Intrinsic Pontine Glioma; Glioma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Neoplasm; Recurrent Childhood Glioblastoma; Recurrent Childhood Medulloblastoma; Recurrent Primitive Neuroectodermal Tumor; Refractory Brain Neoplasm

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

PubMed

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue; Wu, Yuan-Hung

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy

PubMed Central

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID:28662135

Measurable Supratentorial White Matter Volume Changes in Patients with Diffuse Intrinsic Pontine Glioma Treated with an Anti-Vascular Endothelial Growth Factor Agent, Steroids, and Radiation.

PubMed

Svolos, P; Reddick, W E; Edwards, A; Sykes, A; Li, Y; Glass, J O; Patay, Z

2017-06-01

Assessing the response to treatment in infiltrative brain tumors by using lesion volume-based response criteria is challenging. We hypothesized that in such tumors, volume measurements alone may not accurately capture changes in actual tumor burden during treatment. We longitudinally evaluated volume changes in both normal-appearing supratentorial white matter and the brain stem lesions in patients treated for diffuse intrinsic pontine glioma to determine to what extent adjuvant systemic therapies may skew the accuracy of tumor response assessments based on volumetric analysis. The anatomic MR imaging and diffusion tensor imaging data of 26 patients with diffuse intrinsic pontine glioma were retrospectively analyzed. Treatment included conformal radiation therapy in conjunction with vandetanib and dexamethasone. Volumetric and diffusion data were analyzed with time, and differences between time points were evaluated statistically. Normalized brain stem lesion volume decreased during combined treatment (slope = -0.222, P < .001) and increased shortly after completion of radiation therapy (slope = 0.422, P < .001). Supratentorial white matter volume steadily and significantly decreased with time (slope = -0.057, P < .001). Longitudinal changes in brain stem lesion volume are robust; less pronounced but measurable changes occur in the supratentorial white matter. Volume changes in nonirradiated supratentorial white matter during the disease course reflect the effects of systemic medication on the water homeostasis of normal parenchyma. Our data suggest that adjuvant nontumor-targeted therapies may have a more substantial effect on lesion volume changes than previously thought; hence, an apparent volume decrease in infiltrative tumors receiving combined therapies may lead to overestimation of the actual response and tumor control. © 2017 by American Journal of Neuroradiology.

The Integration of Biology Into the Treatment of Diffuse Intrinsic Pontine Glioma: A Review of the North American Clinical Trial Perspective.

PubMed

Clymer, Jessica; Kieran, Mark W

2018-01-01

Dramatic advances in the molecular analysis of diffuse intrinsic pontine glioma have occurred over the last decade and resulted in the identification of potential therapeutic targets. In spite of these advances, no significant improvement in the outcome has been achieved and median survival remains approximately 10 months. An understanding of the approaches that have been taken to date, why they failed, and how that information can lead the field forward is critical if we are to change the status quo . In this review, we will discuss the clinical trial landscape in North America with an overview of historical approaches that failed and what might account for this failure. We will then provide a discussion of how our understanding of the genotype of this disease has led to the development of a number of trials targeting the mutations and epigenome of diffuse intrinsic pontine gliomas and the issues related to these trials. Similarly, the introduction of methodologies to address penetration across the blood-brain barrier will be considered in the context of both targeted approaches, epigenetic modification, and immune surveillance of these tumors. The comprehensive analysis of these data, generated through cooperative groups, collaborative clinical trials, and pilot studies in North America will be the focus of the IVth Memorial Alicia Pueyo international symposium in Barcelona on March 12th, 2018 and will be compared and contrasted with a similar comprehensive analysis of the European data with the goal of bringing all of these data together to develop a uniform platform on which new rational trials can be based.

Correction to: Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

PubMed

Massimino, Maura; Biassoni, Veronica; Miceli, Rosalba; Schiavello, Elisabetta; Warmuth-Metz, Monika; Modena, Piergiorgio; Casanova, Michela; Pecori, Emilia; Giangaspero, Felice; Antonelli, Manila; Buttarelli, Francesca Romana; Potepan, Paolo; Pollo, Bianca; Nunziata, Raffaele; Spreafico, Filippo; Podda, Marta; Anichini, Andrea; Clerici, Carlo Alfredo; Sardi, Iacopo; De Cecco, Loris; Bode, Udo; Bach, Ferdinand; Gandola, Lorenza

2018-05-16

The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale).

Endoscopic third ventriculostomy for hydrocephalus in brainstem glioma: a case series.

PubMed

Kobayashi, Natsuki; Ogiwara, Hideki

2016-07-01

A brainstem glioma is an incurable brain tumor that can be complicated by hydrocephalus. A ventriculoperitoneal (VP) shunt is generally performed for the control of hydrocephalus. This study aimed to reveal the safety and efficacy of an endoscopic third ventriculostomy (ETV) for hydrocephalus in brainstem gliomas. Six patients who had pontine glioma with hydrocephalus underwent an ETV between May 2010 and November 2015. In all the cases, there were one or more symptoms of hydrocephalus (headache, nausea, vomiting, or lethargy). Retrospective review of these patients was performed using the medical records and neuroimagings. The ETV was performed safely and there were no intraoperative complications in all patients. The mean follow-up period was 12.3 months. An immediate symptomatic relief of hydrocephalus and an adequate control of symptoms were achieved without a VP shunt in all patients. The ETV is considered to be an effective and safe procedure for the treatment of hydrocephalus in brainstem gliomas. Determining the ventriculostomy site according to the preoperative MRI in each case is considered to be important for the safe procedure.

Brainstem angiocentric glioma: report of 2 cases.

PubMed

Weaver, Kristin J; Crawford, Lexi M; Bennett, Jeffrey A; Rivera-Zengotita, Marie L; Pincus, David W

2017-10-01

Angiocentric glioma is a rare tumor that was recognized by the WHO Classification of Tumours of the Central Nervous System as a distinct clinicopathological entity in 2007. Since this initial description, the vast majority of cases of angiocentric glioma reported in the literature have involved tumors of the cerebral hemispheres. To date, only 1 case of angiocentric glioma arising from the posterior midbrain has been reported. The authors present the cases of 2 pediatric patients who were found to have brainstem angiocentric gliomas. The clinical course, radiological and pathological features, treatment, and follow-up are described. The first case is one of a 5-year-old girl who presented with double vision, headache, and nausea and was found to have a midbrain lesion with pathological features consistent with angiocentric glioma. She was treated with resection and endoscopic third ventriculostomy (ETV), followed by close observation and serial neuroimaging. The second case is one of a 6-year-old boy who presented with progressive mouth drooping and problems with balance. He was found to have a pontine lesion with pathological features consistent with angiocentric glioma. This patient was treated with ETV, followed by close observation and serial neuroimaging. This report includes 6 and 1.5 years of follow-up of the patients, respectively. While there are limited data regarding the prognosis or long-term management of patients with brainstem angiocentric gliomas, the cases described in this report suggest an indolent course for this tumor, similar to the course of angiocentric gliomas located in the cerebral hemispheres.

Study of LOXO-101 (Larotrectinib) in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE)

ClinicalTrials.gov

2017-09-05

Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms; Sarcoma; Colorectal Neoplasms; Salivary Gland Neoplasms; Biliary Tract Neoplasms; Brain Neoplasm, Primary; Carcinoma, Ductal, Breast; Melanoma; Solid Tumors; Glioblastoma; Bile Duct Neoplasms; Astrocytoma; Head and Neck Squamous Cell Carcinoma; Pontine Glioma; Pancreatic Neoplasms; Ovarian Neoplasms; Carcinoma, Renal Cell; Cholangiocarcinoma; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas

Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

DTIC Science & Technology

2012-09-01

Hydrocephalus mice were excluded from this calculation. With this particular experiment the hydrocephalus rate is 57% (due to the formation of...is completed. We have generated 10 tumors by injecting 14 mice and an example of one is described in the figure below. Hydrocephalus mice were...excluded from the 4 analysis. The hydrocephalus rate was 51% for this experiment due to the formation of leptomeningeal tumor

16,16-Dimethyl prostaglandin E2 increases survival in mice following irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walden, T.L. Jr.; Patchen, M.; Snyder, S.L.

1987-03-01

16,16-Dimethyl prostaglandin E2 (DiPGE2), a stable analog of PGE2, increases the LD50/30 survival in CD2F1 male mice when given prior to ionizing radiation. Subcutaneous administration of 40 micrograms of DiPGE2 30 min prior to /sup 60/Co gamma irradiation extends the LD50/30 from 9.39 Gy in the control animals to 16.14 Gy in DiPGE2 treated, with a dose reduction factor of 1.72 (95% confidence limits: 1.62, 1.82). The degree of protection is dependent on both the time of administration and the dose of the prostaglandin. Ten micrograms administered 5 min prior to receiving a lethal dose of 10 Gy provides 90%more » survival but only 10% survival if administered 30 min prior to irradiation. Experiments to determine the in vivo concentration of DiPGE2 in organs postinjection show increased levels over time, but these are not correlated with protection. At 30 min after injection, as much as 80% of the DiPGE2 present in the spleen and plasma is unmetabolized. These results suggest that the protection results from the physiologic action of DiPGE2 rather than direct in vivo detoxification of radicals.« less

Phase 1/2 Study of LOXO-195 in Patients With Previously Treated NTRK Fusion Cancers

ClinicalTrials.gov

2018-05-30

Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms; Sarcoma; Colorectal Neoplasms; Salivary Gland Neoplasms; Biliary Tract Neoplasms; Brain Neoplasm, Primary; Melanoma; Glioblastoma; Bile Duct Neoplasms; Astrocytoma; Head and Neck Squamous Cell Carcinoma; Pontine Glioma; Pancreatic Neoplasms; Ovarian Neoplasms; Carcinoma, Renal Cell; Cholangiocarcinoma; Skin Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Intestinal Neoplasms; Thyroid Cancer; GIST; Malignant Peripheral Nerve Sheath Tumors; Breast Secretory Carcinoma; Uterine Neoplasms; Fibrosarcoma; Infantile Fibrosarcoma; Congenital Mesoblastic Nephroma; Central Nervous System Neoplasms

Four-year follow-up study in a NF1 boy with a focal pontine hamartoma.

PubMed

Parisi, Pasquale; Persechino, Severino; Paolino, Maria Chiara; Nicita, Francesco; Torrente, Isabella; Bozzao, Alessandro; Villa, Maria Pia

2013-02-11

Neurofibromatosis is a collective name for a group of genetic conditions in which benign tumours affect the nervous system. Type 1 is caused by a genetic mutation in the NF1 gene (OMIM 613113) and symptoms can vary dramatically between individuals, even within the same family. Some people have very mild skin changes, whereas others suffer severe medical complications. The condition usually appears in childhood and is diagnosed if two of the following are present: six or more café-au-lait patches larger than 1.5 cm in diameter, axillary or groin freckling, 2 or more Lisch nodules (small pigmented areas in the iris of the eye), 2 or more neurofibromas, optic pathway gliomas, bone dysplasia, and a first-degree family relative with Neurofibromatosis type 1. The pattern of inheritance is autosomal dominant, however, half of all NF1 cases are 'sporadic' and there is no family history. Neurofibromatosis type 1 is an extremely variable condition whose morbidity and mortality is largely dictated by the occurrence of the many complications that may involve any of the body systems. We describe a family affected by NF1 in whom genetic molecular analysis identified the same mutation in the son and father. Routine MRI showed pontine focal lesions in the eight-year-old son, though not in the father. We performed a four years follow-up study and at follow-up pontine hamartoma size remained unchanged in the son, and the father showed still no brain lesions, confirming thus an intra-familial phenotype variability.

EG-01EPIGENETIC INACTIVATION OF ARGININE BIOSYNTHESIS PATHWAY IN PAEDIATRIC HIGH GRADE GLIOMA

PubMed Central

Channathodiyil, Prasanna; Kardooni, Hoda; Khozoie, Combiz; Nelofer, Syed; Darling, John; Morris, Mark; Warr, Tracy

2014-01-01

Aberrant cellular metabolism contributes significantly to the growth and proliferation of several tumour types. Identification of genes that control critical metabolic pathways is a major factor in the development of novel therapies that target metabolic defects in tumour cells. Our aim is to identify such genes in paediatric high grade glioma that are altered due to promoter hyper-methylation of cytosine residues in CpG dinucleotides. Genome wide DNA methylation profiling using Illumina infinium methylation 450K bead chip array was performed on 18 well-characterised short term cultures derived from paediatric high grade astrocytoma including 3 from diffuse intrinsic pontine glioma. Data analyses were based on beta scores of probes for each gene as measures of intensities of methylation. Genes were selected with beta scores of tumour > =0.70 and that of normal human astrocytes < =0.30. We identified that two vital genes involved in the regulation of arginine biosynthetic pathway, argininosuccinate synthetase 1(ASS1) and argininosuccinate lyase (ASL) were methylated in 9/18 (50%) cases. Hyper methylation was confirmed by methylation-specific PCR and up-regulation of gene expression following treatment with 2 µM 5-aza-2'-deoxyctidine. Down-regulation of ASS1 in hyper methylated samples was confirmed by Western blot analysis. Our findings report epigenetic deregulation of ASS1 and ASL in a subset of paediatric high grade glioma. The enzymes encoded by these genes are essential elements of urea cycle that function together in the de novo synthesis of arginine from citrulline. Tumour cells with deficient ASS1/ASL depend on external sources of arginine for survival and have been reported to be sensitive to autophagic cell death induced by arginine starvation. Therefore, further investigation may render the possibility of arginine-deprivation therapy in such sub type of paediatric high grade glioma. This therapeutic approach is of interest as tumour cells with abnormal expression of ASS1/ASL can be specifically targeted, while the normal cells can be spared.

Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1.

PubMed

Josupeit, Rafael; Bender, Sebastian; Kern, Sonja; Leuchs, Barbara; Hielscher, Thomas; Herold-Mende, Christel; Schlehofer, Jörg R; Dinsart, Christiane; Witt, Olaf; Rommelaere, Jean; Lacroix, Jeannine

2016-05-19

Combining virus-induced cytotoxic and immunotherapeutic effects, oncolytic virotherapy represents a promising therapeutic approach for high-grade glioma (HGG). A clinical trial has recently provided evidence for the clinical safety of the oncolytic parvovirus H-1 (H-1PV) in adult glioblastoma relapse patients. The present study assesses the efficacy of H-1PV in eliminating HGG initiating cells. H-1PV was able to enter and to transduce all HGG neurosphere culture models (n = 6), including cultures derived from adult glioblastoma, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Cytotoxic effects induced by the virus have been observed in all HGG neurospheres at half maximal inhibitory concentration (IC50) doses of input virus between 1 and 10 plaque forming units per cell. H-1PV infection at this dose range was able to prevent tumorigenicity of NCH421k glioblastoma multiforme (GBM) "stem-like" cells in NOD/SCID mice. Interestingly NCH421R, an isogenic subclone with equal capacity of xenograft formation, but resistant to H-1PV infection could be isolated from the parental NCH421k culture. To reveal changes in gene expression associated with H-1PV resistance we performed a comparative gene expression analysis in these subclones. Several dysregulated genes encoding receptor proteins, endocytosis factors or regulators innate antiviral responses were identified and represent intriguing candidates for to further study molecular mechanisms of H-1PV resistance.

Malignant Brain Tumours in Children : Present and Future Perspectives.

PubMed

Rutka, James T

2018-05-01

In contrast to many of the malignant tumors that occur in the central nervous system in adults, the management, responses to therapy, and future perspectives of children with malignant lesions of the brain hold considerable promise. Within the past 5 years, remarkable progress has been made with our understanding of the basic biology of the molecular genetics of several pediatric malignant brain tumors including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumour, and high grade glioma/diffuse intrinsic pontine glioma. The recent literature in pediatric neuro-oncology was reviewed, and a summary of the major findings are presented. Meaningful sub-classifications of these tumors have arisen, placing children into discrete categories of disease with requirements for targeted therapy. While the mainstay of therapy these past 30 years has been a combination of central nervous system irradiation and conventional chemotherapy, now with the advent of high resolution genetic mapping, targeted therapies have emerged, and less emphasis is being placed on craniospinal irradiation. In this article, the present and future perspective of pediatric brain malignancy are reviewed in detail. The progress that has been made offers significant hope for the future for patients with these tumours.

Protection of mice against mixed fission neutron-gamma (n: gamma = 1:1) irradiation by WR-2721, 16,16-dimethyl PGE2, and the combination of both agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steel, L.K.; Walden, T.L. Jr.; Hughes, H.N.

1988-09-01

The survival of mice after whole-body exposure to a modified fission neutron-gamma field (n: gamma = 1:1) was used to examine radiation protection by WR-2721, 16,16-dimethyl PGE2(DiPGE2), and the combination of both agents. Administration of WR-2721 (453 mg/kg) increased the LD50/30 from 5.24 to 7.17 Gy (DMF = 1.37), whereas pretreatment with DiPGE2 (1.6 mg/kg) increased the LD50/30 to 5.77 Gy (dose modification factor (DMF) = 1.10). The combination of 453 mg/kg WR-2721 and 0.4 mg/kg DiPGE2 resulted in an LD50/30 of 7.33 Gy, yielding a DMF of 1.39. However, no significant difference in protection was obtained with the combinationmore » of the two agents compared to that seen with WR-2721 alone.« less

Basilar artery atherosclerotic plaques in paramedian and lacunar pontine infarctions: a high-resolution MRI study.

PubMed

Klein, Isabelle F; Lavallée, Philippa C; Mazighi, Mikael; Schouman-Claeys, Elisabeth; Labreuche, Julien; Amarenco, Pierre

2010-07-01

Pontine infarction is most often related to basilar artery atherosclerosis when the lesion abuts on the basal surface (paramedian pontine infarction), whereas small medial pontine lesion is usually attributed to small vessel lipohyalinosis. A previous study has found that high-resolution MRI can detect basilar atherosclerotic plaques in up to 70% of patient with paramedian pontine infarction, even in patients with normal angiograms, but none has evaluated the presence of basilar artery plaque by high-resolution MRI in patients with small medial pontine lesion in the medial part of the pons. Consecutive patients with pontine infarction underwent basilar angiography using time-of-flight and contrast-enhanced 3-dimensional MR angiography to assess the presence of basilar artery stenosis and high-resolution MRI to assess the presence of atherosclerotic plaque. Basilar artery angiogram was scored as "normal," "irregular," or "stenosed" >or=30%" and basilar artery by high-resolution MRI was scored as "normal" or "presence of plaque." Medial pontine infarcts were divided into paramedian pontine infarction and small medial pontine lesion groups. Forty-one patients with pontine infarction were included, 26 with paramedian pontine infarction and 15 with small medial pontine lesion. High-resolution MRI detected basilar artery atherosclerosis in 42% of patients with a pontine infarction and normal basilar angiograms. Among patients with paramedian pontine infarction, 65% had normal basilar angiograms but 77% had basilar artery atherosclerosis detected on high-resolution MRI. Among patients with small medial pontine lesion, 46% had normal basilar angiograms but 73% had basilar artery plaques detected on by high-resolution MRI. This study suggests that medial pontine lacunes may be due to a penetrating artery disease secondary to basilar artery atherosclerosis. High-resolution MRI could help precise stroke subtyping.

Cortical and subcortical afferents to the nucleus reticularis tegmenti pontis and basal pontine nuclei in the macaque monkey.

PubMed

Giolli, R A; Gregory, K M; Suzuki, D A; Blanks, R H; Lui, F; Betelak, K F

2001-01-01

Anatomical findings are presented that identify cortical and subcortical sources of afferents to the nucleus reticularis tegmenti pontis (NRTP) and basal pontine nuclei. Projections from the middle temporal visual area (MT), medial superior temporal visual area (MST), lateral intraparietal area (LIP), and areas 7a and 7b to the basal pontine nuclei were studied using 3H-leucine autoradiography. The results complemented a parallel study of retrograde neuronal labeling attributable to injecting WGA-HRP into NRTP and neighboring pontine nuclei. Small 3H-leucine injections confined to MT, MST, LIP, area 7a, or area 7b, produced multiple patches of pontine terminal label distributed as follows: (1) An injection within MT produced terminal label limited to the dorsolateral and lateral pontine nuclei. (2) Injections restricted to MST or LIP showed patches of terminal label in the dorsal, dorsolateral, lateral, and peduncular pontine nuclei. (3) Area 7a targets the dorsal, dorsolateral, lateral, peduncular, and ventral pontine nuclei, whereas area 7b projects, additionally, to the dorsomedial and paramedian pontine nuclei. Notably, no projections were seen to NRTP from any of these cortical areas. In contrast, injections made by other investigators into cortical areas anterior to the central sulcus revealed cerebrocortical afferents to NRTP, in addition to nuclei of the basal pontine gray. With our pontine WGA-HRP injections, retrograde neuronal labeling was observed over a large extent of the frontal cortex continuing onto the medial surface which included the lining of the cingulate sulcus and cingulate gyrus. Significant subcortical sources for afferents to the NRTP and basal pontine nuclei were the zona incerta, ventral mesencephalic tegmentum, dorsomedial hypothalamic area, rostral interstitial nucleus of the medial longitudinal fasciculus, red nucleus, and subthalamic nucleus. The combined anterograde and retrograde labeling data indicated that visuo-motor cortico-pontine pathways arising from parietal cortices target only the basal pontine gray, whereas the NRTP, together with select pontine nuclei, is a recipient of afferents from frontal cortical areas. The present findings implicate the existence of parallel direct and indirect cortico-pontine pathways from frontal motor-related cortices to NRTP and neighboring pontine nuclei.

Pontin is required for pre-TCR signaling at the β-selection checkpoint in T cell development.

PubMed

Boo, Kyungjin; Baek, Sung Hee; Lee, Ho

2014-04-25

Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Based on high expression in lymphoid tissues, we examined whether Pontin has a T cell-specific function. We generated Pontin(f/f);Lck-Cre mice, in which Pontin can be conditionally deleted in T cells and then explored T cell-specific function of Pontin in vivo. Here, we show that specific abrogation of Pontin expression in T cells almost completely blocked development of αβ T cells at the β-selection checkpoint by inducing cell apoptosis indicating that Pontin is essential for early T cell development. Pontin-deficient thymocytes show a comparable expression level of T cell receptor (TCR)β chain, but have enhanced activation of p53 and Notch signaling compared to wild-type thymocytes. Intriguingly, the developmental block of αβ T cells can be partially rescued by loss of p53. Together, our data demonstrate a novel role of Pontin as a crucial regulator in pre-TCR signaling during T cell development. Copyright © 2014 Elsevier Inc. All rights reserved.

Pontin Acts as a Potential Biomarker for Poor Clinical Outcome and Promotes Tumor Invasion in Hilar Cholangiocarcinoma.

PubMed

Sun, Qi; Li, Fanni; Yu, Songyang; Zhang, Xiang; Shi, Feiyu; She, Junjun

2018-01-01

Hilar cholangiocarcinoma (HC) is a devastating malignancy that carries a poor overall prognosis. As a member of the AAA+ superfamily, Pontin becomes highly expressed in several malignant tumors, which contributes to tumor progression and influences tumor prognosis. In our research, Pontin expression in tumor specimens resected from 86 HC patients was detected by immunohistochemistry. Interestingly, high expression of Pontin was significantly associated with lymph node metastasis ( p = 0.011) and tumor node metastasis (TNM) stage ( p = 0.005). The Kaplan-Meier overall survival rate and multivariate analyses were performed to evaluate the prognosis of patients with HC. Patients with high Pontin expression had significantly poorer overall survival outcomes. Multivariate analyses found that Pontin was an independent prognostic factor ( p = 0.001). Moreover, bioinformatics analysis confirmed the increase in Pontin mRNA expression levels in cholangiocarcinoma tissues. In addition, in vitro experiments showed that Pontin expression was inhibited at the mRNA as well as protein levels after transfection with Pontin siRNA in human cholangiocarcinoma cell lines. Moreover, significant suppression of cell invasion was observed after the downregulation of Pontin. Taken together, the present study suggested that Pontin could act as a potential prognostic predictor, which might be a new valuable molecular candidate for the prevention and treatment of HC.

Tumors of the central nervous system: clinical aspects, molecular mechanisms, unanswered questions, and future research directions.

PubMed

Babcock, Michael A; Kostova, Felina V; Guha, Abhijit; Packer, Roger J; Pollack, Ian F; Maria, Bernard L

2008-10-01

Central nervous system tumors are the most common solid tumors in children. Many histological subtypes and biological variants exist. The 2007 Neurobiology of Disease in Children Symposium, held in conjunction with the 36th annual meeting of the Child Neurology Society, aimed to define current knowledge in the field and to develop specific aims for future clinical, translational, and fundamental science. Because of advances in structural and metabolic imaging, surgical technique, and combination therapies, the life expectancy of children with some of the most common tumors, such as cerebellar astrocytomas and medulloblastomas, has improved. Other common tumor types, including diffuse pontine gliomas and malignant embryonal tumors, still have a dismal prognosis. As novel therapies are identified for pediatric central nervous system tumors, long-term survival may be associated with considerable disability. A cooperative effort is crucial to early diagnosis and to translating basic research findings into safe, effective new treatments.

ED-11DEMOGRAPHIC, CLINICAL AND SURVIVAL FEATURES OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN ISTANBUL UNIVERSITY, ONCOLOGY INSTITUTE DURING 22 YEARS (1990-2012)

PubMed Central

Kebudi, Rejin; Darendeliler, Emin; Gorgun, Omer; Agaoglu, Fulya Yaman; Uludag, Dilek; Ayan, Inci

2014-01-01

OBJECTIVES: The aim of this study is to identify demographic, clinical and survival features of childhood central nervous system (CNS) tumors admitted to Istanbul University, Oncology Institute, Pediatric Hematology-Oncology in 22 years. METHODS: Charts of patients <19 years admitted were evaluated retrospectively. (Istanbul University Cerrahpasa Medical Faculty Clinical Trials, Ethics Committee no. 83045809-3507). RESULTS: CNS tumors (n = 494) comprised 20,5 % of the 2413 children with cancer, diagnosed between 1990-2012. Male/female:1,25. Median age was 6,5 years (0.13-18yrs). 51 patients had NF1, 4 had tuberosclerosis. Distrubution according to histopathology/diagnosis was as follows: 35 % (n = 173) Medulloblastoma and other embryonal tumors, 17% (n = 84) astrocytoma other than optic gliomas, 16,5% (n = 82) ependymoma and choroid plexus tumors, 14% (n = 69) optic glioma, and 12,8% (n = 63) diffuse pontine gliomas. 5-yrs and 10-yrs overall survival (OS) in the whole group were 61% and 55,4% respectively. 29,6 % of the patients had metastasis in the CSF and/or the spinal axis and/or gross residual tumor, these had 5-yrs and 10-yrs OS of 36,5% and 27,2 %, whereas the rest had 5-yrs and 10-yrs OS are 73% and 68,9% (p < 0,001). Medulloblastoma and other embryonal tumors had 5-yrs and 10-yrs OS 58,4% and 57,5% . Ependymoma and choroid plexus carcinomas had 5-yrs and 10-yrs OS of 48,4% and 31,4%. Low grade and high grade astrocytomas had 10-yrs OS of 95 % and 40% respectively (p < 0,001). Second tumors were diagnosed in two medulloblastoma patients, one malignant nerve sheath tumor at 9 years, a case with concurrent high glade glioma and mediastinal lymphoblastic lymphoma at 3,5 years. CONCLUSIONS: The most common solid tumor in our cohort, similar to developed countries, was CNS tumors. Embryonal tumors comprised the majority of the CNS tumors treated in our institution. 5 year survival was 61 %. These children should be followed up for late effects including second tumors.

Architecture of the pontin/reptin complex, essential in the assembly of several macromolecular complexes

PubMed Central

Torreira, Eva; Jha, Sudhakar; López-Blanco, José R.; Arias-Palomo, Ernesto; Chacón, Pablo; Cañas, Cristina; Ayora, Sylvia; Dutta, Anindya; Llorca, Oscar

2008-01-01

Summary Pontin and reptin belong to the AAA+ family and they are essential for the structural integrity and catalytic activity of several chromatin remodeling complexes. They are also indispensable for the assembly of several ribonucleoprotein complexes, including telomerase. Here, we propose a structural model of the yeast pontin/reptin complex based on a cryo-electron microscopy reconstruction at 13 Å. Pontin/reptin hetero-dodecamers were purified from in vivo assembled complexes forming a double ring. Two rings interact through flexible domains projecting from each hexamer, constituting an atypical asymmetric form of oligomerization. These flexible domains and the AAA+ cores reveal significant conformational changes when compared to the crystal structure of human pontin that generate enlarged channels. This structure of endogenously assembled pontin/reptin complexes is different to previously described structures, suggesting that pontin and reptin could acquire distinct structural states to regulate their broad functions as molecular motors and scaffolds for nucleic acids and proteins. PMID:18940606

Behavioral toxicity of selected radioprotectors

NASA Astrophysics Data System (ADS)

Landauer, M. R.; Davis, H. D.; Kumar, K. S.; Weiss, J. F.

1992-10-01

Effective radioprotection with minimal behavioral disruption is essential for the selection of protective agents to be used in manned spaceflight. This overview summarizes the studies on the behavioral toxicity of selected radioprotectors classified as phosphorothioates (WR-2721, WR-3689), bioactive lipids (16, 16 dimethylprostaglandin E2(DiPGE2), platelet activating factor (PAF), leukotriene C4), and immunomodulators (glucan, synthetic trehalose dicorynomycolate, and interleukin-1). Behavioral toxicity was examined in laboratory mice using a locomotor activity test. For all compounds tested, there was a dose-dependent decrease in locomotor behavior that paralleled the dose-dependent increase in radioprotection. While combinations of radioprotective compounds (DiPGE2 plus WR-2721) increased radioprotection, they also decreased locomotor activity. The central nervous system stimulant, caffeine, was able to mitigate the locomotor decrement produced by WR-3689 or PAF.

Nitric oxide in B6 mouse and nitric oxide-sensitive soluble guanylate cyclase in cat modulate acetylcholine release in pontine reticular formation.

PubMed

Lydic, Ralph; Garza-Grande, Ricardo; Struthers, Richard; Baghdoyan, Helen A

2006-05-01

ACh regulates arousal, and the present study was designed to provide insight into the neurochemical mechanisms modulating ACh release in the pontine reticular formation. Nitric oxide (NO)-releasing beads microinjected into the pontine reticular formation of C57BL/6J (B6) mice significantly (P < 0.0001) increased ACh release. Microdialysis delivery of the NO donor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC-12) to the mouse pontine reticular formation also caused a concentration-dependent increase in ACh release (P < 0.001). These are the first neurochemical data showing that ACh release in the pontine reticular formation of the B6 mouse is modulated by NO. The signal transduction cascade through which NO modulates ACh release in the pontine reticular formation has not previously been characterized. Therefore, an additional series of studies quantified the effects of a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), on ACh release in the cat medial pontine reticular formation. During naturally occurring states of sleep and wakefulness, but not anesthesia, ODQ caused a significant (P < 0.001) decrease in ACh release. These results show for the first time that NO modulates ACh in the medial pontine reticular formation of the cat via an NO-sensitive sGC signal transduction cascade. Isoflurane and halothane anesthesia have been shown to decrease ACh release in the medial pontine reticular formation. The finding that ODQ did not alter ACh release during isoflurane or halothane anesthesia demonstrates that these anesthetics disrupt the NO-sensitive sGC-cGMP pathway. Considered together, results from the mouse and cat indicate that NO modulates ACh release in arousal-promoting regions of the pontine reticular formation via an NO-sensitive sGC-cGMP pathway.

Pontin functions as an essential coactivator for Oct4-dependent lincRNA expression in mouse embryonic stem cells.

PubMed

Boo, Kyungjin; Bhin, Jinhyuk; Jeon, Yoon; Kim, Joomyung; Shin, Hi-Jai R; Park, Jong-Eun; Kim, Kyeongkyu; Kim, Chang Rok; Jang, Hyonchol; Kim, In-Hoo; Kim, V Narry; Hwang, Daehee; Lee, Ho; Baek, Sung Hee

2015-04-10

The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states. Although the importance of various epigenetic machineries for controlling pluripotency of embryonic stem (ES) cells has been previously studied, how chromatin modifiers cooperate with specific transcription factors still remains largely elusive. Here, we find that Pontin chromatin remodelling factor plays an essential role as a coactivator for Oct4 for maintenance of pluripotency in mouse ES cells. Genome-wide analyses reveal that Pontin and Oct4 share a substantial set of target genes involved in ES cell maintenance. Intriguingly, we find that the Oct4-dependent coactivator function of Pontin extends to the transcription of large intergenic noncoding RNAs (lincRNAs) and in particular linc1253, a lineage programme repressing lincRNA, is a Pontin-dependent Oct4 target lincRNA. Together, our findings demonstrate that the Oct4-Pontin module plays critical roles in the regulation of genes involved in ES cell fate determination.

Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness.

PubMed

Vanini, Giancarlo; Baghdoyan, Helen A

2013-03-01

Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the extracellular space regulate arousal state and cognition by volume transmission via extrasynaptic GABAA receptors. GABAergic transmission in the pontine reticular formation promotes wakefulness. No previous studies have determined whether an agonist at extrasynaptic GABAA receptors administered into the pontine reticular formation alters sleep and wakefulness. Therefore, this study used gaboxadol (THIP; agonist at extrasynaptic GABAA receptors that contain a δ subunit) to test the hypothesis that extrasynaptic GABAA receptors within the pontine reticular formation modulate sleep and wakefulness. Within/between subjects. University of Michigan. Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 10). Microinjection of gaboxadol, the nonsubtype selective GABAA receptor agonist muscimol (positive control), and saline (negative control) into the rostral pontine reticular formation. Gaboxadol significantly increased wakefulness and decreased both nonrapid eye movement sleep and rapid eye movement sleep in a concentration-dependent manner. Relative to saline, gaboxadol did not alter electroencephalogram power. Microinjection of muscimol into the pontine reticular formation of the same rats that received gaboxadol increased wakefulness and decreased sleep. Tonic inhibition via extrasynaptic GABAA receptors that contain a δ subunit may be one mechanism by which the extracellular pool of endogenous GABA in the rostral pontine reticular formation promotes wakefulness. Vanini G; Baghdoyan HA. Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness. SLEEP 2013;36(3):337-343.

Projections from the pontine nuclei proper and reticular tegmental nucleus onto the cerebellar cortex in the cat. An autoradiographic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawamura, K.; Hashikawa, T.

1981-09-20

After injections of 0.5 microliter of tritiated leucine and/or proline into various parts of the pontine nuclei proper or the pontine tegmental reticular nucleus (N.r.t.) of 34 cats, labeled terminals of pontocerebellar fibers were found in the cerebellar cortex. Fibers from the pontine nuclei and N.r.t. terminate as mossy fibers in the granular layer of the cerebellum, and no evidence is obtained of labeled fibers in the molecular layer. The pontocerebellar projection is, in general, bilateral with a contralateral preponderance, and a complex organization has been shown to exist in the cat. Clear evidence of divergence of this projection frommore » a small pontine area has been demonstrated. Thus, the dorsolateral nucleus has a heavy projection to lobule VII, besides modest projections to lobules VI, VIII, and IX, crus I and II, paraflocculus, and paramedian lobule. On the other hand, a particular cerebellar region receives afferent fibers from several pontine regions, confirming previous HRP studies. This is a convergent feature of the pontocerebellar projections. In addition, small adjoining areas within a pontine subdivision have different patterns of cerebellar projections, showing preferential sites of terminations. The cerebellar projection from the N.r.t. shows an essentially similar organization as the projection from the pontine nuclei proper, an apparent difference being only that the former is more extensive in the fields of termination than the latter. Some evidence for a parasagittal termination of pontocerebellar projections to the paramedian lobule has been found in this study.« less

GABAergic Neurotransmission in the Pontine Reticular Formation Modulates Hypnosis, Immobility, and Breathing during Isoflurane Anesthesia

PubMed Central

Vanini, Giancarlo; Watson, Christopher J.; Lydic, Ralph; Baghdoyan, Helen A.

2009-01-01

Background Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that: 1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and 2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. Methods To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer’s (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Results Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane co-varied with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Conclusion Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate. PMID:19034094

Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia.

PubMed

Vanini, Giancarlo; Watson, Christopher J; Lydic, Ralph; Baghdoyan, Helen A

2008-12-01

Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA uptake inhibitor nipecotic acid, and the GABA synthesis inhibitor 3-mercaptopropionic acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic acid and 3-mercaptopropionic acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic acid also increased breathing rate. Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.

Extrasynaptic GABAA Receptors in Rat Pontine Reticular Formation Increase Wakefulness

PubMed Central

Vanini, Giancarlo; Baghdoyan, Helen A.

2013-01-01

Study Objectives: Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the extracellular space regulate arousal state and cognition by volume transmission via extrasynaptic GABAA receptors. GABAergic transmission in the pontine reticular formation promotes wakefulness. No previous studies have determined whether an agonist at extrasynaptic GABAA receptors administered into the pontine reticular formation alters sleep and wakefulness. Therefore, this study used gaboxadol (THIP; agonist at extrasynaptic GABAA receptors that contain a δ subunit) to test the hypothesis that extrasynaptic GABAA receptors within the pontine reticular formation modulate sleep and wakefulness. Design: Within/between subjects. Setting: University of Michigan. Patients or Participants: Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 10). Interventions: Microinjection of gaboxadol, the nonsubtype selective GABAA receptor agonist muscimol (positive control), and saline (negative control) into the rostral pontine reticular formation. Measurements and Results: Gaboxadol significantly increased wakefulness and decreased both nonrapid eye movement sleep and rapid eye movement sleep in a concentration-dependent manner. Relative to saline, gaboxadol did not alter electroencephalogram power. Microinjection of muscimol into the pontine reticular formation of the same rats that received gaboxadol increased wakefulness and decreased sleep. Conclusion: Tonic inhibition via extrasynaptic GABAA receptors that contain a δ subunit may be one mechanism by which the extracellular pool of endogenous GABA in the rostral pontine reticular formation promotes wakefulness. Citation: Vanini G; Baghdoyan HA. Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness. SLEEP 2013;36(3):337-343. PMID:23450652

Isolated Cataplexy and REM Sleep Behavior Disorder After Pontine Stroke

PubMed Central

Reynolds, Thomas Q.; Roy, Asim

2011-01-01

Cataplexy is a complex neurologic phenomenon during wakefulness probably resulting from impairment of pontine and hypothalamic control over muscle tone. REM sleep behavior disorder (RSBD) is characterized by the presence of REM sleep without atonia manifesting clinically as disruptive or injurious behaviors. We present here a patient with both cataplexy and RSBD following pontine encephalomalacia. The clinical presentation provides insight into the possible pathobiology of both waking and sleeping disorders of REM sleep regulation. Citation: Reynolds TQ; Roy A. Isolated cataplexy and REM sleep behavior disorder after pontine stroke. J Clin Sleep Med 2011;7(2):211-213. PMID:21509338

Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats.

PubMed

Sugaya, Kimio; Nishijima, Saori; Kadekawa, Katsumi; Ashitomi, Katsuhiro; Ueda, Tomoyuki; Yamamoto, Hideyuki

2014-10-01

The rostral pontine reticular formation has a strong inhibitory effect on micturition by facilitating lumbosacral glycinergic neurons. We assessed the influence of the rostral pontine reticular formation on the micturition reflex after noradrenaline injection in the medial frontal lobe. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation. Continuous cystometry was performed in 28 female rats. After the interval between bladder contractions was shortened by noradrenaline injection in the medial frontal lobe we injected glutamate or flavoxate hydrochloride in the rostral pontine reticular formation or intravenously injected flavoxate or propiverine. The change in bladder activity was examined. Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions. In contrast to the bladder contraction interval before and after noradrenaline injection in the medial frontal lobe, the interval was prolonged after noradrenaline injection when glutamate or flavoxate was injected in the rostral pontine reticular formation, or flavoxate was injected intravenously. Noradrenaline injection in the medial frontal lobe plus intravenous propiverine injection also prolonged the interval compared to that after noradrenaline injection alone. However, the interval after noradrenaline injection in the medial frontal lobe plus intravenous injection of propiverine was shorter than that before noradrenaline injection only. Medial frontal lobe neurons excited by noradrenaline may facilitate the micturition reflex via activation of inhibitory interneurons, which inhibit descending rostral pontine reticular formation neurons that innervate the lumbosacral glycinergic inhibitory neurons. Therefore, the mechanism of micturition reflex facilitation by the activation of medial frontal lobe neurons involves the rostral pontine reticular formation. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Dorsomedial pontine neurons with descending projections to the medullary reticular formation express orexin-1 and adrenergic alpha2A receptor mRNA.

PubMed

Volgin, Denys V; Malinowska, Monika; Kubin, Leszek

2009-08-14

Neurons located in the dorsomedial pontine rapid eye movement (REM) sleep-triggering region send axons to the medial medullary reticular formation (mMRF). This pathway is believed to be important for the generation of REM sleep motor atonia, but other than that they are glutamatergic little is known about neurochemical signatures of these pontine neurons important for REM sleep. We used single-cell reverse transcription and polymerase chain reaction (RT-PCR) to determine whether dorsomedial pontine cells with projections to the mMRF express mRNA for selected membrane receptors that mediate modulatory influences on REM sleep. Fluorescein (FITC)-labeled latex microspheres were microinjected into the mMRF of 26-34-day-old rats under pentobarbital anesthesia. After 5-6 days, rats were sacrificed, pontine slices were obtained and neurons were dissociated from 400 to 600 microm micropunches extracted from dorsomedial pontine reticular formation. We found that 32 out of 51 FITC-labeled cells tested (63+/-7% (SE)) contained the orexin type 1 receptor (ORX1r) mRNA, 27 out of 73 (37+/-6%) contained the adrenergic alpha(2A) receptor (alpha(2A)r) RNA, and 6 out of 31 (19+/-7%) contained both mRNAs. The percentage of cells positive for the ORX1r mRNA was significantly lower (p<0.04) for the dorsomedial pontine cells that were not retrogradely labeled from the mMRF (32+/-11%), whereas alpha(2A)r mRNA was present in a similar percentage of FITC-labeled and unlabeled neurons. Our data suggest that ORX and adrenergic pathways converge on a subpopulation of cells of the pontine REM sleep-triggering region that have descending projections to the medullary region important for the motor control during REM sleep.

The far lateral transpontomedullary sulcus approach to pontine cavernous malformations: technical report and surgical results.

PubMed

Abla, Adib A; Benet, Arnau; Lawton, Michael T

2014-09-01

Pontine cavernous malformations (CMs) located on a peripheral pontine surface or the fourth ventricular floor are resectable lesions, but those deep within the pons away from a pial surface are typically observed. However, the anterior bulge of the pons formed by the brachium pontis creates a unique entry point for access to deep pontine lesions from below, working upward through the pontomedullary sulcus. We developed a transpontomedullary sulcus (TPMS) approach to these lesions. The TPMS approach used the far lateral craniotomy and upper vagoaccessory triangle to define the surgical corridor. The entry point was above the olive, lateral to the pyramidal tracts and cranial nerve (CN) VI, above the preolivary sulcus and CN XII, and medial to CNs VII and VIII and CNs IX through XI. Four patients underwent this approach. All presented with hemorrhage and CN VI palsies. All pontine CMs were resected completely. Three patients were improved or unchanged, with good outcomes (modified Rankin Scale score ≤2) in all patients. The central pons remains difficult territory to access, and new surgical corridors are needed. The bulging underbelly of the pons allows access to pontine lesions deep to the pial surface from below. The far lateral TPMS approach is a novel and more direct alternative to the retrosigmoid transmiddle cerebellar peduncle approach. Unlike the retrosigmoid approach, the TPMS approach requires minimal parenchymal transgression and uses a brainstem entry point medial to most lower CNs. Favorable results demonstrate the feasibility of resecting pontine CMs that might have been previously deemed unresectable.

Progressive deficit in isolated pontine infarction: the association with etiological subtype, lesion topography and outcome.

PubMed

Gökçal, Elif; Niftaliyev, Elvin; Baran, Gözde; Deniz, Çiğdem; Asil, Talip

2017-09-01

It is important to predict progressive deficit (PD) in isolated pontine infarction, a relatively common problem of clinical stroke practice. Traditionally, lacunar infarctions are known with their progressive course. However, few studies have analyzed the branch atheromatous disease subtype as a subtype of lacunar infarction, separately. There are also conflicting results regarding the relationship with the topography of lesion and PD. In this study, we classified etiological subtypes and lesion topography in isolated pontine infarction and aimed to investigate the association of etiological subtypes, lesion topography and clinical outcome with PD. We analyzed demographics, laboratory parameters, and risk factors of 120 patients having isolated pontine infarction and admitted within 24 h retrospectively. PD was defined as an increase in the National Institutes of Health Stroke scale ≥2 units in 5 days after onset. Patients were classified as following: large artery disease (LAA), basilar artery branch disease (BABD) and small vessel disease (SVD). Upper, middle and lower pontine infarcts were identified longitudinally. Functional outcome at 3 months was determined according to modified Rankin scores. Of 120 patients, 41.7% of the patients were classified as BABD, 30.8% as SVD and 27.5% as LAA. 23 patients (19.2%) exhibited PD. PD was significantly more frequent in patient with BABD (p 0.006). PD was numerically higher in patients with lower pontine infarction. PD was associated with BABD and poor functional outcome. It is important to discriminate the BABD neuroradiologically from other stroke subtypes to predict PD which is associated with poor functional outcome in patients with isolated pontine infarctions.

Adenosine A1 Receptors in Mouse Pontine Reticular Formation Modulate Nociception Only in the Presence of Systemic Leptin

PubMed Central

Watson, Sarah L.; Watson, Christopher J.; Baghdoyan, Helen A.; Lydic, Ralph

2014-01-01

Human obesity is associated with increased leptin levels and pain, but the specific brain regions and neurochemical mechanisms underlying this association remain poorly understood. This study used adult male C57BL/6J (B6, n = 14) mice and leptin-deficient, obese B6.Cg-Lepob/J (obese, n = 10) mice to evaluate the hypothesis that nociception is altered by systemic leptin levels and by adenosine A1 receptors in the pontine reticular formation. Nociception was quantified as paw withdrawal latency (PWL) in s after onset of a thermal stimulus. PWL was converted to percent maximum possible effect (%MPE). After obtaining baseline PWL measures, the pontine reticular formation was microinjected with saline (control), three concentrations of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA), or super-active mouse leptin receptor antagonist (SMLA) followed by SPA 15 min later, and PWL was again quantified. In obese, leptin-deficient mice, nociception was quantified before and during leptin replacement via subcutaneous osmotic pumps. SPA was administered into the pontine reticular formation of leptin-replaced mice and PWL testing was repeated. During baseline (before vehicle or SPA administration), PWL was significantly (p = 0.0013) lower in leptin-replaced obese mice than in B6 mice. Microinjecting SPA into the pontine reticular formation of B6 mice caused a significant (p = 0.0003) concentration-dependent increase in %MPE. SPA also significantly (p < 0.05) increased %MPE in B6 mice and in leptin-replaced obese mice, but not in leptin-deficient obese mice. Microinjection of the mouse super-active leptin antagonist (SMLA) into the pontine reticular formation before SPA did not alter PWL. The results show for the first time that pontine reticular formation administration of the adenosine A1 receptor agonist SPA produced antinociception only in the presence of systemic leptin. The concentration-response data support the interpretation that adenosine A1 receptors localized to the pontine reticular formation significantly alter nociception. PMID:24976513

Adenosine A₁ receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin.

PubMed

Watson, S L; Watson, C J; Baghdoyan, H A; Lydic, R

2014-09-05

Human obesity is associated with increased leptin levels and pain, but the specific brain regions and neurochemical mechanisms underlying this association remain poorly understood. This study used adult male C57BL/6J (B6, n=14) mice and leptin-deficient, obese B6.Cg-Lep(ob)/J (obese, n=10) mice to evaluate the hypothesis that nociception is altered by systemic leptin levels and by adenosine A₁ receptors in the pontine reticular formation. Nociception was quantified as paw withdrawal latency (PWL) in s after onset of a thermal stimulus. PWL was converted to percent maximum possible effect (%MPE). After obtaining baseline PWL measures, the pontine reticular formation was microinjected with saline (control), three concentrations of the adenosine A₁ receptor agonist N(6)-p-sulfophenyladenosine (SPA), or super-active mouse leptin receptor antagonist (SMLA) followed by SPA 15 min later, and PWL was again quantified. In obese, leptin-deficient mice, nociception was quantified before and during leptin replacement via subcutaneous osmotic pumps. SPA was administered into the pontine reticular formation of leptin-replaced mice and PWL testing was repeated. During baseline (before vehicle or SPA administration), PWL was significantly (p=0.0013) lower in leptin-replaced obese mice than in B6 mice. Microinjecting SPA into the pontine reticular formation of B6 mice caused a significant (p=0.0003) concentration-dependent increase in %MPE. SPA also significantly (p<0.05) increased %MPE in B6 mice and in leptin-replaced obese mice, but not in leptin-deficient obese mice. Microinjection of SMLA into the pontine reticular formation before SPA did not alter PWL. The results show for the first time that pontine reticular formation administration of the adenosine A₁ receptor agonist SPA produced antinociception only in the presence of systemic leptin. The concentration-response data support the interpretation that adenosine A₁ receptors localized to the pontine reticular formation significantly alter nociception. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Dorsomedial pontine neurons with descending projections to the medullary reticular formation express orexin-1 and adrenergic α2A receptor mRNA

PubMed Central

Volgin, Denys V.; Malinowska, Monika; Kubin, Leszek

2009-01-01

Neurons located in the dorsomedial pontine rapid eye movement (REM) sleep-triggering region send axons to the medial medullary reticular formation (mMRF). This pathway is believed to be important for the generation of REM sleep motor atonia, but other than that they are glutamatergic little is known about neurochemical signatures of these pontine neurons important for REM sleep. We used single-cell reverse transcription and polymerase chain reaction (RT-PCR) to determine whether dorsomedial pontine cells with projections to the mMRF express mRNA for selected membrane receptors that mediate modulatory influences on REM sleep. Fluorescein (FITC)-labeled latex microspheres were microinjected into the mMRF of 26–34 day-old rats under pentobarbital anesthesia. After 5–6 days, rats were sacrificed, pontine slices were obtained and neurons were dissociated from 400–600 μm micropunches extracted from dorsomedial pontine reticular formation. We found that 32 out of 51 FITC-labeled cells tested (63%±7(SE)) contained the orexin type 1 receptor (ORX1r) mRNA, 27 out of 73 (37%±6) contained the adrenergic α2A receptor (α2Ar) RNA, and 6 out of 31 (19%±7) contained both mRNAs. The percentage of cells positive for the ORX1r mRNA was significantly lower (p<0.04) for the dorsomedial pontine cells that were not retrogradely labeled from the mMRF (32%±11), whereas α2Ar mRNA was present in a similar percentage of FITC-labeled and unlabeled neurons. Our data suggest that ORX and adrenergic pathways converge on a subpopulation of cells of the pontine REM sleep-triggering region that have descending projections to the medullary region important for the motor control during REM sleep. PMID:19427365

Pontine control of ejaculation and female orgasm.

PubMed

Huynh, Hieu K; Willemsen, Antoon T M; Lovick, Thelma A; Holstege, Gert

2013-12-01

The physiological component of ejaculation shows parallels with that of micturition, as both are essentially voiding activities. Both depend on supraspinal influences to orchestrate the characteristic pattern of activity in the pelvic organs. Unlike micturition, little is known about the supraspinal pathways involved in ejaculation and female orgasm. To identify brainstem regions activated during ejaculation and female orgasm and to compare them with those activated during micturition. Ejaculation in men and orgasm in women were induced by manual stimulation of the penis or clitoris by the participants' partners. Positron emission tomography (PET) with correction for head movements was used to capture the pattern of brain activation at the time of sexual climax. PET scans showing areas of activation during sexual climax. Ejaculation in men and orgasm in women resulted in activation in a localized region within the dorsolateral pontine tegmentum on the left side and in another region in the ventrolateral pontine tegmentum on the right side. The dorsolateral pontine area was also active in women who attempted but failed to have an orgasm and in women who imitated orgasm. The ventrolateral pontine area was only activated during ejaculation and physical orgasm in women. Activation of a localized region on the left side in the dorsolateral pontine tegmentum, which we termed the pelvic organ-stimulating center, occurs during ejaculation in men and physical orgasm in women. This same region has previously been shown to be activated during micturition, but on the right side. The pelvic organ-stimulating center, via projections to the sacral parasympathetic motoneurons, controls pelvic organs involved in voiding functions. In contrast, the ventrolateral pontine area, which we term the pelvic floor-stimulating center, produces the pelvic floor contractions during ejaculation in men and physical orgasm in women via direct projections to pelvic floor motoneurons. © 2013 International Society for Sexual Medicine.

Gestational diabetes and central pontine myelinolysis with quadriplegia: a case report.

PubMed

Lee, I-Wen; Su, Mei-Tsz; Kuo, Pao-Lin; Chang, Chia-Ming

2010-07-01

Central pontine myelinolysis (CPM) has been reported in women with severe hyperemesis gravidarum-induced hyponatremia followed by rapid correction. Gestational diabetes with adipsia complicated by acute hypernatremia resulting in CPM has never been reported. Here is a case of a disabled female who presented with polydipsia, polyuria, seizures, fetal death in utero, hyperglycemia, and hyper-osmolar hypernatremia on her 31st gestational week. The dead fetus was delivered and the patient's plasma glucose and sodium were later stabilized. When the patient developed quadriplegia and respiratory failure 5 days later, brain magnetic resonance imaging showed central pontine and extra-pontine myelinolysis. Gestational diabetes complicated by hyper-osmolar crisis may cause fetal death and severe neurologic sequela. Early recognition and delivery of the fetus and placenta may improve the electrolyte and fluid imbalance.

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.

PubMed

Tracy, Jo Anne; Thompson, Judith K; Krupa, David J; Thompson, Richard F

2013-10-01

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network. 2013 APA, all rights reserved

AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report.

PubMed

Mikesch, Jan-Henrik; Hartmann, Wolfgang; Angenendt, Linus; Huber, Otmar; Schliemann, Christoph; Arteaga, Maria Francisca; Wardelmann, Eva; Rudack, Claudia; Berdel, Wolfgang E; Stenner, Markus; Grünewald, Inga

2018-06-05

Salivary gland cancer (SGC) is a rare and heterogeneous disease with significant differences in recurrence and metastasis characteristics. As yet, little is known about the mechanisms underlying the initiation and/or progression of these diverse tumors. In recent years, the AAA+ ATPase family members Pontin (RuvBL1, Tip49a) and Reptin (RuvBL2, Tip49b) have been implicated in various processes, including transcription regulation, chromatin remodeling and DNA damage repair, that are frequently deregulated in cancer. The aim of this study was to assess the clinical and functional significance of Reptin and Pontin expression in SGC. Immunohistochemical staining of Pontin, Reptin, β-catenin, Cyclin D1, TP53 and MIB-1 was performed on a collection of 94 SGC tumor samples comprising 13 different histological subtypes using tissue microarrays. We found that Reptin and Pontin were expressed in the majority of SGC samples across all histological subtypes. Patients with a high Reptin expression showed a significantly inferior 5-year overall survival rate compared to patients with a low Reptin expression (47.7% versus 78.3%; p = 0.033), whereas no such difference was observed for Pontin. A high Reptin expression strongly correlated with a high expression of the proliferation marker MIB-1 (p = 0.003), the cell cycle regulator Cyclin D1 (p = 0.006), accumulation of TP53 as a surrogate p53 mutation marker (p = 0.042) and cytoplasmic β-catenin expression (p = 0.002). Increased Pontin expression was found to significantly correlate with both cytoplasmic and nuclear β-catenin expression (p = 0.037 and p = 0.018, respectively), which is indicative for its oncogenic function. Our results suggest a role of Reptin and Pontin in SGC tumor progression and/or patient survival. Therefore, SGC patients exhibiting a high Reptin expression may benefit from more aggressive therapeutic regimens. Future studies should clarify whether such patients may be considered for more radical surgery, extended adjuvant therapy and/or targeted therapy.

Central Pontine Myelinolysis

MedlinePlus

... aims to understand the biological mechanisms involved in water balance in the body. Information from the National Library of Medicine’s MedlinePlus C entral Pontine Myelinolysis × What research is being done? The NINDS conducts and supports ...

Possible conditioned stimulus pathway for classical eyelid conditioning in rabbits. I. Anatomical evidence for direct projections from the pontine nuclei to the cerebellar interpositus nucleus.

PubMed

Steinmetz, J E; Sengelaub, D R

1992-03-01

Wheat germ agglutinin and cholera toxin-conjugated horseradish peroxidase (HRP) were used to retrogradely and anterogradely trace connectivity between the lateral regions of the pontine nuclei and the anterior interpositus nucleus of the cerebellum in rabbits. Projections from the pontine nuclei were found to terminate in the anterior interpositus nucleus and the interpositus was found to send projections to the pontine nuclei. Projections from the nucleus reticularis tegmenti pontis, dorsal accessory inferior olive, and Larsell's lobule HVI of the cerebellum were also found to terminate in the interpositus nucleus and projections from the interpositus nucleus to the inferior olivary complex were observed. The projections from brain stem regions to the interpositus nucleus are discussed as possible pathways that are involved in classical eyelid conditioning.

The ascending reticular activating system from pontine reticular formation to the hypothalamus in the human brain: a diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2015-03-17

The ascending reticular activating system (ARAS) is responsible for regulation of consciousness. Precise evaluation of the ARAS is important for diagnosis and management of patients with impaired consciousness. In the current study, we attempted to reconstruct the portion of the ARAS from the pontine reticular formation (RF) to the hypothalamus in normal subjects, using diffusion tensor imaging (DTI). A total of 31 healthy subjects were recruited for this study. DTI scanning was performed using 1.5-T, and the ARAS from the pontine RF to the hypothalamus was reconstructed. Values of fractional anisotropy, mean diffusivity, and tract volume of the ARAS from the pontine RF to the hypothalamus were measured. In all subjects, the ARAS from the pontine RF to the hypothalamus originated from the RF at the level of the mid-pons, where the trigeminal nerve could be seen, ascended through the periaqueductal gray matter of the midbrain anterolaterally to the anterior commissure level, and then terminated into the hypothalamus. No significant differences in DTI parameters were observed between the left and right hemispheres and between males and females (p<0.05). We identified the ARAS between the pontine RF and the hypothalamus in normal subjects using DTI. We believe that the reconstruction methodology and the results of this study would be useful to clinicians involved in the care of patients with impaired consciousness and researchers in studies of the ARAS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Noninvasive Assessment of Intracranial Pressure Status in Idiopathic Intracranial Hypertension Using Displacement Encoding with Stimulated Echoes (DENSE) MRI: A Prospective Patient Study with Contemporaneous CSF Pressure Correlation.

PubMed

Saindane, A M; Qiu, D; Oshinski, J N; Newman, N J; Biousse, V; Bruce, B B; Holbrook, J F; Dale, B M; Zhong, X

2018-02-01

Intracranial pressure is estimated invasively by using lumbar puncture with CSF opening pressure measurement. This study evaluated displacement encoding with stimulated echoes (DENSE), an MR imaging technique highly sensitive to brain motion, as a noninvasive means of assessing intracranial pressure status. Nine patients with suspected elevated intracranial pressure and 9 healthy control subjects were included in this prospective study. Controls underwent DENSE MR imaging through the midsagittal brain. Patients underwent DENSE MR imaging followed immediately by lumbar puncture with opening pressure measurement, CSF removal, closing pressure measurement, and immediate repeat DENSE MR imaging. Phase-reconstructed images were processed producing displacement maps, and pontine displacement was calculated. Patient data were analyzed to determine the effects of measured pressure on pontine displacement. Patient and control data were analyzed to assess the effects of clinical status (pre-lumbar puncture, post-lumbar puncture, or control) on pontine displacement. Patients demonstrated imaging findings suggesting chronically elevated intracranial pressure, whereas healthy control volunteers demonstrated no imaging abnormalities. All patients had elevated opening pressure (median, 36.0 cm water), decreased by the removal of CSF to a median closing pressure of 17.0 cm water. Patients pre-lumbar puncture had significantly smaller pontine displacement than they did post-lumbar puncture after CSF pressure reduction ( P = .001) and compared with controls ( P = .01). Post-lumbar puncture patients had statistically similar pontine displacements to controls. Measured CSF pressure in patients pre- and post-lumbar puncture correlated significantly with pontine displacement ( r = 0.49; P = .04). This study establishes a relationship between pontine displacement from DENSE MR imaging and measured pressure obtained contemporaneously by lumbar puncture, providing a method to noninvasively assess intracranial pressure status in idiopathic intracranial hypertension. © 2018 by American Journal of Neuroradiology.

Long-term survival of an infant with diffuse brainstem lesion diagnosed by prenatal MRI: a case report and review of the literature.

PubMed

Suo-Palosaari, M; Rantala, H; Lehtinen, S; Kumpulainen, T; Salokorpi, N

2016-06-01

We describe a unique case of expansive diffuse brainstem lesion diagnosed prenatally by magnetic resonance imaging (MRI) with long-term survival. Findings of fetal and postpartum MRI were highly consistent with the characteristics of diffuse brainstem glioma. Diagnosis was based on the features of MRI, and histopathology was not confirmed by biopsy. Although the prognosis of diffuse brainstem tumor is usually poor, this child was asymptomatic at birth and the neurological condition is still normal at 4 years of age without any treatment. During routine imaging follow-up, diameters of the expansion have remained stable, while the size of the lesion compared to the posterior fossa size has diminished. In addition to brainstem tumor, a skin lesion of the back was observed and MRI of the thoracic spine showed a large asymptomatic extradural cystic lesion suggesting an arachnoid cyst. The pontine tumor of this infant, in agreement with a few previously reported cases, suggests a subgroup of beneficial outcome of expansive diffuse brainstem lesions, particularly in the neonatal period. In this article, we discuss the prognosis and characteristics of pediatric brainstem tumors and differential diagnosis of neonatal brainstem lesions.

Locked-in syndrome caused by a solitary pontine abscess.

PubMed Central

Murphy, M J; Brenton, D W; Aschenbrener, C A; Van Gilder, J C

1979-01-01

The clinical and pathological findings in a patient with locked-in syndrome caused by a solitary pontine abscess are reported for the first time. Successful treatment of brainstem abscess rests on early and accurate diagnosis. Images PMID:501372

Inhibitory effect of the nucleus reticularis pontis oralis on the pontine micturition center and pontine urine storage center in decerebrate cats.

PubMed

Sugaya, Kimio; Nishijima, Saori; Miyazato, Minoru; Oda, Masami; Ogawa, Yoshihide

2006-10-01

The influence of the nucleus reticularis pontis oralis (PoO) on the pontine micturition center (PMC) and pontine urine storage center (PUSC) was examined in decerebrate cats by electrical and chemical stimulations of the PMC, PUSC or PoO. Microinjection of carbachol into the rostral and dorsolateral part of the PoO rapidly inhibited reflex micturition and external urethral sphincter (EUS) activity. After confirming the inhibition of reflex micturition and EUS activity by microinjection of carbachol into the PoO, intravenous injection of atropine sulfate or its microinjection into the PoO recovered both reflex micturition and EUS activity. Microinjection of carbachol into the PMC evoked micturition and then inhibited reflex micturition, but intravenous injection of atropine or its microinjection into the PoO recovered reflex micturition. After confi rming the inhibition of reflex micturition and EUS activity by microinjection of carbachol into the PoO, electrical stimulation of the PUSC enhanced EUS activity, but electrical stimulation of the PMC failed to evoke micturition. However, electrical stimulation of the PMC evoked micturition after microinjection of atropine into the PoO. These results suggest that the PoO strongly inhibits the PMC and less strongly inhibits the PUSC. Therefore, the PoO seems to be the pontine micturition inhibitory area.

A novel central pathway links arterial baroreceptors and pontine parasympathetic neurons in cerebrovascular control.

PubMed

Agassandian, Khristofor; Fazan, Valeria P S; Margaryan, Naira; Dragon, Deidre Nitschke; Riley, Jeffrey; Talman, William T

2003-10-01

1. We tested the hypothesis that arterial baroreceptor reflexes modulate cerebrovascular tone through a pathway that connects the cardiovascular nucleus tractus solitarii with parasympathetic preganglionic neurons in the pons. 2. Anesthetized rats were used in all studies. Laser flowmetry was used to measure cerebral blood flow. We assessed cerebrovascular responses to increases in arterial blood pressure in animals with lesions of baroreceptor nerves, the nucleus tractus solitarii itself, the pontine preganglionic parasympathetic neurons, or the parasympathetic ganglionic nerves to the cerebral vessels. Similar assessments were made in animals after blockade of synthesis of nitric oxide, which is released by the parasympathetic nerves from the pterygopalatine ganglia. Finally the effects on cerebral blood flow of glutamate stimulation of pontine preganglionic parasympathetic neurons were evaluated. 3. We found that lesions at any one of the sites in the putative pathway or interruption of nitric oxide synthesis led to prolongation of autoregulation as mean arterial pressure was increased to levels as high as 200 mmHg. Conversely, stimulation of pontine parasympathetic preganglionic neurons led to cerebral vasodilatation. The second series of studies utilized classic anatomical tracing methods to determine at the light and electron microscopic level whether neurons in the cardiovascular nucleus tractus solitarii, the site of termination of baroreceptor afferents, projected to the pontine preganglionic neurons. Fibers were traced with anterograde tracer from the nucleus tractus solitarii to the pons and with retrograde tracer from the pons to the nucleus tractus solitarii. Using double labeling techniques we further studied synapses made between labeled projections from the nucleus tractus solitarii and preganglionic neurons that were themselves labeled with retrograde tracer placed into the pterygopalatine ganglion. 4. These anatomical studies showed that the nucleus tractus solitarii directly projects to pontine preganglionic neurons and makes asymmetric, seemingly excitatory, synapses with those neurons. These studies provide strong evidence that arterial baroreceptors may modulate cerebral blood flow through direct connections with pontine parasympathetic neurons. Further study is needed to clarify the role this pathway plays in integrative physiology.

Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep.

PubMed

Shouse, M N; Siegel, J M

1992-01-31

Transection, lesion and unit recording studies have localized rapid eye movement (REM) sleep mechanisms to the pons. Recent work has emphasized the role of pontine cholinergic cells, especially those of the pedunculopontine tegmentum (PPT). The present study differentiated REM sleep deficits associated with lesions of the PPT from other pontine regions implicated in REM sleep generation, including those with predominantly cholinergic vs non-cholinergic cells. Twelve hour polygraphic recordings were obtained in 18 cats before and 1-2 weeks after bilateral electrolytic or radio frequency lesions of either: (1) PPT, which contains the dorsolateral pontine cholinergic cell column; (2) laterodorsal tegmental nucleus (LDT), which contains the dorsomedial pontine cholinergic cell column; (3) locus ceruleus (LC), which contains mostly noradrenergic cells; or (4) subceruleus (LC alpha, peri-LC alpha and the lateral tegmental field), which also contains predominantly noncholinergic cells. There were three main findings: (i) Only lesions of PPT and subceruleus significantly affected REM sleep time. These lesions produced comparable reductions in REM sleep time but influenced REM sleep components quite differently: (ii) PPT lesions, estimated to damage 90 +/- 4% of cholinergic cells, reduced the number of REM sleep entrances and phasic events, including ponto-geniculooccipital (PGO) spikes and rapid eye movements (REMs), but did not prevent complete atonia during REM sleep: (iii) Subceruleus lesions eliminated atonia during REM sleep. Mobility appeared to arouse the cat prematurely from REM sleep and may explain the brief duration of REM sleep epochs seen exclusively in this group. Despite the reduced amount of REM sleep, the total number of PGO spikes and REM sleep entrances increased over baseline values. Collectively, the results distinguish pontine loci regulating phasic events vs atonia. PPT lesions reduced phasic events, whereas subceruleus lesions created REM sleep without atonia. Severe REM sleep deficits after large pontine lesions, including PPT and subceruleus, might be explained by simultaneous production of both REM sleep syndromes. However, extensive loss of ACh neurons in the PPT does not disrupt REM sleep atonia.

Harnessing Autopsied DIPG Tumor Tissues for Orthotopic Xenograft Model Development in the Brain Stems of SCID Mice

DTIC Science & Technology

2012-09-01

patched-1-deficient mouse medulloblastoma . Cancer Res. 2009;69:4682-4690. 14. Mao XG, Zhang X, Xue XY, et al. Brain Tumor Stem-Like Cells Identified by...propagating cells in a mouse model of medulloblastoma . Cancer Cell. 2009;15:135-147. 16. Yagi H, Yanagisawa M, Suzuki Y, et al. HNK-1 epitope-carrying

Central Pontine and Extrapontine Myelinolysis: The Great Masquerader—An Autopsy Case Report

PubMed Central

Jacob, Sajish; Nikolic, Dejan; Gundogdu, Betul; Ong, Shirley

2014-01-01

Central pontine myelinolysis is a demyelinating disorder characterized by the loss of myelin in the center of the basis pontis usually caused by rapid correction of chronic hyponatremia. The clinical features vary depending on the extent of involvement. Demyelination can occur outside the pons as well and diagnosis can be challenging if both pontine and extrapontine areas are involved. We herein report a case of myelinolysis involving pons, lateral geniculate bodies, subependymal region, and spinal cord. To the best of our knowledge, this case represents the second case of spinal cord involvement in osmotic demyelination syndrome and the first case of involvement of thoracic region of spinal cord. PMID:24716023

Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation

PubMed Central

Grace, Kevin P.; Horner, Richard L.

2015-01-01

Rapid eye movement (REM) sleep – characterized by vivid dreaming, motor paralysis, and heightened neural activity – is one of the fundamental states of the mammalian central nervous system. Initial theories of REM sleep generation posited that induction of the state required activation of the “pontine REM sleep generator” by cholinergic inputs. Here, we review and evaluate the evidence surrounding cholinergic involvement in REM sleep generation. We submit that: (i) the capacity of pontine cholinergic neurotransmission to generate REM sleep has been firmly established by gain-of-function experiments, (ii) the function of endogenous cholinergic input to REM sleep generating sites cannot be determined by gain-of-function experiments; rather, loss-of-function studies are required, (iii) loss-of-function studies show that endogenous cholinergic input to the PTF is not required for REM sleep generation, and (iv) cholinergic input to the pontine REM sleep generating sites serve an accessory role in REM sleep generation: reinforcing non-REM-to-REM sleep transitions making them quicker and less likely to fail. PMID:26388832

Pontine Mechanisms of Respiratory Control

PubMed Central

Dutschmann, Mathias; Dick, Thomas E.

2015-01-01

Pontine respiratory nuclei provide synaptic input to medullary rhythmogenic circuits to shape and adapt the breathing pattern. An understanding of this statement depends on appreciating breathing as a behavior, rather than a stereotypic rhythm. In this review, we focus on the pontine-mediated inspiratory off-switch (IOS) associated with postinspiratory glottal constriction. Further, IOS is examined in the context of pontine regulation of glottal resistance in response to multimodal sensory inputs and higher commands, which in turn rules timing, duration, and patterning of respiratory airflow. In addition, network plasticity in respiratory control emerges during the development of the pons. Synaptic plasticity is required for dynamic and efficient modulation of the expiratory breathing pattern to cope with rapid changes from eupneic to adaptive breathing linked to exploratory (foraging and sniffing) and expulsive (vocalizing, coughing, sneezing, and retching) behaviors, as well as conveyance of basic emotions. The speed and complexity of changes in the breathing pattern of behaving animals implies that “learning to breathe” is necessary to adjust to changing internal and external states to maintain homeostasis and survival. PMID:23720253

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs.

PubMed

Machado-Pinilla, Rosario; Liger, Dominique; Leulliot, Nicolas; Meier, U Thomas

2012-10-01

The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes.

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs

PubMed Central

Machado-Pinilla, Rosario; Liger, Dominique; Leulliot, Nicolas; Meier, U. Thomas

2012-01-01

The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes. PMID:22923768

Right-sided dominance of the bilateral vestibular system in the upper brainstem and thalamus.

PubMed

Dieterich, Marianne; Kirsch, V; Brandt, T

2017-10-01

MRI diffusion tensor imaging tractography was performed on the bilateral vestibular brainstem pathways, which run from the vestibular nuclei via the paramedian and posterolateral thalamic subnuclei to the parieto-insular vestibular cortex. Twenty-one right-handed healthy subjects participated. Quantitative analysis revealed a rope-ladder-like system of vestibular pathways in the brainstem with crossings at pontine and mesencephalic levels. Three structural types of right-left fiber distributions could be delineated: (1) evenly distributed pathways at the lower pontine level from the vestibular nuclei to the pontine crossing, (2) a moderate, pontomesencephalic right-sided lateralization between the pontine and mesencephalic crossings, and (3) a further increase of the right-sided lateralization above the mesencephalic crossing leading to the thalamic vestibular subnuclei. The increasing lateralization along the brainstem was the result of an asymmetric number of pontine and mesencephalic crossing fibers which was higher for left-to-right crossings. The dominance of the right vestibular meso-diencephalic circuitry in right-handers corresponds to the right-hemispheric dominance of the vestibular cortical network. The structural asymmetry apparent in the upper brainstem might be interpreted in relation to the different functions of the vestibular system depending on their anatomical level: a symmetrical sensorimotor reflex control of eye, head, and body mediated by the lower brainstem; a lateralized right-sided upper brainstem-thalamic function as part of the dominant right-sided cortical/subcortical vestibular system that enables a global percept of body motion and orientation in space.

Deterioration of pre-existing hemiparesis due to injury of the ipsilateral anterior corticospinal tract.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2013-05-29

The anterior corticospinal tract (CST) has been suggested as one of the ipsilateral motor pathways, which contribute to motor recovery following stroke. In this study, we report on a patient who showed deterioration of pre-existing hemiparesis due to an injury of the ipsilateral anterior CST following a pontine infarct, as evaluated by diffusion tensor tractography (DTT). A 55-year-old male patient showed quadriparesis after the onset of an infarct in the right pontine basis. He had history of an infarct in the left middle cerebral artery territory 7 years ago. Consequently, he showed right hemiparesis before onset of the right pontine infarct. Following this, his right hemiparesis deteriorated whereas his left hemiparesis newly developed. The DTTs for whole CST of the right hemisphere in the patient and both hemispheres in control subjects descended through the known CST pathway. By contrast, the DTT for the left whole CST of the patient showed a complete injury finding. The DTTs for the anterior CST of control subjects passed through the known pathway of the CST from cerebral cortex to medulla and terminated in the anterior funiculus of the upper cervical cord. However, the DTT for right anterior CST in the patient showed discontinuation below the right pontine infarct. It appeared that the deterioration of the pre-existing right hemiparesis was ascribed to an injury of the right anterior CST due to the right pontine infarct.

Visual Hallucinations and Pontine Demyelination in a Child: Possible REM Dissociation?

PubMed Central

Vita, Maria Gabriella; Batocchi, Anna Paola; Dittoni, Serena; Losurdo, Anna; Cianfoni, Alessandro; Stefanini, Maria Chiara; Vollono, Catello; Marca, Giacomo Della; Mariotti, Paolo

2008-01-01

An 11 year-old-boy acutely developed complex visual and acoustic hallucinations. Hallucinations, consisting of visions of a threatening, evil character of the Harry Potter saga, persisted for 3 days. Neurological and psychiatric examinations were normal. Ictal EEG was negative. MRI documented 3 small areas of hyperintense signal in the brainstem, along the paramedian and lateral portions of pontine tegmentum, one of which showed post-contrast enhancement. These lesions were likely of inflammatory origin, and treatment with immunoglobulins was started. Polysomnography was normal, multiple sleep latency test showed a mean sleep latency of 8 minutes, with one sleep-onset REM period. The pontine tegmentum is responsible for REM sleep regulation, and contains definite “REM-on” and “REM-off” regions. The anatomical distribution of the lesions permits us to hypothesize that hallucinations in this boy were consequent to a transient impairment of REM sleep inhibitory mechanisms, with the appearance of dream-like hallucinations during wake. Citation: Vita MG; Batocchi AP; Dittoni S; Losurdo A; Cianfoni A; Stefanini MC; Vollono C; Della Marca G; Mariotti P. Visual hallucinations and pontine demyelination in a child: possible REM dissociation? J Clin Sleep Med 2008;4(6):588–590. PMID:19110890

Motor recovery mechanism in a quadriplegic patient with locked-in syndrome.

PubMed

Kwon, Hyeok Gyu; Jang, Sung Ho

2012-01-01

Locked-in syndrome (LIS) is a rare neurologic condition caused by bilateral pontine lesions. Quadriplegia is one of the most serious clinical manifestations in patients with LIS. However, little is known about the motor recovery mechanism of quadriplegia in patients with LIS. In the current study, we present with a quadriplegic patient with bilateral pontine infarcts, whose motor function appeared to be reorganized into the peri-infarct areas of the infarcted pons, as demonstrated by diffusion tensor tractography (DTT). A 60-year-old was diagnosed as LIS due to bilateral pontine infarcts 6 years ago. The patient presented with complete paralysis of all four extremities at onset. After slow motor recovery, the patient was able to move all joint muscles against gravity and demonstrated some fine motor activity at the time of DTT scanning (6 years after onset). Results of DTTs for the corticospinal tract (CST) in both hemispheres showed that the CSTs originated from the primary motor cortex, descended along the known CST pathway, and passed through lateral areas of infarcts in the pons. Therefore, motor function of the four extremities of this patient appears to have been recovered by the CST, which passed through the lateral areas to the pontine infarcts.

Arousal mechanisms related to posture and locomotion: 1. Descending modulation.

PubMed

Garcia-Rill, Edgar; Homma, Yutaka; Skinner, Robert D

2004-01-01

Much of the controversy surrounding the induction of locomotion following stimulation of mesopontine sites, including the pedunculopontine nucleus (PPN), appears based on procedural differences, including stimulus onset, delay preceding stepping, and frequency of stimuli. The results reviewed in this chapter address these issues and provide novel information suggesting that descending projections from the PPN may exert a frequency-dependent effect. Stimulation at approximately 60 Hz (which induces prolonged tonic firing) may exercise a "push" towards locomotion (activation of pontine interneurons) as well as a "pull" away from decreased muscle tone (inhibiting giant pontine reticulospinal cells). Higher frequencies of stimulation (> 100 Hz, which induces phasic burst-like activity) may "push" towards decreases in muscle tone, including the atonia of rapid eye movement sleep (activating giant pontine reticulospinal cells).

Isolated facial myokymia as a presenting feature of pontine neurocysticercosis.

PubMed

Bhatia, Rohit; Desai, Soaham; Garg, Ajay; Padma, Madakasira V; Prasad, Kameshwar; Tripathi, Manjari

2008-01-01

A 45-year-old healthy man presented with 2 weeks history of continuous rippling and quivering movements of his right side of face and neck suggestive of myokymia. MRI scan of the head revealed neurocysticercus in the pons. Treatment with steroids and carbamezapine produced a significant benefit. This is the first report of pontine neurocysticercosis presenting as an isolated facial myokymia. 2007 Movement Disorder Society

Vasoactive intestinal polypeptide microinjections into the oral pontine tegmentum enhance rapid eye movement sleep in the rat.

PubMed

Bourgin, P; Lebrand, C; Escourrou, P; Gaultier, C; Franc, B; Hamon, M; Adrien, J

1997-03-01

Rapid eye movement sleep can be elicited in the rat by microinjection of the cholinergic agonist carbachol into the oral pontine reticular nucleus. Intracerebroventricular administration, during the light period, of vasoactive intestinal peptide enhances rapid eye movement sleep in several species. Since this peptide is co-localized with acetylcholine in many neurons in the central nervous system, it was assumed that the oral pontine tegmentum could also be one target for vasoactive intestinal peptide to induce rapid eye movement sleep. This hypothesis was tested by recording the sleep-wakefulness cycle in freely-moving rats injected with vasoactive intestinal peptide or its fragments (1-12 and 10-28) directly into the oral pontine reticular nucleus. when administered into the posterior part of this nucleus, vasoactive intestinal peptide at 1 and 10 ng (in 0.1 microliter of saline), but not its fragments, induced a 2-fold enhancement of rapid eye movement sleep during 4 h, at the expense of wakefulness. At the dose of 10 ng, a significant increase in rapid eye movement sleep persisted for up to 8 h. Moreover, when the peptide was injected into the centre of the positive zone, rapid eye movement sleep was enhanced during three to eight consecutive days. These data provide the first evidence that rapid eye movement sleep can be elicited at both short- and long-term by a single intracerebral microinjection of vasoactive intestinal peptide. Peptidergic mechanisms, possibly in association with cholinergic mechanisms, within the caudal part of the oral pontine reticular nucleus may play a critical role in the long-term regulation of rapid eye movement sleep in rats.

Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

PubMed Central

Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

2007-01-01

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048

Organization of pontine reticulospinal inputs to motoneurons controlling axial and limb muscles in the neonatal mouse

PubMed Central

Sivertsen, Magne S.; Glover, Joel C.

2014-01-01

Using optical recording of synaptically mediated calcium transients and selective spinal lesions, we investigated the pattern of activation of spinal motoneurons (MNs) by the pontine reticulospinal projection in isolated brain stem-spinal cord preparations from the neonatal mouse. Stimulation sites throughout the region where the pontine reticulospinal neurons reside reliably activated MNs at cervical, thoracic, and lumbar levels. Activation was similar in MNs ipsi- and contralateral to the stimulation site, similar in medial and lateral motor columns that contain trunk and limb MNs, respectively, and similar in the L2 and L5 segments that predominantly contain flexor and extensor MNs, respectively. In nonlesioned preparations, responses in both ipsi- and contralateral MNs followed individual stimuli in stimulus trains nearly one-to-one (with few failures). After unilateral hemisection at C1 on the same side as the stimulation, responses had substantially smaller magnitudes and longer latencies and no longer followed individual stimuli. After unilateral hemisection at C1 on the side opposite to the stimulation, the responses were also smaller, but their latencies were not affected. Thus we distinguish two pontine reticulospinal pathways to spinal MNs, one uncrossed and the other crossed, of which the uncrossed pathway transmits more faithfully and appears to be more direct. PMID:24944221

The reticular formation.

PubMed

Horn, Anja K E

2006-01-01

The reticular formation of the brainstem contains functional cell groups that are important for the control of eye, head, or lid movements. The mesencephalic reticular formation is primarily involved in the control of vertical gaze, the paramedian pontine reticular formation in horizontal gaze, and the medullary pontine reticular formation in head movements and gaze holding. In this chapter, the locations, connections, and histochemical properties of the functional cell groups are reviewed and correlated with specific subdivisions of the reticular formation.

Visual hallucinations and pontine demyelination in a child: possible REM dissociation?

PubMed

Vita, Maria Gabriella; Batocchi, Anna Paola; Dittoni, Serena; Losurdo, Anna; Cianfoni, Alessandro; Stefanini, Maria Chiara; Vollono, Catello; Della Marca, Giacomo; Mariotti, Paolo

2008-12-15

An 11 year-old-boy acutely developed complex visual and acoustic hallucinations. Hallucinations, consisting of visions of a threatening, evil character of the Harry Potter saga, persisted for 3 days. Neurological and psychiatric examinations were normal. Ictal EEG was negative. MRI documented 3 small areas of hyperintense signal in the brainstem, along the paramedian and lateral portions of pontine tegmentum, one of which showed post-contrast enhancement. These lesions were likely of inflammatory origin, and treatment with immunoglobulins was started. Polysomnography was normal, multiple sleep latency test showed a mean sleep latency of 8 minutes, with one sleep-onset REM period. The pontine tegmentum is responsible for REM sleep regulation, and contains definite "REM-on" and "REM-off" regions. The anatomical distribution of the lesions permits us to hypothesize that hallucinations in this boy were consequent to a transient impairment of REM sleep inhibitory mechanisms, with the appearance of dream-like hallucinations during wake.

Pontine infarction induced by injury of the perforating branch of the basilar artery after blunt head impact: case report.

PubMed

Yanagawa, Youichi; Iwamoto, Shin-ichiro; Nishi, Kouichirou

2008-08-01

A 77-year-old male pedestrian was hit by a car. On admission, he had disturbance of consciousness and left hemiplegia. Computed tomography (CT) indicated only left frontal subcutaneous hematoma and minor hemorrhage in the left frontal lobe, suggesting axonal injury. CT on hospital day 2 revealed a low density area in the right paramedian pons, but CT angiography showed no dissection or occlusion of the vertebrobasilar artery. The diagnosis was pontine infarction resulting from shearing force injury to the paramedian branch of the basilar artery. He was transferred to another hospital for rehabilitation without improvement of symptoms on hospital day 51. Paramedian pontine infarction tends to occur in patients with risk factors for arteriosclerosis, including hypertension, diabetes mellitus, hyperlipidemia, or smoking. The present elderly patient had hypertension and hyperlipidemia, so arteriosclerosis in the paramedian branch may have contributed to his susceptibility to such injury.

Rehabilitation of the Pontine Ataxia-Dysmetria Syndrome.

PubMed

Li, Stephanie; Hartman, Kasondra; Surapaneni, Krishna; Altschuler, Eric L

2017-06-01

We present a case of a patient with significant ataxia and dysmetria following a lacunar pontine infarction and review the literature on this uncommon syndrome. The patient had an excellent clinical course with near resolution of symptoms and signs in less than 3 weeks. We illustrate the patient's ataxia and dysmetria with videos and also use the videos to demonstrate and characterize the features of the dysmetria. Interestingly, the characteristics of the dysmetria appear to be different from those seen in patients with dysmetria arising from a cerebellar or thalamic lesion. We discuss the likely neurophysiologic mechanisms responsible for the condition and recovery. Simple noninvasive study of patients with ataxia and dysmetria secondary to a pontine lacunar infarct may be most helpful in elucidating the contribution of pontocerebellar fibers to motor control. V. Copyright © 2017 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.

PubMed

Kerr, Georgina; Sheldon, Helen; Chaikuad, Apirat; Alfano, Ivan; von Delft, Frank; Bullock, Alex N; Harris, Adrian L

2015-04-01

Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.

The AAA+ proteins Pontin and Reptin enter adult age: from understanding their basic biology to the identification of selective inhibitors

PubMed Central

Matias, Pedro M.; Baek, Sung Hee; Bandeiras, Tiago M.; Dutta, Anindya; Houry, Walid A.; Llorca, Oscar; Rosenbaum, Jean

2015-01-01

Pontin and Reptin are related partner proteins belonging to the AAA+ (ATPases Associated with various cellular Activities) family. They are implicated in multiple and seemingly unrelated processes encompassing the regulation of gene transcription, the remodeling of chromatin, DNA damage sensing and repair, and the assembly of protein and ribonucleoprotein complexes, among others. The 2nd International Workshop on Pontin and Reptin took place at the Instituto de Tecnologia Química e Biológica António Xavier in Oeiras, Portugal on October 10–12, 2014, and reported significant new advances on the mechanisms of action of these two AAA+ ATPases. The major points under discussion were related to the mechanisms through which these proteins regulate gene transcription, their roles as co-chaperones, and their involvement in pathophysiology, especially in cancer and ciliary biology and disease. Finally, they may become anticancer drug targets since small chemical inhibitors were shown to produce anti-tumor effects in animal models. PMID:25988184

Pediatric Pontine Cavernous Malformations: The Presigmoid, Posterior Petrosal Approach.

PubMed

Kulwin, Charles G; Payner, Troy D; Nelson, Rick F; Ackerman, Laurie L; Fulkerson, Daniel H

2018-03-03

Brainstem cavernous malformations (cavernomas) in children have a high risk of hemorrhage and neurological deterioration. This risk is magnified if the child has a genetic predisposition for cavernoma formation. The surgical management is challenging and carries a significant risk of morbidity. To describe the feasibility of a posterior petrosal approach to brainstem cavernomas in a pediatric population. A single institution operative experience with this technique was reviewed; 2 cases were identified and are technically described here with supportive figures and illustrations, as well as a focused literature review. Two pediatric cases with multiple symptomatic hemorrhages from large expanding pontine cavernomas were identified. Both cavernomas were resected through a presigmoid posterior petrosal approach. While this approach is well described in the adult literature for ventral brainstem lesions, its description for the treatment of pontine cavernomas in the pediatric populations is scarce. This study demonstrates the utility and feasibility of the posterior petrosal approach in two pediatric patients at different points in cranial base development.

Neurofibromatosis type 1 associated with vertebrobasilar dolichoectasia and pontine ischemic stroke.

PubMed

Giannantoni, Nadia Mariagrazia; Broccolini, Aldobrando; Frisullo, Giovanni; Pilato, Fabio; Profice, Paolo; Morosetti, Roberta; Di Lella, Giuseppe; Zampino, Giuseppe; Della Marca, Giacomo

2015-01-01

Neurofibromatosis type 1 (NF1) is a heterogeneous, common, neurocutaneous disorder presenting different complications during a life span, including cerebrovascular dysplasia. To our knowledge this is the first reported case of NF1 associated with vertebrobasilar dolichoectasia and pontine ischemic stroke. We describe a 57-year-old man with NF1 who presented an acute onset right-sided facial palsy and hemiplegia, dysarthria, and gait imbalance. Magnetic resonance imaging showed an acute left paramedian pontine infarct and a hypoplastic right vertebral artery. Brain Computed Tomography Angiography revealed the occurrence of vertebrobasilar dolichoectasia. Co-occurrence of VBD and NF1 might not be merely casual and it may significantly heighten the mortality rate in this multisystem disorder. We suggest a possible role of VBD in the genesis of our patient's clinical-radiological features and prompt the early detection of asymptomatic arteriopathy in individuals with NF1 in order to ameliorate patients' quality of life and life expectancy. Copyright © 2014 by the American Society of Neuroimaging.

The AAA+ proteins Pontin and Reptin enter adult age: from understanding their basic biology to the identification of selective inhibitors.

PubMed

Matias, Pedro M; Baek, Sung Hee; Bandeiras, Tiago M; Dutta, Anindya; Houry, Walid A; Llorca, Oscar; Rosenbaum, Jean

2015-01-01

Pontin and Reptin are related partner proteins belonging to the AAA+ (ATPases Associated with various cellular Activities) family. They are implicated in multiple and seemingly unrelated processes encompassing the regulation of gene transcription, the remodeling of chromatin, DNA damage sensing and repair, and the assembly of protein and ribonucleoprotein complexes, among others. The 2nd International Workshop on Pontin and Reptin took place at the Instituto de Tecnologia Química e Biológica António Xavier in Oeiras, Portugal on October 10-12, 2014, and reported significant new advances on the mechanisms of action of these two AAA+ ATPases. The major points under discussion were related to the mechanisms through which these proteins regulate gene transcription, their roles as co-chaperones, and their involvement in pathophysiology, especially in cancer and ciliary biology and disease. Finally, they may become anticancer drug targets since small chemical inhibitors were shown to produce anti-tumor effects in animal models.

Convergence of pontine and proprioceptive streams onto multimodal cerebellar granule cells

PubMed Central

Huang, Cheng-Chiu; Sugino, Ken; Shima, Yasuyuki; Guo, Caiying; Bai, Suxia; Mensh, Brett D; Nelson, Sacha B; Hantman, Adam W

2013-01-01

Cerebellar granule cells constitute the majority of neurons in the brain and are the primary conveyors of sensory and motor-related mossy fiber information to Purkinje cells. The functional capability of the cerebellum hinges on whether individual granule cells receive mossy fiber inputs from multiple precerebellar nuclei or are instead unimodal; this distinction is unresolved. Using cell-type-specific projection mapping with synaptic resolution, we observed the convergence of separate sensory (upper body proprioceptive) and basilar pontine pathways onto individual granule cells and mapped this convergence across cerebellar cortex. These findings inform the long-standing debate about the multimodality of mammalian granule cells and substantiate their associative capacity predicted in the Marr-Albus theory of cerebellar function. We also provide evidence that the convergent basilar pontine pathways carry corollary discharges from upper body motor cortical areas. Such merging of related corollary and sensory streams is a critical component of circuit models of predictive motor control. DOI: http://dx.doi.org/10.7554/eLife.00400.001 PMID:23467508

Differential suppression of upper airway motor activity during carbachol-induced, REM sleep-like atonia.

PubMed

Fenik, V; Davies, R O; Pack, A I; Kubin, L

1998-10-01

Microinjections of carbachol into the pontine tegmentum of decerebrate cats have been used to study the mechanisms underlying the suppression of postural and respiratory motoneuronal activity during the resulting rapid eye movement (REM) sleep-like atonia. During REM sleep, distinct respiratory muscles are differentially affected; e.g., the activity of the diaphragm shows little suppression, whereas the activity of some upper airway muscles is quite strong. To determine the pattern of the carbachol-induced changes in the activity of different groups of upper airway motoneurons, we simultaneously recorded the efferent activity of the recurrent laryngeal nerve (RL), pharyngeal branch of the vagus nerve (Phar), and genioglossal branch of the hypoglossal (XII) and phrenic (Phr) nerves in 12 decerebrate, paralyzed, vagotomized, and artificially ventilated cats. Pontine carbachol caused a stereotyped suppression of the spontaneous activity that was significantly larger in Phar expiratory (to 8.3% of control) and XII inspiratory motoneurons (to 15%) than in Phr inspiratory (to 87%), RL inspiratory (to 79%), or RL expiratory motoneurons (to 72%). The suppression in upper airway motor output was significantly greater than the depression caused by a level of hypocapnia that reduced Phr activity as much as carbachol. We conclude that pontine carbachol evokes a stereotyped pattern of suppression of upper airway motor activity. Because carbachol evokes a state having many neurophysiological characteristics similar to those of REM sleep, it is likely that pontine cholinoceptive neurons have similar effects on the activity of upper airway motoneurons during both states.

Sleep patterning and behaviour in cats with pontine lesions creating REM without atonia.

PubMed

Sanford; Morrison; Mann; Harris; Yoo; Ross

1994-12-01

Lesions of the dorsal pontine tegmentum release muscle tone and motor behaviour, much of it similar to orienting during wakefulness, into rapid eye movement sleep (REM), a state normally characterized by paralysis. Sleep after pontine lesions may be altered, with more REM-A episodes of shorter duration compared to normal REM. We examined behaviour, ponto-geniculo-occipital (PGO) waves (which may be central markers of orienting) and sleep in lesioned cats: (i) to characterize the relationship of PGO waves to behaviour in REM-A; (ii) to determine whether post-lesion changes in the timing and duration of REM-A episodes were due to activity-related awakenings: and (iii) to determine whether alterations in sleep changed the circadian sleep/wake cycle in cats. Behavioural release in REM-A was generally related to episode length, but episode length was not necessarily shorter than normal REM in cats capable of full locomotion in REM-A. PGO wave frequency was reduced overall during REM-A, but was higher during REM-A with behaviour than during quiet REM-A without overt behaviour. Pontine lesions did not significantly alter the circadian sleep/wake cycle: REM-A had approximately the same Light/Dark distribution as normal REM. Differences in the patterning of normal REM and REM-A within sleep involve more than mere movement-induced awakenings. Brainstem lesions that eliminate the atonia of REM may damage neural circuitry involved in REM initiation and maintenance; this circuitry is separate from circadian control mechanisms.

Long-term implantation of deep brain stimulation electrodes in the pontine micturition centre of the Göttingen minipig.

PubMed

Jensen, Kristian N; Deding, Dorthe; Sørensen, Jens Christian; Bjarkam, Carsten R

2009-07-01

To implant deep brain stimulation (DBS) electrodes in the porcine pontine micturition centre (PMC) in order to establish a large animal model of PMC-DBS. Brain stems from four Göttingen minipigs were sectioned coronally into 40-mum-thick histological sections and stained with Nissl, auto-metallographic myelin stain, tyrosine hydroxylase and corticotrophin-releasing factor immunohistochemistry in order to identify the porcine PMC. DBS electrodes were then stereotaxically implanted on the right side into the PMC in four Göttingen minipigs, and the bladder response to electrical stimulation was evaluated by subsequent cystometry performed immediately after the operation and several weeks later. A paired CRF-dense area homologous to the PMC in other species was encountered in the rostral pontine tegmentum medial to the locus coeruleus and ventral to the floor of the fourth ventricle. Electrical stimulation of the CRF-dense area resulted in an increased detrusor pressure followed by visible voiding in some instances. The pigs were allowed to survive between 14 and 55 days, and electrical stimulation resulting in an increased detrusor pressure was performed on more than one occasion without affecting consciousness or general thriving. None of the pigs developed postoperative infections or died prematurely. DBS electrodes can be implanted for several weeks in the identified CRF-dense area resulting in a useful large animal model for basic research on micturition and the future clinical use of this treatment modality in neurogenic supra-pontine voiding disorders.

Induction of specific T helper-9 cells to inhibit glioma cell growth

PubMed Central

Zheng, Haiyan; Yang, Baohua; Xu, Dedong; Wang, Wenbo; Tan, Jie; Sun, Liyuan; Li, Qinghua; Sun, Li; Xia, Xuewei

2017-01-01

The effects of Staphylococcal enterotoxin B (SEB) on regulation of immune response have been recognized; whether SEB can enhance the effects of immunotherapy on glioma remains to be investigated. This study tests a hypothesis that administration with SEB enhances the effects of specific immunotherapy on glioma growth in mice. In this study, a glioma-bearing mouse model was developed by adoptive transfer with GL261 cells (a mouse glioma cell line). The mice were treated with the GL261 cell extracts (used as an Ag) with or without administration of SEB. We observed that treating glioma-bearing mice with the glioma Ag and SEB induced glioma-specific Th9 cells in both glioma tissue and the spleen. Treating CD4+ CD25− T cells with SEB increased p300 phosphorylation, histone H3K4 acetylation at the interleukin (IL)-9 promoter locus, and increased the IL-9 transcriptional factor binding to the IL-9 promoter. Treating CD4+ CD25− T cells with both SEB and glioma Ag induced glioma-specific Th9 cells. The glioma-specific Th9 cells induced glioma cell apoptosis in the culture. Treating the glioma-bearing mice with SEB and glioma Ag significantly inhibited the glioma growth. In conclusion, SEB plus glioma Ag immunotherapy inhibits the experimental glioma growth, which may be a novel therapeutic remedy for the treatment of glioma. PMID:28002799

[Pontine cavernous angioma (cavernoma) with initial ENT manifestations].

PubMed

Pino Rivero, V; González Palomino, A; Pantoja Hernández, C G; Trinidad Ruíz, G; Marqués Rebollo, L; Blasco Huelva, A

2006-01-01

We report the case of a 22 years old female who consulted us for facial parestesias, hearing loss in right ear and sudden tinnitus. Her audiometry showed an unilateral discreet sensorineural hipoacusia and the cranial IRM, a mass of 20 mm diameter in right pontine region and bulbus informed as cavernous angioma with signs of recent bleeding. The patient was sent to Neurosurgery but she refused the intervention. The risk of hemorrhage in the cavernomas is estimated at 0.25% to 1.6% per year and represents the main reason to advise a surgical treatment.

Pathological Laughing: Brain SPECT Findings.

PubMed

Morland, David; Wolff, Valérie; Blondet, Cyrille; Marescaux, Christian; Namer, Izzie Jacques

2015-09-01

We present the case of a 40-year-old man consulting for uncontrollable episodes of laughing related to emotional lability and not systematically linked to feelings of happiness. Seven months earlier he had presented a pontine ischemic stroke related to an occlusion of the basilar and left vertebral arteries. No epileptic activity or new MRI brain lesions were found. Brain perfusion SPECT performed showed marked hypoperfusion in the right frontal inferior and temporoinsular regions, suggesting a diaschisis phenomenon caused by pontine lesions and highlighted laughing regulation pathways. The patient was successfully treated with a serotonergic reuptake inhibitor, fluoxetine.

Central pontine myelinolysis: a rare presentation secondary to hyperglycaemia.

PubMed

Saini, Monica; Mamauag, Marlie Jane; Singh, Rajinder

2015-04-01

Central pontine myelinolysis (CPM) is classically described as a demyelinating condition that results from the rapid correction of hyponatraemia. CPM has also been reported to arise from hyperglycaemia in association with concomitant acidosis, hypernatraemia and hyperosmolar syndrome. Herein, we report a rare presentation of CPM, which was purely secondary to hyperosmolar hyperglycaemia. The patient presented with ataxia and pseudobulbar affect, which evolved subacutely over a duration of two weeks. It is important to note that, in addition to acute changes in osmolality, a subacute shift secondary to hyperglycaemia may also lead to CPM.

The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.

PubMed

Feng, Jie; Hao, Shuyu; Pan, Changcun; Wang, Yu; Wu, Zhen; Zhang, Junting; Yan, Hai; Zhang, Liwei; Wan, Hong

2015-11-01

Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets. Copyright © 2015. Published by Elsevier Inc.

Pontine cholinergic reticular mechanisms cause state-dependent changes in the discharge of parabrachial neurons.

PubMed

Gilbert, K A; Lydic, R

1994-01-01

The present study examined the hypothesis that cholinoceptive reticular mechanisms in the gigantocellular tegmental field (FTG) of the medial pontine reticular formation cause state-dependent changes in the discharge of parabrachial neurons. In chronically implanted, unanesthetized cats, extracellular recordings were made from nonrespiratory and respiratory neurons in the parabrachial nuclear complex (PBNC) during the natural sleep-wake cycle and during the rapid eye movement (REM) sleeplike state caused by FTG microinjection of carbachol or neostigmine. PBNC cells that increased discharge during natural REM sleep (REM-on cells) revealed similar increased discharge during the carbachol-induced REM sleeplike state (DCarb). Cells that decreased discharge in natural REM sleep (REM-off cells) displayed decreased discharge during both DCarb and the neostigmine-induced REM sleeplike states. The limited sample of parabrachial respiratory neurons revealed significantly diminished discharge during the cholinergically induced REM sleeplike state. Thus cholinoceptive mechanisms localized to specific regions of the pontine reticular formation can cause state-dependent changes in the firing rates of respiratory and nonrespiratory neurons in the PBNC.

A 63-year-old man with peripheral facial nerve paralysis and a pulmonary lesion.

PubMed

Yserbyt, J; Wilms, G; Lievens, Y; Nackaerts, K

2009-01-01

Occasionally, malignant neoplasms may cause peripheral facial nerve paralysis as a presenting symptom. A 63-year-old man was referred to the Emergency Department because of a peripheral facial nerve paralysis, lasting for 10 days. Initial diagnostic examinations revealed no apparent cause for this facial nerve paralysis. Chest X-ray, however, showed a suspicious tumoural mass, located in the right hilar region, as confirmed by CAT scan. The diagnosis of an advanced stage lung adenocarcinoma was finally confirmed by bronchial biopsy. MRI scanning showed diffuse brain metastases and revealed a pontine lesion as the most probable underlying cause of this case of peripheral facial nerve paralysis. Platin-based palliative chemotherapy was given, after an initial pancranial irradiation. According to the MRI findings, the pontine lesion was responsible for the peripheral facial nerve paralysis, as an initial presenting symptom in this case of lung adenocarcinoma. This clinical case of a peripheral facial nerve paralysis was caused by a pontine brain metastasis and illustrates a rather rare presenting symptom of metastatic lung cancer.

Intramedullary cavernous angioma of the spinal cord in a pediatric patient, with multiple cavernomas, familial occurrence and partial spontaneous regression: case report and review of the literature.

PubMed

Santoro, Antonio; Piccirilli, Manolo; Brunetto, Giacoma Maria Floriana; Delfini, Roberto; Cantore, Giampaolo

2007-11-01

The authors present their experience with the 17th pediatric intramedullary cavernoma reported in English literature. The patient firstly underwent surgery for a left frontal cavernoma when he was 2 years old. Also the child's mother was operated for a C2-C3 intramedullary cavernoma. He grew up normally and the radiological follow-up was negative for other brainstem cavernous malformations. When he was 11 years old he complained a worsening tetraparesis. A cerebral and spinal magnetic resonance (MR) imaging revealed the presence of a C1 intramedullary cavernoma and a pontine cavernoma. He underwent surgery for the cervical lesion, which was completely removed. The postoperative course was regular with a total recovery from the neurological deficit. The boy underwent a radiological follow-up, monitoring the pontine lesion, which spontaneously regressed when he was 19 years old. The rarity of the pediatric intramedullary cavernoma, the familial occurrence, and the spontaneous regression of the pontine cavernoma make this case very peculiar.

Exploring the regulatory role of isocitrate dehydrogenase mutant protein on glioma stem cell proliferation.

PubMed

Lu, H-C; Ma, J; Zhuang, Z; Qiu, F; Cheng, H-L; Shi, J-X

2016-08-01

Glioma is the most lethal form of cancer that originates mostly from the brain and less frequently from the spine. Glioma is characterized by abnormal regulation of glial cell differentiation. The severity of the glioma was found to be relaxed in isocitrate dehydrogenase 1 (IDH1) mutant. The present study focused on histological discrimination and regulation of cancer stem cell between IDH1 mutant and in non-IDH1 mutant glioma tissue. Histology, immunohistochemistry and Western blotting techniques are used to analyze the glioma nature and variation in glioma stem cells that differ between IDH1 mutant and in non-IDH1 mutant glioma tissue. The aggressive form of non-IDH1 mutant glioma shows abnormal cellular histological variation with prominent larger nucleus along with abnormal clustering of cells. The longer survival form of IDH1 mutant glioma has a control over glioma stem cell proliferation. Immunohistochemistry with stem cell markers, CD133 and EGFRvIII are used to demonstrate that the IDH1 mutant glioma shows limited dependence on cancer stem cells and it shows marked apoptotic signals in TUNEL assay to regulate abnormal cells. The non-IDH1 mutant glioma failed to regulate misbehaving cells and it promotes cancer stem cell proliferation. Our finding supports that the IDH1 mutant glioma has a regulatory role in glioma stem cells and their survival.

Central pontine myelinolysis: a rare presentation secondary to hyperglycaemia

PubMed Central

Saini, Monica; Mamauag, Marlie Jane; Singh, Rajinder

2015-01-01

Central pontine myelinolysis (CPM) is classically described as a demyelinating condition that results from the rapid correction of hyponatraemia. CPM has also been reported to arise from hyperglycaemia in association with concomitant acidosis, hypernatraemia and hyperosmolar syndrome. Herein, we report a rare presentation of CPM, which was purely secondary to hyperosmolar hyperglycaemia. The patient presented with ataxia and pseudobulbar affect, which evolved subacutely over a duration of two weeks. It is important to note that, in addition to acute changes in osmolality, a subacute shift secondary to hyperglycaemia may also lead to CPM. PMID:25917480

Combination of photodynamic therapy and temozolomide on glioma in a rat C6 glioma model.

PubMed

Zhang, Xiaoming; Guo, Mian; Shen, Lei; Hu, Shaoshan

2014-12-01

For glioma, temozolomide (TMZ) is a commonly used chemotherapy drug and photodynamic therapy (PDT) is an important adjuvant therapy. The aim of this study was to evaluate the effect of their combination for the treatment of glioma. A rat C6 glioma model using male Wistar rats (n=180) weighing 280-300 g was established. Glioma-bearing rats (n=100) were treated with mock, hematoporphyrin monomethyl ether (HMME), laser or PDT. The expression of P-glycoprotein (P-gp) in endothelial cells of the blood-tumor-barrier and in glioma tissues was detected using immunohistochemistry and western blot, respectively. Glioma-bearing rats (n=40) were treated with normal saline, TMZ (60 mg/m(2) for five consecutive days), PDT (630 nm for 10 min) or a combination of TMZ and PDT. TMZ concentration in glioma tissues was detected using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and cell death was observed using transmission microscopy. Concurrently, another batch of 40 glioma-bearing rats was subjected to the same treatment, and the survival of these rats was estimated using Kaplan-Meier analysis. PDT significantly decreased the expression of P-gp in endothelial cells comprising the blood-tumor-barrier and in glioma tissues. The combination of TMZ with PDT significantly increased TMZ concentration in glioma tissues, enhanced glioma cell apoptosis and prolonged the median survival of glioma-bearing rats. The combination of PDT with TMZ shows synergistic effect in rat C6 glioma model, indicating its potential clinical use in glioma treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao

Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression ofmore » Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.« less

Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum.

PubMed

Mazzone, Paolo; Vilela Filho, Osvaldo; Viselli, Fabio; Insola, Angelo; Sposato, Stefano; Vitale, Flora; Scarnati, Eugenio

2016-07-01

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.

Bidirectional plasticity of pontine pneumotaxic postinspiratory drive: implication for a pontomedullary respiratory central pattern generator.

PubMed

Poon, Chi-Sang; Song, Gang

2014-01-01

The "pneumotaxic center" in the rostral dorsolateral pons as delineated by Lumsden nine decades ago is known to play an important role in promoting the inspiratory off-switch (IOS) for inspiratory-expiratory phase transition as a fail-safe mechanism for preventing apneusis in the absence of vagal input. Traditionally, the pontine pneumotaxic mechanism has been thought to contribute a tonic descending input that lowers the IOS threshold in medullary respiratory central pattern generator (rCPG) circuits, but otherwise does not constitute part of the rCPG. Recent evidence indicates that descending input from the Kölliker-Fuse nucleus (KFN) within the pneumotaxic center is essential for gating the postinspiratory phase of the three-phase respiratory rhythm to control the IOS in vagotomized animals. A critical question arising is whether such a descending pneumotaxic input from KFN that drives postinspiratory activity is tonic (null hypothesis) or rhythmic with postinspiratory phase modulation (alternative hypothesis). Here, we show that multifarious evidence reported in the literature collectively indicates that the descending pneumotaxic input may exhibit NMDA receptor-dependent short-term plasticity in the form of a biphasic neural differentiator that bidirectionally and phase-selectively modulates postinspiratory phase duration in response to vagal and peripheral chemoreceptor inputs independent of the responses in inspiratory and late-expiratory activities. The phase-selectivity property of the descending pneumotaxic input implicates a population of pontine early-expiratory (postinspiratory/expiratory-decrementing) neurons as the most likely neural correlate of the pneumotaxic mechanism that drives post-I activity, suggesting that the pontine pneumotaxic mechanism may be an integral part of a pontomedullary rCPG that underlies the three-phase respiratory rhythm. © 2014 Elsevier B.V. All rights reserved.

Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide.

PubMed

Beckmann, Diego V; Carvalho, Fabiano B; Mazzanti, Cinthia M; Dos Santos, Rosmarini P; Andrades, Amanda O; Aiello, Graciane; Rippilinger, Angel; Graça, Dominguita L; Abdalla, Fátima H; Oliveira, Lizielle S; Gutierres, Jessié M; Schetinger, Maria Rosa C; Mazzanti, Alexandre

2014-05-17

The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination. Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB+Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc+EB were treated once daily with quercetin (50mg/kg) diluted in 25% ethanol solution (1ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured. The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission. These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS. Copyright © 2014. Published by Elsevier Inc.

Predicting pain relief: Use of pre-surgical trigeminal nerve diffusion metrics in trigeminal neuralgia.

PubMed

Hung, Peter S-P; Chen, David Q; Davis, Karen D; Zhong, Jidan; Hodaie, Mojgan

2017-01-01

Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to surgery. A proportion of patients, however, do not benefit and suffer ongoing pain. There are currently no imaging tools that permit the prediction of treatment response. To address this paucity, we used diffusion tensor imaging (DTI) to determine whether pre-surgical trigeminal nerve microstructural diffusivities can prognosticate response to TN treatment. In 31 TN patients and 16 healthy controls, multi-tensor tractography was used to extract DTI-derived metrics-axial (AD), radial (RD), mean diffusivity (MD), and fractional anisotropy (FA)-from the cisternal segment, root entry zone and pontine segment of trigeminal nerves for false discovery rate-corrected Student's t -tests. Ipsilateral diffusivities were bootstrap resampled to visualize group-level diffusivity thresholds of long-term response. To obtain an individual-level statistical classifier of surgical response, we conducted discriminant function analysis (DFA) with the type of surgery chosen alongside ipsilateral measurements and ipsilateral/contralateral ratios of AD and RD from all regions of interest as prediction variables. Abnormal diffusivity in the trigeminal pontine fibers, demonstrated by increased AD, highlighted non-responders (n = 14) compared to controls. Bootstrap resampling revealed three ipsilateral diffusivity thresholds of response-pontine AD, MD, cisternal FA-separating 85% of non-responders from responders. DFA produced an 83.9% (71.0% using leave-one-out-cross-validation) accurate prognosticator of response that successfully identified 12/14 non-responders. Our study demonstrates that pre-surgical DTI metrics can serve as a highly predictive, individualized tool to prognosticate surgical response. We further highlight abnormal pontine segment diffusivities as key features of treatment non-response and confirm the axiom that central pain does not commonly benefit from peripheral treatments.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals.

PubMed

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood-brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p -aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood-brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p -aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells.

Gap junctions modulate glioma invasion by direct transfer of microRNA.

PubMed

Hong, Xiaoting; Sin, Wun Chey; Harris, Andrew L; Naus, Christian C

2015-06-20

The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity.

Functional analysis of the DEPDC1 oncoantigen in malignant glioma and brain tumor initiating cells.

PubMed

Kikuchi, Ryogo; Sampetrean, Oltea; Saya, Hideyuki; Yoshida, Kazunari; Toda, Masahiro

2017-06-01

DEP domain containing 1 (DEPDC1) is a novel oncoantigen expressed in cancer cells, which presents oncogenic activity and high immunogenicity. Although DEPDC1 has been predicted to be a useful antigen for the development of a cancer vaccine, its pathophysiological roles in glioma have not been investigated. Here, we analyzed the expression and function of DEPDC1 in malignant glioma. DEPDC1 expression in glioma cell lines, glioma tissues, and brain tumor initiating cells (BTICs) was assessed by western blot and quantitative polymerase chain reaction (PCR). The effect of DEPDC1 downregulation on cell growth and nuclear factor kappa B (NFκB) signaling in glioma cells was investigated. Overall survival was assessed in mouse glioma models using human glioma cells and induced mouse brain tumor stem cells (imBTSCs) to determine the effect of DEPDC1 suppression in vivo. DEPDC1 expression was increased in glioma cell lines, tissues, and BTICs. Suppression of endogenous DEPDC1 expression by small interfering RNA (siRNA) inhibited glioma cell viability and induced apoptosis through NFκB signaling. In mouse glioma models using human glioma cells and imBTSCs, downregulation of DEPDC1 expression prolonged overall survival. These results suggest that DEPDC1 represents a target molecule for the treatment of glioma.

The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

PubMed Central

Wang, Yahua; Ying, Xue; Xu, Haolun; Yan, Helu; Li, Xia; Tang, Hui

2017-01-01

Glioblastoma is a kind of malignant gliomas that is almost impossible to cure due to the poor drug transportation across the blood–brain barrier and the existence of glioma stem cells. We prepared a new kind of targeted liposomes in order to improve the drug delivery system onto the glioma cells and induce the apoptosis of glioma stem cells afterward. In this experiment, curcumin was chosen to kill gliomas, while quinacrine was used to induce apoptosis of the glioma stem cells. Also, p-aminophenyl-α-D-mannopyranoside could facilitate the transport of liposomes across the blood–brain barrier and finally target the brain glioma cells. The cell experiments in vitro indicated that the targeted liposomes could significantly improve the anti-tumor effects of the drugs, while enhancing the uptake effects, apoptosis effects, and endocytic effects of C6 glioma cells and C6 glioma stem cells. Given the animal experiments in vivo, we discovered that the targeted liposomes could obviously increase the survival period of brain glioma-bearing mice and inhibit the growth of gliomas. In summary, curcumin and quinacrine liposomes modified with p-aminophenyl-α-D-mannopyranoside is a potential preparation to treat brain glioma cells and brain glioma stem cells. PMID:28260885

Gap junctions modulate glioma invasion by direct transfer of microRNA

PubMed Central

Hong, Xiaoting; Sin, Wun Chey; Harris, Andrew L.; Naus, Christian C.

2015-01-01

The invasiveness of high-grade glioma is the primary reason for poor survival following treatment. Interaction between glioma cells and surrounding astrocytes are crucial to invasion. We investigated the role of gap junction mediated miRNA transfer in this context. By manipulating gap junctions with a gap junction inhibitor, siRNAs, and a dominant negative connexin mutant, we showed that functional glioma-glioma gap junctions suppress glioma invasion while glioma-astrocyte and astrocyte-astrocyte gap junctions promote it in an in vitro transwell invasion assay. After demonstrating that glioma-astrocyte gap junctions are permeable to microRNA, we compared the microRNA profiles of astrocytes before and after co-culture with glioma cells, identifying specific microRNAs as candidates for transfer through gap junctions from glioma cells to astrocytes. Further analysis showed that transfer of miR-5096 from glioma cells to astrocytes is through gap junctions; this transfer is responsible, in part, for the pro-invasive effect. Our results establish a role for glioma-astrocyte gap junction mediated microRNA signaling in modulation of glioma invasive behavior, and that gap junction coupling among astrocytes magnifies the pro-invasive signaling. Our findings reveal the potential for therapeutic interventions based on abolishing alteration of stromal cells by tumor cells via manipulation of microRNA and gap junction channel activity. PMID:25978028

Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

PubMed Central

Ju, Rui-Jun; Zeng, Fan; Liu, Lei; Mu, Li-Min; Xie, Hong-Jun; Zhao, Yao; Yan, Yan; Wu, Jia-Shuan; Hu, Ying-Jie; Lu, Wan-Liang

2016-01-01

The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels. PMID:27042063

Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1

PubMed Central

Zhu, Wen; Carney, Karen E.; Pigott, Victoria M.; Falgoust, Lindsay M.; Clark, Paul A.; Kuo, John S.; Sun, Dandan

2016-01-01

Microglia play important roles in extracellular matrix remodeling, tumor invasion, angiogenesis, and suppression of adaptive immunity in glioma. Na+/H+ exchanger isoform 1 (NHE1) regulates microglial activation and migration. However, little is known about the roles of NHE1 in intratumoral microglial activation and microglia–glioma interactions. Our study revealed up-regulation of NHE1 protein expression in both glioma cells and tumor-associated Iba1+ microglia in glioma xenografts and glioblastoma multiforme microarrays. Moreover, we observed positive correlation of NHE1 expression with Iba1 intensity in microglia/macrophages. Glioma cells, via conditioned medium or non-contact glioma-microglia co-cultures, concurrently upregulated microglial expression of NHE1 protein and other microglial activation markers (iNOS, arginase-1, TGF-β, IL-6, IL-10 and the matrix metalloproteinases MT1-MMP and MMP9). Interestingly, glioma-stimulated microglia reciprocally enhanced glioma proliferation and migration. Most importantly, inhibition of microglial NHE1 activity via small interfering RNA (siRNA) knockdown or the potent NHE1-specific inhibitor HOE642 significantly attenuated microglial activation and abolished microglia-stimulated glioma migration and proliferation. Taken together, our findings provide the first evidence that NHE1 function plays an important role in glioma–microglia interactions, enhancing glioma proliferation and invasion by stimulating microglial release of soluble factors. NHE1 upregulation is a novel marker of the glioma-associated microglial activation phenotype. Inhibition of NHE1 represents a novel glioma therapeutic strategy by targeting tumor-induced microglial activation. PMID:27287871

Extracellular diffusion quantified by magnetic resonance imaging during rat C6 glioma cell progression.

PubMed

Song, G; Luo, T; Dong, L; Liu, Q

2017-07-03

Solution reflux and edema hamper the convection-enhanced delivery of the standard treatment for glioma. Therefore, a real-time magnetic resonance imaging (MRI) method was developed to monitor the dosing process, but a quantitative analysis of local diffusion and clearance parameters has not been assessed. The objective of this study was to compare diffusion into the extracellular space (ECS) at different stages of rat C6 gliomas, and analyze the effects of the extracellular matrix (ECM) on the diffusion process. At 10 and 20 days, after successful glioma modeling, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was introduced into the ECS of rat C6 gliomas. Diffusion parameters and half-life of the reagent were then detected using MRI, and quantified according to the mathematical model of diffusion. The main ECM components [chondroitin sulfate proteoglycans (CSPGs), collagen IV, and tenascin C] were detected by immunohistochemical and immunoblot analyses. In 20-day gliomas, Gd-DTPA diffused more slowly and derived higher tortuosity, with lower clearance rate and longer half-life compared to 10-day gliomas. The increased glioma ECM was associated with different diffusion and clearance parameters in 20-day rat gliomas compared to 10-day gliomas. ECS parameters were altered with C6 glioma progression from increased ECM content. Our study might help better understand the glioma microenvironment and provide benefits for interstitial drug delivery to treat brain gliomas.

Associations of High-Grade Glioma With Glioma Risk Alleles and Histories of Allergy and Smoking

PubMed Central

Lachance, Daniel H.; Yang, Ping; Johnson, Derek R.; Decker, Paul A.; Kollmeyer, Thomas M.; McCoy, Lucie S.; Rice, Terri; Xiao, Yuanyuan; Ali-Osman, Francis; Wang, Frances; Stoddard, Shawn M.; Sprau, Debra J.; Kosel, Matthew L.; Wiencke, John K.; Wiemels, Joseph L.; Patoka, Joseph S.; Davis, Faith; McCarthy, Bridget; Rynearson, Amanda L.; Worra, Joel B.; Fridley, Brooke L.; O’Neill, Brian Patrick; Buckner, Jan C.; Il’yasova, Dora; Jenkins, Robert B.; Wrensch, Margaret R.

2011-01-01

Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997–2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratioallergy-glioma = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratioallergy-glioma = 0.76, 95% confidence interval: 0.59, 0.97; Pinteraction = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratioallergy-glioma = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratioallergy-glioma = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors’ observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma. PMID:21742680

The oculomotor role of the pontine nuclei and the nucleus reticularis tegmenti pontis.

PubMed

Thier, Peter; Möck, Martin

2006-01-01

Cerebral cortex and the cerebellum interact closely in order to facilitate spatial orientation and the generation of motor behavior, including eye movements. This interaction is based on a massive projection system that allows the exchange of signals between the two cortices. This cerebro-cerebellar communication system includes several intercalated brain stem nuclei, whose eminent role in the organization of oculomotor behavior has only recently become apparent. This review focuses on the two major nuclei of this group taking a precerebellar position, the pontine nuclei and the nucleus reticularis tegmenti pontis, both intimately involved in the visual guidance of eye movements.

Subarachnoid, subdural and interdural spaces at the clival region: an anatomical study.

PubMed

Ayberk, Giyas; Ozveren, Mehmet Faik; Aslan, Sevil; Yaman, Mesut Emre; Yaman, Onur; Kayaci, Selim; Tekdemir, Ibrahim

2011-01-01

We aimed to show the significance of the anterior pontine membrane as a determining structure between the subdural and subarachnoid space in the clival region. Five adult cadaver heads and five cerebral hemispheres were used. The skull vault and hemipheres were removed by sectioning through the pontomesencephalic junction. Five other heads hemispheres were removed but the arachnoid membrane was protected and the cerebral side of the clival dura mater was dissected. In another specimen, the dural porus of the abducens nerve was sectioned for histological evaluation. Three cases of hematoma at the clivus were presented to support our findings. The anterior pontine membrane is the arachnoid membrane forming the anterior wall of the prepontine cistern with its lateral extension at the skull base. This membrane forms the subdural and subarachnoid spaces by forming a barrier between the clival dura mater and neurovascular structures of the brainstem. There were rigid fibrous trabeculations between both cerebral and periosteal dural layers forming the basilar plexus as the interdural space in the clivus. The anterior pontine membrane separates the subdural and subarachnoid spaces at the clival region. The hematomas of the clival region require to be evaluated with consideration given to the existance of the subdural space.

Altered resting-state functional activity in isolated pontine infarction patients with pathological laughing and crying.

PubMed

Liu, Tao; Li, Jianjun; Huang, Shixiong; Li, Changqinq; Zhao, Zhongyan; Wen, Guoqiang; Chen, Feng

2017-10-13

We used resting-state functional magnetic resonance imaging to investigate the global spontaneous neural activity involved in pathological laughing and crying after stroke. Twelve pathological laughing and crying patients with isolated pontine infarction were included, along with 12 age- and gender-matched acute isolated pontine infarction patients without pathological laughing and crying, and 12 age- and gender-matched healthy controls. We examined both the amplitude of low-frequency fluctuation and the regional homogeneity in order to comprehensively evaluate the intrinsic activity in patients with post-stroke pathological laughing and crying. In the post-stroke pathological laughing and crying group, changes in these measures were observed mainly in components of the default mode network (medial prefrontal cortex/anterior cingulate cortex, middle temporal gyrus, inferior temporal gyrus, superior frontal gyrus, middle frontal gyrus and inferior parietal lobule), sensorimotor network (supplementary motor area, precentral gyrus and paracentral lobule), affective network (medial prefrontal cortex/anterior cingulate cortex, parahippocampal gyrus, middle temporal gyrus and inferior temporal gyrus) and cerebellar lobes (cerebellum posterior lobe). We therefore speculate that when disinhibition of the volitional system is lost, increased activation of the emotional system causes pathological laughing and crying.

Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression.

PubMed

Han, Guosheng; Zhao, Wenyuan; Wang, Laixing; Yue, Zhijian; Zhao, Rui; Li, Yanan; Zhou, Xiaoping; Hu, Xiaowu; Liu, Jianmin

2014-01-16

Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem-like cells invasion as well as the signaling pathway. We found that glioma stem-like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence. © 2013 Published by Elsevier B.V.

Products of cells from gliomas: VIII. Multiple-well immunoperoxidase assay of immunoreactivity of primary hybridoma supernatants with human glioma and brain tissue and cultured glioma cells.

PubMed

McKeever, P E; Wahl, R L; Shakui, P; Jackson, G A; Letica, L H; Liebert, M; Taren, J A; Beierwaltes, W H; Hoff, J T

1990-06-01

To test the feasibility of primary screening of hybridoma supernatants against human glioma tissue, over 5000 combinations of hybridoma supernatants with glioma tissue, cultured glioma cells, and normal central neural tissue were screened with a new multiple-well (M-well) screening system. This is an immunoperoxidase assay system with visual endpoints for screening 20-30 hybridoma supernatants per single microscope slide. There were extensive differences between specificities to tissue and to cultured glioma cells when both were screened with M-wells and when cultured cells were screened with standard semi-automated fluorescence. Primary M-well screening with glioma tissue detected seven hybridoma supernatants that specifically identified parenchymal cells of glioma tissue and that were not detected with cultured cells. Immunoreactivities of individual supernatants for vascular components (nine supernatants), necrosis (five supernatants), and nuclei (three supernatants) were detected. Other supernatants bound multiple sites on glioma tissue and/or subpopulations of neurons and glia of normal tissue. The results show that primary screening with glioma tissue detects a number of different specificities of hybridoma supernatants to gliomas not detected by conventional screening with cultured cells. These are potentially applicable to diagnosis and therapy.

High expression of Bruton's tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma.

PubMed

Yue, Chenglong; Niu, Mingshan; Shan, Qian Qian; Zhou, Ting; Tu, Yiming; Xie, Peng; Hua, Lei; Yu, Rutong; Liu, Xuejiao

2017-09-25

Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed. In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo. Our data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells. Taken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma.

PubMed

Gritsenko, Pavlo; Leenders, William; Friedl, Peter

2017-10-01

Diffuse invasion of glioma cells into the brain parenchyma leads to nonresectable brain tumors and poor prognosis of glioma disease. In vivo, glioma cells can adopt a range of invasion strategies and routes, by moving as single cells, collective strands and multicellular networks along perivascular, perineuronal and interstitial guidance cues. Current in vitro assays to probe glioma cell invasion, however, are limited in recapitulating the modes and adaptability of glioma invasion observed in brain parenchyma, including collective behaviours. To mimic in vivo-like glioma cell invasion in vitro, we here applied three tissue-inspired 3D environments combining multicellular glioma spheroids and reconstituted microanatomic features of vascular and interstitial brain structures. Radial migration from multicellular glioma spheroids of human cell lines and patient-derived xenograft cells was monitored using (1) reconstituted basement membrane/hyaluronan interfaces representing the space along brain vessels; (2) 3D scaffolds generated by multi-layered mouse astrocytes to reflect brain interstitium; and (3) freshly isolated mouse brain slice culture ex vivo. The invasion patterns in vitro were validated using histological analysis of brain sections from glioblastoma patients and glioma xenografts infiltrating the mouse brain. Each 3D assay recapitulated distinct aspects of major glioma invasion patterns identified in mouse xenografts and patient brain samples, including individually migrating cells, collective strands extending along blood vessels, and multicellular networks of interconnected glioma cells infiltrating the neuropil. In conjunction, these organotypic assays enable a range of invasion modes used by glioma cells and will be applicable for mechanistic analysis and targeting of glioma cell dissemination.

Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway

PubMed Central

Wang, Guangzhi; Liu, Mingna; Wang, Hongjun; Yu, Shan; Jiang, Zhenfeng; Sun, Jiahang; Han, Ke; Shen, Jia; Zhu, Minwei; Lin, Zhiguo; Jiang, Chuanlu; Guo, Mian

2016-01-01

Introduction: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. Method: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. Results: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. Conclusions: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future. PMID:27471559

Glioma infiltration sign on high b-value diffusion-weighted imaging in gliomas and its prognostic value.

PubMed

Zeng, Qiang; Ling, Chenhan; Shi, Feina; Dong, Fei; Jiang, Biao; Zhang, Jianmin

2018-03-01

Glioma cells may infiltrate beyond the tumor margins revealed on conventional structural images. To investigate whether the presence of a glioma infiltration sign on high b-value diffusion-weighted imaging (DWI) can predict the prognosis of gliomas. Retrospective cohort. Fifty-two patients with gliomas (14 WHO grade II; 13 WHO grade III; 25 WHO grade IV). 3.0T, including a T 1 -weighted contrast-enhanced (T 1 w-CE) sequence, contrast-enhanced T 2 -flair sequence, and a DWI sequence. T 1 w-CE images and contrast-enhanced T 2 -flair images were used for identifying the tumor region for enhancing and nonenhancing gliomas, respectively. The glioma infiltration sign was defined as the presence of a peritumoral abnormal high signal region on DWI map, which was adjacent to the tumor region and had higher signal than surrounding areas. This sign was assessed on a high b-value DWI map with b = 3000 s/mm 2 . For patients with glioma infiltration sign, DWI3000 max , DWI1000 max , ADC3000 min , and ADC1000 min were measured by drawing a region of interest over the peritumoral abnormal high signal region. Survival analysis was conducted by using Cox regression. Glioma infiltration sign was observed in 28 (53.8%) patients. The occurrence rate of this sign was 92.0% in grade IV gliomas, 30.8% in grade III gliomas, and 7.1% in grade II gliomas. The glioma infiltration sign could independently predict both the progression-free survival (hazard ratio [HR], 95% confidence interval [CI] = 8.58 [3.19-23.03], P < 0.001) and overall survival (HR, 95% CI = 11.90 [3.41-41.55], P < 0.001) after adjustment. For patients with glioma infiltration sign, DWI3000 max (P = 0.005) and ADC3000 min (P = 0.008) were both independent predictors of overall survival after adjustment, while DWI1000 max and ADC1000 min were not. The glioma infiltration sign on high b-value DWI is an independent predictor of poor prognosis in glioma patients. High b-value DWI might be a convenient method to detect glioma infiltration. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

[Expression and mechanism of Twist2 in glioma].

PubMed

Wang, L Z; Wang, W J; Xiong, Y F; Xu, S; Wang, S S; Tu, Y; Wang, Z Y; Yan, X L; Mei, J H; Wang, C L

2017-12-08

Objective: To investigate the significance of Twist2 in glioma and whether it is involved in the malignant transformation of glioma by epithelial-mesenchymal transition (EMT). Methods: Using immunohistochemical method detected the expression level of Twist2 in 60 cases of gliomas (including WHO grades Ⅱ, Ⅲ and Ⅳ, each for 20 cases) and 20 cases of non-tumor brain tissues. Real-time fluorescence quantitative PCR and Western blot were used to detect the expression level of Twist2 mRNA and protein in 61 cases of fresh glioma tissue (WHO grade Ⅱ 16 cases, Ⅲ 21 cases, Ⅳ 24 cases) and 12 cases of adjacent tissues, and the expression levels of E-cadherin, N-cadherin and vimentin were also investigated in fresh glioma tissue. Results: Immunohistochemistry results showed that the percentages of Twist2 expression in glioma was 90%(54/60) compared with 30%(6/20) in non-tumor brain tissues( P <0.01). The percentages of Twist2 expression were 75% (15/20), 95% (19/20), and 100% (20/20) in the WHO gradesⅡ, Ⅲ and Ⅳ gliomas, respectively. WHO grades Ⅳ and Ⅲ were significantly higher than that of WHO grade Ⅱ ( P <0.01). There was no significant difference between WHO grade Ⅳand WHO Ⅲ glioma ( P >0.05). Real-time fluorescence quantitative PCR and Western blot showed that the expression level of Twist 2 in gliomas was significantly higher than that in para-cancerous tissues ( P <0.01), and those in WHO grades Ⅳ and Ⅲ gliomas were significantly higher than that in WHO grade Ⅱ glioma ( P <0.01). There was no significant difference between WHO grade Ⅳand grade Ⅲ glioma ( P >0.05). Detection of key protein expression in EMT by Western blot displayed that the expression of E-cadherin was negatively associated with Twist2 in glioma ( r =-0.972, P <0.01). The expression of N-cadherin and vimentin was positively associated with Twist2 in glioma( r =0.971, P <0.01; r =0.968, P <0.01). Conclusions: The expression of Twist2 in human glioma is positively correlated with the malignant grade of glioma, which may be involved in the malignant progression of glioma by EMT.

Investigation of adhesion and mechanical properties of human glioma cells by single cell force spectroscopy and atomic force microscopy.

PubMed

Andolfi, Laura; Bourkoula, Eugenia; Migliorini, Elisa; Palma, Anita; Pucer, Anja; Skrap, Miran; Scoles, Giacinto; Beltrami, Antonio Paolo; Cesselli, Daniela; Lazzarino, Marco

2014-01-01

Active cell migration and invasion is a peculiar feature of glioma that makes this tumor able to rapidly infiltrate into the surrounding brain tissue. In our recent work, we identified a novel class of glioma-associated-stem cells (defined as GASC for high-grade glioma--HG--and Gasc for low-grade glioma--LG) that, although not tumorigenic, act supporting the biological aggressiveness of glioma-initiating stem cells (defined as GSC for HG and Gsc for LG) favoring also their motility. Migrating cancer cells undergo considerable molecular and cellular changes by remodeling their cytoskeleton and cell interactions with surrounding environment. To get a better understanding about the role of the glioma-associated-stem cells in tumor progression, cell deformability and interactions between glioma-initiating stem cells and glioma-associated-stem cells were investigated. Adhesion of HG/LG-cancer cells on HG/LG-glioma-associated stem cells was studied by time-lapse microscopy, while cell deformability and cell-cell adhesion strengths were quantified by indentation measurements by atomic force microscopy and single cell force spectroscopy. Our results demonstrate that for both HG and LG glioma, cancer-initiating-stem cells are softer than glioma-associated-stem cells, in agreement with their neoplastic features. The adhesion strength of GSC on GASC appears to be significantly lower than that observed for Gsc on Gasc. Whereas, GSC spread and firmly adhere on Gasc with an adhesion strength increased as compared to that obtained on GASC. These findings highlight that the grade of glioma-associated-stem cells plays an important role in modulating cancer cell adhesion, which could affect glioma cell migration, invasion and thus cancer aggressiveness. Moreover this work provides evidence about the importance of investigating cell adhesion and elasticity for new developments in disease diagnostics and therapeutics.

Upregulation of B23 promotes tumor cell proliferation and predicts poor prognosis in glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Jianguo; Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province; Sun, Jie

B23 (also known as Nucleophosmin, NPM, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. In this study we intended to investigate the clinical significance of B23 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that B23 was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of B23 was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan–Meier analysis revealed that a higher B23 expression in patients with glioma was associated with a poorer prognosis. In vitro, after the releasemore » of glioma cell lines from serum starvation, the expression of B23 was upregulated, as well as PCNA (Proliferating Cell Nuclear Antigen) and cyclin A. In addition, knockdown of B23 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. Taken together, our results implied that B23 could be a candidate prognostic biomarker as well as a potential therapeutical target of glioma. - Highlights: • B23 expression increased as the malignant degree of glioma increased, which was consistent with Ki-67 expression. • High expression of B23 could be a strong determinant of poor prognosis in glioma. • B23 may be involved in the proliferation of glioma in a cell-cycle-dependent pathway. • Knockdown of B23 expression by siRNA could affect the progression of glioma. • B23 may be a potential prognosis biomarker and a possible therapeutic target for glioma.« less

Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis

PubMed Central

Chen, Dongfeng; Persson, Annette; Sun, Yingyu; Salford, Leif G.; Nord, David Gisselsson; Englund, Elisabet; Jiang, Tao; Fan, Xiaolong

2013-01-01

Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis. PMID:23630597

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

PubMed

Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika; Wang, Zhaoming; Henriksson, Roger; Hallmans, Göran; Bondy, Melissa L; Johansen, Christoffer; Feychting, Maria; Ahlbom, Anders; Kitahara, Cari M; Wang, Sophia S; Ruder, Avima M; Carreón, Tania; Butler, Mary Ann; Inskip, Peter D; Purdue, Mark; Hsing, Ann W; Mechanic, Leah; Gillanders, Elizabeth; Yeager, Meredith; Linet, Martha; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2013-05-15

Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. Copyright © 2012 UICC.

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Bin; Hu, Zhiqiang, E-mail: zhiqhutg@126.com; Huang, Hui

Highlights: • KDM5B is overexpressed in glioma samples. • KDM5B stimulated proliferation of glioma cells. • Inhibition of p21contributes to KDM5B-induced proliferation. - Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues.more » Kaplan–Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management.« less

Gpx 4 is involved in the proliferation, migration and apoptosis of glioma cells.

PubMed

Zhao, Hongyu; Ji, Bin; Chen, Jianguo; Huang, Qingfeng; Lu, Xueguan

2017-06-01

Glioma is one of the most common and aggressive types of human brain tumor, it is important to explore novel glioma-associated genes. In this report, we defined Gpx4 as a therapeutic target for glioma. Western blot and immunohistochemistry(IHC) analysis revealed that the protein level of Gpx4 was higher in glioma tissues and cell lines. In addition, IHC stain revealed that there was statistical significance between the expression of Gpx4 and the WHO grade (P=0.004) and Ki-67(P=0.000) expression. Kaplan-Meier curve showed that high expression of Gpx4 was associated with poor prognosis of glioma patients (P<0.01). To determine whether Gpx4 could regulate the proliferation and migration of glioma cells, we transfected glioma cells with Gpx4-siRNA and then investigated cell proliferation with cell counting kit (CCK) -8, flow cytometry assay and colony formation analyses, and we used wound-healing and transwell assays to investigate cell migration. Our results indicated that knockdown of Gpx4 would inhibit the proliferation and migration of glioma cells. Besides, silencing of Gpx4 could induce the apoptosis of glioma cells. This research indicated that Gpx4 might be thought of as a new prognostic factor in glioma and be closely correlated with glioma cell proliferation, migration and apoptosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Knockdown of DIXDC1 Inhibits the Proliferation and Migration of Human Glioma Cells.

PubMed

Chen, Jianguo; Shen, Chaoyan; Shi, Jinlong; Shen, Jianhong; Chen, Wenjuan; Sun, Jie; Fan, Shaocheng; Bei, Yuanqi; Xu, Peng; Chang, Hao; Jiang, Rui; Hua, Lu; Ji, Bin; Huang, Qingfeng

2017-08-01

DIX domain containing 1 (DIXDC1), the human homolog of coiled-coil-DIX1 (Ccd1), is a positive regulator of Wnt signaling pathway. Recently, it was found to act as a candidate oncogene in colon cancer, non-small-cell lung cancer, and gastric cancer. In this study, we aimed to investigate the clinical significance of DIXDC1 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that DIXDC1 was overexpressed in glioma tissues and glioma cell lines. The expression level of DIXDC1 was evidently linked to glioma pathological grade and Ki-67 expression. Kaplan-Meier curve showed that high expression of DIXDC1 may lead to poor outcome of glioma patients. Serum starvation and refeeding assay indicated that the expression of DIXDC1 was associated with cell cycle. To determine whether DIXDC1 could regulate the proliferation and migration of glioma cells, we transfected glioma cells with interfering RNA-targeting DIXDC1; investigated cell proliferation with Cell Counting Kit (CCK)-8, flow cytometry assays, and colony formation analyses; and investigated cell migration with wound healing assays and transwell assays. According to our data, knockdown of DIXDC1 significantly inhibited proliferation and migration of glioma cells. These data implied that DIXDC1 might participate in the development of glioma, suggesting that DIXDC1 can become a potential therapeutic strategy for glioma.

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

PubMed Central

Ying, Xue; Wang, Yahua; Xu, Haolun; Li, Xia; Yan, Helu; Tang, Hui; Wen, Chen; Li, Yingchun

2017-01-01

Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells. PMID:28969057

Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer

PubMed Central

Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Armstrong, Georgina N.; Shete, Sanjay; Lau, Ching C.; Bainbridge, Matthew N.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Lai, Rose; Il'yasova, Dora; Houlston, Richard S.; Schildkraut, Joellen; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel H.; Wrensch, Margaret; Davis, Faith G.; Merrell, Ryan; Johansen, Christoffer; Sadetzki, Siegal; Bondy, Melissa L.; Melin, Beatrice S.; Adatto, Phyllis; Morice, Fabian; Payen, Sam; McQuinn, Lacey; McGaha, Rebecca; Guerra, Sandra; Paith, Leslie; Roth, Katherine; Zeng, Dong; Zhang, Hui; Yung, Alfred; Aldape, Kenneth; Gilbert, Mark; Weinberger, Jeffrey; Colman, Howard; Conrad, Charles; de Groot, John; Forman, Arthur; Groves, Morris; Levin, Victor; Loghin, Monica; Puduvalli, Vinay; Sawaya, Raymond; Heimberger, Amy; Lang, Frederick; Levine, Nicholas; Tolentino, Lori; Saunders, Kate; Thach, Thu-Trang; Iacono, Donna Dello; Sloan, Andrew; Gerson, Stanton; Selman, Warren; Bambakidis, Nicholas; Hart, David; Miller, Jonathan; Hoffer, Alan; Cohen, Mark; Rogers, Lisa; Nock, Charles J; Wolinsky, Yingli; Devine, Karen; Fulop, Jordonna; Barrett, Wendi; Shimmel, Kristen; Ostrom, Quinn; Barnett, Gene; Rosenfeld, Steven; Vogelbaum, Michael; Weil, Robert; Ahluwalia, Manmeet; Peereboom, David; Staugaitis, Susan; Schilero, Cathy; Brewer, Cathy; Smolenski, Kathy; McGraw, Mary; Naska, Theresa; Rosenfeld, Steven; Ram, Zvi; Blumenthal, Deborah T.; Bokstein, Felix; Umansky, Felix; Zaaroor, Menashe; Cohen, Avi; Tzuk-Shina, Tzeela; Voldby, Bo; Laursen, René; Andersen, Claus; Brennum, Jannick; Henriksen, Matilde Bille; Marzouk, Maya; Davis, Mary Elizabeth; Boland, Eamon; Smith, Marcel; Eze, Ogechukwu; Way, Mahalia; Lada, Pat; Miedzianowski, Nancy; Frechette, Michelle; Paleologos, Nina; Byström, Gudrun; Svedberg, Eva; Huggert, Sara; Kimdal, Mikael; Sandström, Monica; Brännström, Nikolina; Hayat, Amina; Tihan, Tarik; Zheng, Shichun; Berger, Mitchel; Butowski, Nicholas; Chang, Susan; Clarke, Jennifer; Prados, Michael; Rice, Terri; Sison, Jeannette; Kivett, Valerie; Duo, Xiaoqin; Hansen, Helen; Hsuang, George; Lamela, Rosito; Ramos, Christian; Patoka, Joe; Wagenman, Katherine; Zhou, Mi; Klein, Adam; McGee, Nora; Pfefferle, Jon; Wilson, Callie; Morris, Pagan; Hughes, Mary; Britt-Williams, Marlin; Foft, Jessica; Madsen, Julia; Polony, Csaba; McCarthy, Bridget; Zahora, Candice; Villano, John; Engelhard, Herbert; Borg, Ake; Chanock, Stephen K; Collins, Peter; Elston, Robert; Kleihues, Paul; Kruchko, Carol; Petersen, Gloria; Plon, Sharon; Thompson, Patricia; Johansen, C.; Sadetzki, S.; Melin, B.; Bondy, Melissa L.; Lau, Ching C.; Scheurer, Michael E.; Armstrong, Georgina N.; Liu, Yanhong; Shete, Sanjay; Yu, Robert K.; Aldape, Kenneth D.; Gilbert, Mark R.; Weinberg, Jeffrey; Houlston, Richard S.; Hosking, Fay J.; Robertson, Lindsay; Papaemmanuil, Elli; Claus, Elizabeth B.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Sloan, Andrew E.; Barnett, Gene; Devine, Karen; Wolinsky, Yingli; Lai, Rose; McKean-Cowdin, Roberta; Il'yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Yechezkel, Galit Hirsh; Bruchim, Revital Bar-Sade; Aslanov, Lili; Sadetzki, Siegal; Johansen, Christoffer; Kosteljanetz, Michael; Broholm, Helle; Bernstein, Jonine L.; Olson, Sara H.; Schubert, Erica; DeAngelis, Lisa; Jenkins, Robert B.; Yang, Ping; Rynearson, Amanda; Andersson, Ulrika; Wibom, Carl; Henriksson, Roger; Melin, Beatrice S.; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Merrell, Ryan; Lada, Patricia; Wrensch, Margaret; Wiencke, John; Wiemels, Joe; McCoy, Lucie; McCarthy, Bridget J.; Davis, Faith G.

2014-01-01

Background Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. PMID:24723567

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

PubMed Central

Backes, Christina; Harz, Christian; Fischer, Ulrike; Schmitt, Jana; Ludwig, Nicole; Petersen, Britt-Sabina; Mueller, Sabine C.; Kim, Yoo-Jin; Wolf, Nadine M.; Katus, Hugo A.; Meder, Benjamin; Furtwängler, Rhoikos; Franke, Andre; Bohle, Rainer; Henn, Wolfram; Graf, Norbert; Keller, Andreas; Meese, Eckart

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors. We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma. The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease. PMID:25537509

Pediatric Glioma at the Optic Pathway and Thalamus

PubMed Central

Park, Eun Suk; Park, Jun Bum; Ra, Young-Shin

2018-01-01

Gliomas are the most common pediatric tumors of the central nervous system. In this review, we discuss the clinical features, treatment paradigms, and evolving concepts related to two types of pediatric gliomas affecting two main locations: the optic pathway and thalamus. In particular, we discuss recently revised pathologic classification, which adopting molecular parameter. We believe that our review contribute to the readers’ better understanding of pediatric glioma because pediatric glioma differs in many ways from adult glioma according to the newest advances in molecular characterization of this tumor. A better understanding of current and evolving issues in pediatric glioma is needed to ensure effective management decision. PMID:29742884

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study.

PubMed

Amirian, E Susan; Zhou, Renke; Wrensch, Margaret R; Olson, Sara H; Scheurer, Michael E; Il'yasova, Dora; Lachance, Daniel; Armstrong, Georgina N; McCoy, Lucie S; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Bernstein, Jonine L; Merrell, Ryan T; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Melin, Beatrice S; Bondy, Melissa L

2016-02-01

Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. ©2016 American Association for Cancer Research.

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study

PubMed Central

Amirian, E. Susan; Zhou, Renke; Wrensch, Margaret R.; Olson, Sara H.; Scheurer, Michael E.; Il’yasova, Dora; Lachance, Daniel; Armstrong, Georgina N.; McCoy, Lucie S.; Lau, Ching C.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill S.; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S.; Jenkins, Robert B.; Bernstein, Jonine L.; Merrell, Ryan T.; Davis, Faith G.; Lai, Rose; Shete, Sanjay; Amos, Christopher I.; Melin, Beatrice S.; Bondy, Melissa L.

2015-01-01

Background Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. Methods The GICC contains detailed information on history of atopic conditions for 4533 cases and 4171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis odds ratios, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Results Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared to not having respiratory allergies (mOR: 0.72, 95% CI: 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. Conclusions A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. Impact As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biological mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. PMID:26908595

Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study.

PubMed

Berntsson, Shala G; Merrell, Ryan T; Amirian, E Susan; Armstrong, Georgina N; Lachance, Daniel; Smits, Anja; Zhou, Renke; Jacobs, Daniel I; Wrensch, Margaret R; Olson, Sara H; Il'yasova, Dora; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Bernstein, Jonine L; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Bondy, Melissa L; Melin, Beatrice S

2018-04-23

The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma.

PubMed

Wu, Jia-Shuan; Mu, Li-Min; Bu, Ying-Zi; Liu, Lei; Yan, Yan; Hu, Ying-Jie; Bai, Jing; Zhang, Jing-Ying; Lu, Weiyue; Lu, Wan-Liang

2017-06-20

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-β1 in gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Liping; Xu, Yinghui; Zou, Lijuan, E-mail: zoulijuantg@126.com

2014-03-28

Highlights: • HOXB9 is overexpressed in gliomas. • HOXB9 over expression had shorter survival time than down expression in gliomas. • HOXB9 stimulated the proliferation, migration and sphere formation of glioma cells. • Activation of TGF-β1 contributed to HOXB9-induced oncogenic activities. - Abstract: Glioma is the leading cause of deaths related to tumors in the central nervous system. The mechanisms of gliomagenesis remain elusive to date. Homeobox B9 (HOXB9) has a crucial function in the regulation of gene expression and cell survival, but its functions in glioma formation and development have yet to be elucidated. This study showed that HOXB9more » expression in glioma tissues was significantly higher than that in nontumor tissues. Higher HOXB9 expression was also significantly associated with advanced clinical stage in glioma patients. HOXB9 overexpression stimulated the proliferation, migration, and sphere formation of glioma cells, whereas HOXB9 knockdown elicited an opposite effect. HOXB9 overexpression also increased the tumorigenicity of glioma cells in vivo. Moreover, the activation of transforming growth factor-β1 contributed to HOXB9-induced oncogenic activities. HOXB9 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in glioma for diagnosis or prognosis.« less

Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation.

PubMed

Jiang, Rifeng; Jiang, Jingjing; Zhao, Lingyun; Zhang, Jiaxuan; Zhang, Shun; Yao, Yihao; Yang, Shiqi; Shi, Jingjing; Shen, Nanxi; Su, Changliang; Zhang, Ju; Zhu, Wenzhen

2015-12-08

Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologically confirmed glioma. The kurtosis and conventional diffusion metric values of the tumor were semi-automatically obtained. The relationships of these metrics with the glioma grade and Ki-67 expression were evaluated. The diagnostic efficiency of these metrics in grading was further compared. It was demonstrated that compared with the conventional diffusion metrics, the kurtosis metrics were more promising imaging markers in distinguishing high-grade from low-grade gliomas and distinguishing among grade II, III and IV gliomas; the kurtosis metrics also showed great potential in the prediction of Ki-67 expression. To our best knowledge, we are the first to reveal the ability of DKI to assess the cellular proliferation of gliomas, and to employ the semi-automatic method for the accurate measurement of gliomas. These results could have a significant impact on the diagnosis and subsequent therapy of glioma.

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma.

PubMed

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood-brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma.

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma

PubMed Central

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood–brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma. PMID:28579776

A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

ClinicalTrials.gov

2017-11-07

Adult Anaplastic Astrocytoma; Recurrent Grade III Glioma; Recurrent Grade IV Glioma; Adult Anaplastic Oligodendroglioma; Adult Brain Tumor; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Adult Anaplastic Oligoastrocytoma; Recurrent High Grade Glioma

The molecular profile of microglia under the influence of glioma

PubMed Central

Li, Wei; Graeber, Manuel B.

2012-01-01

Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large number of experimental studies on functional attributes of microglia in glioma provide evidence for their tumor-supporting roles, there also exist hints in support of their anti-tumor properties. Microglial activities during glioma progression seem multifaceted. They have been attributed to the receptors expressed on the microglia surface, to glioma-derived molecules that have an effect on microglia, and to the molecules released by microglia in response to their environment under glioma control, which can have autocrine effects. In this paper, the microglia and glioma literature is reviewed. We provide a synopsis of the molecular profile of microglia under the influence of glioma in order to help establish a rational basis for their potential therapeutic use. The ability of microglia precursors to cross the blood–brain barrier makes them an attractive target for the development of novel cell-based treatments of malignant glioma. PMID:22573310

MiR-200c Inhibits the Tumor Progression of Glioma via Targeting Moesin

PubMed Central

Qin, Yuanyuan; Chen, Weilong; Liu, Bingjie; Zhou, Lei; Deng, Lu; Niu, Wanxiang; Bao, Dejun; Cheng, Chuandong; Li, Dongxue; Liu, Suling; Niu, Chaoshi

2017-01-01

We attempt to demonstrate the regulatory role of miR-200c in glioma progression and its mechanisms behind. Here, we show that miR-200c expression was significantly reduced in the glioma tissues compared to paratumor tissues, especially in malignant glioma. Exogenous overexpression of miR-200c inhibited the proliferation and invasion of glioma cells. In addition, the in vivo mouse xenograft model showed that miR-200c inhibited glioma growth and liver metastasis, which is mainly regulated by targeting moesin (MSN). We demonstrated that the expression of MSN in glioma specimens were negatively correlated with miR-200c expression, and MSN overexpression rescued the phenotype about cell proliferation and invasion induced by miR-200c. Moreover, knockdown of MSN was able to mimic the effects induced by miR-200c in glioma cells. These results indicate that miR-200c plays an important role in the regulation of glioma through targeting MSN. PMID:28529643

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma.

PubMed

Qin, Elizabeth Y; Cooper, Dominique D; Abbott, Keene L; Lennon, James; Nagaraja, Surya; Mackay, Alan; Jones, Chris; Vogel, Hannes; Jackson, Peter K; Monje, Michelle

2017-08-24

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.

Frequent Nek1 overexpression in human gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Jun; Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Cai, Yu, E-mail: aihaozuqiu22@163.com

Never in mitosis A (NIMA)-related kinase 1 (Nek1) regulates cell cycle progression to mitosis. Its expression and potential functions in human gliomas have not been studied. Here, our immunohistochemistry (IHC) assay and Western blot assay results showed that Nek1 expression was significantly upregulated in fresh and paraffin-embedded human glioma tissues. Its level in normal brain tissues was low. Nek1 overexpression in human gliomas was correlated with the proliferation marker (Ki-67), tumor grade, Karnofsky performance scale (KPS) and more importantly, patients’ poor survival. Further studies showed that Nek1 expression level was also increased in multiple human glioma cell lines (U251-MG, U87-MG,more » U118, H4 and U373). Significantly, siRNA-mediated knockdown of Nek1 inhibited glioma cell (U87-MG/U251-MG) growth. Nek1 siRNA also sensitized U87-MG/U251-MG cells to temozolomide (TMZ), causing a profound apoptosis induction and growth inhibition. The current study indicates Nek1 might be a novel and valuable oncotarget of glioma, it is important for glioma cell growth and TMZ-resistance. - Highlights: • Nek1 is upregulated in multiple human glioma tissues and cell lines. • Nek1 overexpression correlates with glioma grades and patients’ KPS score. • Nek1 overexpression correlates with patients’ poor overall survival. • siRNA knockdown of Nek1 inhibits glioma cell growth. • siRNA knockdown of Nek1 sensitizes human glioma cells to temozolomide.« less

Tunicamycin inhibits progression of glioma cells through downregulation of the MEG-3-regulated wnt/β-catenin signaling pathway.

PubMed

Li, Xin; Xue, Lei; Peng, Qin

2018-06-01

Glioma is derived from the oncogenic transformation of brain and spinal cord glial cells, and is one of the most common primary brain tumors. Tunicamycin (TUN) can significantly inhibit glioma growth and aggressiveness by promoting apoptosis in glioma cells. The purpose of the present study was to investigate the effects of TUN on growth of glioma cells and examine the TUN-mediated signaling pathway. The inhibitory effects of TUN on apoptosis, growth, aggressiveness and cell cycle arrest of glioma tumor cells were determined by western blotting, reverse transcription-quantitative polymerase chain reaction, apoptotic assays and immunofluorescence. The results demonstrated that treatment with TUN suppressed growth, migration and invasion of glioma carcinoma cells. In addition, TUN treatment induced apoptosis of glioma cells through downregulation of Bcl-2 and P53 expression levels. Findings also indicated that TUN suppressed proliferation and arrested the glioma cells in the S phase of the cell cycle. Further analysis of the mechanisms of TUN demonstrated that TUN treatment upregulated the expression levels of maternally expressed gene (MEG)-3, wnt and β-catenin in glioma cells. Furthermore, knockdown of MEG-3 expression reversed the TUN-decreased wnt/β-catenin signaling pathway, which subsequently also reversed the TUN-inhibited growth and aggressiveness of glioma cells. In conclusion, the findings in the present study indicated that TUN treatment inhibited growth and aggressiveness through MEG-3-mediated wnt/β-catenin signaling, suggesting that TUN may be an efficient anticancer agent for the treatment of glioma.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): A lymphocytic reactive response of the central nervous system? A case report.

PubMed

Wang, Xiaolin; Huang, Dehui; Huang, Xusheng; Zhang, Jiatang; Ran, Ye; Lou, Xin; Gui, Qiuping; Yu, Shengyuan

2017-04-15

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) was first described in 2010. The characteristic clinical picture, radiological distribution and steroid response have been well-described in previous reports. However, the underlying pathogenesis and nosological position of CLIPPERS in the CNS require further investigation for the primary CNS lymphoma have been identified by autopsy subsequently. Here, we report a 51-year-old woman who was diagnosed with CLIPPERS but progressed to primary CNS lymphomatoid granulomatosis, which supports that CLIPPERS is not just an inflammatory CNS disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

Sodium-reduced continuous venovenous hemodiafiltration (CVVHDF) for the prevention of central pontine myelinolysis (CPM) in hyponatremic patients scheduled for orthotopic liver transplantation.

PubMed

Lenk, Marcus R; Kaspar, Michael

2012-08-01

Two patients in end-stage hepatic failure presented for orthotopic liver transplantation with longstanding severe hyponatremia (121 and 122 mmol/L). Both patients underwent liver transplantation with the concomitant use of continuous venovenous hemodiafiltration. Replacement and dialysate solutions were prepared individually to contain a sodium level that was individually considered safe with regard to the development of central pontine myelinolysis. The sodium increase in both patients was within the expected and planned limits despite a situation of mass transfusion. Both patients did well postoperatively and neither patient suffered neurological deficits. Copyright © 2012 Elsevier Inc. All rights reserved.

Pontine infarction caused by medial branch injury of the basilar artery as a rare complication of cisternal drain placement.

PubMed

Horiuchi, Tetsuyoshi; Yamamoto, Yasunaga; Kuroiwa, Masafumi; Rahmah, Nunung Nur; Hongo, Kazuhiro

2012-04-01

We present a rare complication of cisternal drain placement during aneurysm surgery. A ruptured anterior communicating artery aneurysm was clipped through a right pterional approach. A cisternal drain was inserted from the retro-carotid to the prepontine cistern. Postoperatively, a left-sided paresis of the upper extremity had developed. A CT brain scan revealed that the drain was located between the pons and the basilar artery, resulting in a pontine infarction. Vascular neurosurgeons should keep this complication in mind when placing a cisternal drain tube. The drain tube should not be inserted too deep into the prepontine cistern. Copyright © 2011 Elsevier Ltd. All rights reserved.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma.

PubMed

Wang, Yun; Huang, Nanxin; Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Shen, Hai-Ying; Li, Chengren; Xiao, Lan

2017-06-06

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma

PubMed Central

Li, Hongli; Liu, Shubao; Chen, Xianjun; Yu, Shichang; Wu, Nan; Bian, Xiu-Wu; Li, Chengren

2017-01-01

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma. PMID:28415586

miR-423-5p knockdown enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway.

PubMed

Wan, Yi; Fei, Xifeng; Wang, Zhimin; Jiang, Dongyi; Chen, Hanchun; Wang, Mian; Zhou, Shijun

2017-04-01

This study aimed to investigate the effect of miR-423-5p on the sensitivity of glioma stem cells to apigenin and to explore the potential mechanism. Previous research indicated that apigenin can effectively inhibit the proliferation of many cancer cells, including glioma cells, though our data unexpectedly showed that apigenin had no effect on glioma stem cell apoptosis. As many studies have reported that malignant transformation and progression of glioma are due to glioma stem cells, an anti-glioma stem cell approach has become an important direction for glioma treatment. In this study, we found miR-423-5p to be overexpressed in glioma tissues and corresponding glioma stem cells. Downregulation of miR-423-5p repressed glioma stem cell growth but did not cause apoptosis. Based on the concept of "Pharmaco-miR," this study further demonstrated that the combination of miR-423-5p knockdown and apigenin had a notable additive effect on inhibiting proliferation and promoting apoptosis in glioma stem cells. Hoechst staining showed higher apoptosis rates and typical apoptotic morphological changes of the cell nucleus, and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocya-nine iodide) staining revealed reduced mitochondrial membrane potential. Further research demonstrated that the mechanism is associated with a shift in the Bax/Bcl-2 ratio, an increased cytochrome c level, Apaf-1 induction, and caspase-3 activation. In conclusion, this study indicates that downregulation of miR-423-5p enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway.

The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Xin; Hao, Bin; Liu, Ying

Highlights: • PCBP2 expression is over-expressed in human glioma tissues and cell lines. • SIRT6 is decreased in glioma and correlated with PCBP2. • SIRT6 inhibits PCBP2 expression by deacetylating H3K9. • SIRT6 inhibits glioma growth in vitro and in vivo. - Abstract: More than 80% of tumors that occur in the brain are malignant gliomas. The prognosis of glioma patients is still poor, which makes glioma an urgent subject of cancer research. Previous evidence and our present data show that PCBP2 is over-expressed in human glioma tissues and predicts poor outcome. However, the mechanism by which PCBP2 is regulatedmore » in glioma remains elusive. We find that SIRT6, one of the NAD{sup +}-dependent class III deacetylase SIRTUINs, is down-regulated in human glioma tissues and that the level of SIRT6 is negatively correlated with PCBP2 level while H3K9ac enrichment on the promoter of PCBP2 is positively correlated with PCBP2 expression. Furthermore, we identify PCBP2 as a target of SIRT6. We demonstrate that PCBP2 expression is inhibited by SIRT6, which depends upon deacetylating H3K9ac. Finally, our results reveal that SIRT6 inhibits glioma cell proliferation and colony formation in vitro and glioma cell growth in vivo in a PCBP2 dependent manner. In summary, our findings implicate that SIRT6 inhibits PCBP2 expression through deacetylating H3K9ac and SIRT6 acts as a tumor suppressor in human glioma.« less

Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway

PubMed Central

Rolón-Reyes, Kimberleve; Kucheryavykh, Yuriy V.; Cubano, Luis A.; Inyushin, Mikhail; Skatchkov, Serguei N.; Eaton, Misty J.; Harrison, Jeffrey K.; Kucheryavykh, Lilia Y.

2015-01-01

Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells. PMID:26098895

Antitumor Activity of Rat Mesenchymal Stem Cells during Direct or Indirect Co-Culturing with C6 Glioma Cells.

PubMed

Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Mel'nikov, P A; Cherepanov, S A; Levinsky, A B; Chehonin, V P

2016-02-01

The tumor-suppressive effect of rat mesenchymal stem cells against low-differentiated rat C6 glioma cells during their direct and indirect co-culturing and during culturing of C6 glioma cells in the medium conditioned by mesenchymal stem cells was studied in an in vitro experiment. The most pronounced antitumor activity of mesenchymal stem cells was observed during direct co-culturing with C6 glioma cells. The number of live C6 glioma cells during indirect co-culturing and during culturing in conditioned medium was slightly higher than during direct co-culturing, but significantly differed from the control (C6 glioma cells cultured in medium conditioned by C6 glioma cells). The cytotoxic effect of medium conditioned by mesenchymal stem cells was not related to medium depletion by glioma cells during their growth. The medium conditioned by other "non-stem" cells (rat astrocytes and fibroblasts) produced no tumor-suppressive effect. Rat mesenchymal stem cells, similar to rat C6 glioma cells express connexin 43, the main astroglial gap junction protein. During co-culturing, mesenchymal stem cells and glioma C6 cells formed functionally active gap junctions. Gap junction blockade with connexon inhibitor carbenoxolone attenuated the antitumor effect observed during direct co-culturing of C6 glioma cells and mesenchymal stem cells to the level produced by conditioned medium. Cell-cell signaling mediated by gap junctions can be a mechanism of the tumor-suppressive effect of mesenchymal stem cells against C6 glioma cells. This phenomenon can be used for the development of new methods of cell therapy for high-grade malignant gliomas.

Myristic Acid-Modified DA7R Peptide for Whole-Process Glioma-Targeted Drug Delivery.

PubMed

Ying, Man; Wang, Songli; Zhang, Mingfei; Wang, Ruifeng; Zhu, Hangchang; Ruan, Huitong; Ran, Danni; Chai, Zhilan; Wang, Xiaoyi; Lu, Weiyue

2018-06-13

The clinical treatment of aggressive glioma has been a great challenge, mainly because of the complexity of the glioma microenvironment and the existence of the blood-brain tumor barrier (BBTB)/blood-brain barrier (BBB), which severely hampers the effective accumulation of most therapeutic agents in the glioma region. Additionally, vasculogenic mimicry (VM), angiogenesis, and glioma stem cells (GSC) in malignant glioma also lead to the failure of clinical therapy. To address the aforementioned issues, a whole-process glioma-targeted drug delivery strategy was proposed. The D A7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modified D A7R ligand (MC- D A7R), which combines tumor-homing D A7R with BBB-penetrable MC. MC- D A7R was then immobilized to PEGylated liposomes (MC- D A7R-LS) to form a whole-process glioma-targeting system. MC- D A7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC- D A7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC- D A7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC- D A7R-LS accomplished a remarkable therapeutic outcome, as a result of a synergistic improvement on the glioma microenvironment. Our study highlights the potential of the MC-modified D A7R peptide as a great candidate for the whole-process glioma-targeted drug delivery.

The effects of gene polymorphisms on glioma prognosis.

PubMed

Cui, Ying; Li, Guolin; Yan, Mengdan; Li, Jing; Jin, Tianbo; Li, Shanqu; Mu, Shijie

2017-11-01

Malignant gliomas are the most common primary brain tumors. Various genetic factors play important roles in the development and prognosis of glioma. The present study focuses on the impact of MPHOSPH6, TNIP1 and several other genes (ACYP2, NAF1, TERC, TERT, OBFC1, ZNF208 and RTEL1) on telomere length and how this affects the prognosis of glioma. Forty-three polymorphisms in nine genes from 605 glioma patients were selected. The association between genotype and survival outcome was analyzed using the Kaplan-Meier method, Cox regression analysis and the log-rank test. The 1-year overall survival (OS) rates of patients younger than 40 years of age was higher compared to those in patients older than 40 years of age. The 1-year OS rate of patients who underwent total resection was higher than that of patients whose gliomas were not completely resected. The 1-year OS rates of patients undergoing chemotherapy and of patients who did not undergo chemotherapy were 39.90% and 26.80%, respectively. Univariate analyses showed that ACYP2 rs12615793 and TERT rs2853676 loci affected progression-free survival in glioma patients; both ZNF208 rs8105767 and ACYP2 rs843720 affected the OS of patients with low-grade gliomas. Multivariate analyses suggested that MPHOSPH6 rs1056629 and rs1056654, and TERT rs2853676 loci were associated with good prognoses of patients with glioma or high-grade gliomas, whereas ZNF208 rs8105767 was associated with good prognosis of patients with low-grade glioma. Age, surgical resection and chemotherapy influenced the survival rates of glioma patients. TERT, MPHOSPH6, ACYP2 and ZNF208 genes were found to affect glioma prognosis. Copyright © 2017 John Wiley & Sons, Ltd.

Functional analysis of a novel glioma antigen, EFTUD1

PubMed Central

Saito, Katsuya; Iizuka, Yukihiko; Ohta, Shigeki; Takahashi, Satoshi; Nakamura, Kenta; Saya, Hideyuki; Yoshida, Kazunari; Kawakami, Yutaka; Toda, Masahiro

2014-01-01

Background A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. Methods EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. Results EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. Conclusion These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas. PMID:25015090

USP22 acts as an oncoprotein to maintain glioma malignancy through deubiquitinating BMI1 for stabilization.

PubMed

Qiu, Guan-Zhong; Mao, Xiao-Yuan; Ma, Yue; Gao, Xing-Chun; Wang, Zhen; Jin, Ming-Zhu; Sun, Wei; Zou, Yong-Xiang; Lin, Jing; Fu, Hua-Lin; Jin, Wei-Lin

2018-05-22

USP22 is a member of "death-from-cancer" signature, which plays a key role in cancer progression. Although previous evidence has shown that USP22 is overexpressed and correlated with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy especially cancer stemness remain elusive. Here, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, BMI1, a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlated with BMI1 only in the post-translational level rather than transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis reveals that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially those with elevated BMI1 expression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The impact of body mass index and height on the risk for glioblastoma and other glioma subgroups: a large prospective cohort study.

PubMed

Wiedmann, Markus K H; Brunborg, Cathrine; Di Ieva, Antonio; Lindemann, Kristina; Johannesen, Tom B; Vatten, Lars; Helseth, Eirik; Zwart, John A

2017-07-01

Glioma comprises a heterogeneous group of mostly malignant brain tumors, whereof glioblastoma (GBM) represents the largest and most lethal subgroup. Body height and body mass index (BMI) are risk factors for other cancers, but no previous study has examined anthropometric data in relation to different glioma subgroups. This prospective cohort study includes 1.8 million Norwegian women and men between ages 14 and 80 years at baseline. Body weight and height were measured, and incident cases of glioma were identified by linkage to the National Cancer Registry. Cox regression analyses were performed to evaluate risk for different glioma subgroups in relation to anthropometric measures. During 54 million person-years of follow-up, 4,382 gliomas were identified. Overweight and obesity were not associated with risk for any glioma subgroup. Height was positively associated with risk for GBM and all other gliomas (hazard ratio [HR] per 10 cm increase: 1.24; 95% confidence interval [CI], 1.17-1.31 and 1.18; 95% CI, 1.09-1.29) but not with the proxy for isocitrate dehydrogenase (IDH)-mutant glioma (HR, 1.09; 95% CI, 0.98-1.21). In further subgroup analyses, the effect of height on glioma risk varied significantly with positive associations for oligoastrocytoma (HR, 1.74; 95% CI, 1.20-2.53) and malignant glioma not otherwise specified (NOS) (HR, 1.42; 95% CI, 1.16-1.76, but not with diffuse astrocytoma (WHO grades II and III) or oligodendroglioma. This epidemiologic study consolidates height as a risk factor for GBM and other gliomas. It further indicates that this association is not universal for gliomas but may differ between different glioma subgroups. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Coptis Chinensis affects the function of glioma cells through the down-regulation of phosphorylation of STAT3 by reducing HDAC3.

PubMed

Li, Jiangan; Ni, Lulu; Li, Bing; Wang, Mingdeng; Ding, Zhemin; Xiong, Chunrong; Lu, Xiaojie

2017-12-06

Glioma remains the most common cause of brain cancer-related mortality. Glioma accounts for 50-60% of brain cancer. Due to their low toxicity and infrequent side effects, traditional herbs have been increasingly popular. Coptis Chinensis is commonly used in cancer treatment in combination with other Chinese Medicine herbs. However, little is known about its biological functions and mechanisms in glioma cells. In this study, the anti-glioma cell effect of Coptis Chinensis was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, plate clone test, scratch tests, flow cytometry, western blotting and a glioma xenograft tumor model. The results showed that Coptis Chinensis significantly suppressed glioma cell proliferation, tumor formation, migration and tumor growth, and prolonged the survival time of glioma cell-bearing mice. The flow cytometry result showed that Coptis Chinensis induced cell cycle arrest and apoptosis in glioma cells. Western blotting showed that Coptis Chinensis down-regulated the Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels and reduced the expression of Histone deacetylase 3 (HDAC3) and caspase 3. Coptis Chinensis can inhibit various aspects of glioma cell functions. This study provides favorable scientific evidence for the potential use of natural products such as Coptis Chinensis in the clinical treatment of patients with glioma.

HOXB1 Is a Tumor Suppressor Gene Regulated by miR-3175 in Glioma

PubMed Central

Han, Liang; Liu, Dehua; Li, Zhaohui; Tian, Nan; Han, Ziwu; Wang, Guang; Fu, Yao; Guo, Zhigang; Zhu, Zifeng

2015-01-01

The HOXB1 gene plays a critical role as an oncogene in diverse tumors. However, the functional role of HOXB1 and the mechanism regulating HOXB1 expression in glioma are not fully understood. A preliminary bioinformatics analysis showed that HOXB1 is ectopically expressed in glioma, and that HOXB1 is a possible target of miR-3175. In this study, we investigated the function of HOXB1 and the relationship between HOXB1 and miR-3175 in glioma. We show that HOXB1 expression is significantly downregulated in glioma tissues and cell lines, and that its expression may be closely associated with the degree of malignancy. Reduced HOXB1 expression promoted the proliferation and invasion of glioma cells, and inhibited their apoptosis in vitro, and the downregulation of HOXB1 was also associated with worse survival in glioma patients. More importantly, HOXB1 was shown experimentally to be a direct target of miR-3175 in this study. The downregulated expression of miR-3175 inhibited cell proliferation and invasion, and promoted apoptosis in glioma. The oncogenicity induced by low HOXB1 expression was prevented by an miR-3175 inhibitor in glioma cells. Our results suggest that HOXB1 functions as a tumor suppressor, regulated by miR-3175 in glioma. These results clarify the pathogenesis of glioma and offer a potential target for its treatment. PMID:26565624

Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

PubMed

a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

2016-05-01

Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells

PubMed Central

Shao, Ying-Ying; Zhang, Tao-Lan; Wu, Lan-Xiang; Zou, He-Cun; Li, Shuang; Huang, Jin; Zhou, Hong-Hao

2017-01-01

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as hindering the metastasis and invasion of glioma cells, but the underlying mechanisms are still unclear so far. In this study, methyl thiazolyl tetrazolium (MTT), colony-forming, wound healing, invasion, and apoptosis assays were performed to investigate the effect of DHA on malignant glioma cells. Results showed that DHA induced apoptosis of malignant glioma cells through Protein Kinase B (AKT) axis, induced death of malignant glioma cells by downregulating miR-21, and inhibited the invasion of malignant glioma cells corresponding with up-regulation of the reversion-inducing-cysteine-rich protein with kazal motifs (RECK). These results revealed that AKT axis, miR-21, and RECK play pivotal roles in DHA killing malignant glioma cells, suggesting that DHA is a potential agent for treating glioma. PMID:28208619

A negative association between brainstem pontine grey-matter volume, well-being and resilience in healthy twins.

PubMed

Gatt, Justine M; Burton, Karen L O; Routledge, Kylie M; Grasby, Katrina L; Korgaonkar, Mayuresh S; Grieve, Stuart M; Schofield, Peter R; Harris, Anthony W F; Clark, C Richard; Williams, Leanne M

2018-06-20

Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling. This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygotic pairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup. We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors. We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample. Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience.

Supratentorial lesions contribute to trigeminal neuralgia in multiple sclerosis.

PubMed

Fröhlich, Kilian; Winder, Klemens; Linker, Ralf A; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Hilz, Max J; Schwab, Stefan; Seifert, Frank

2018-06-01

Background It has been proposed that multiple sclerosis lesions afflicting the pontine trigeminal afferents contribute to trigeminal neuralgia in multiple sclerosis. So far, there are no imaging studies that have evaluated interactions between supratentorial lesions and trigeminal neuralgia in multiple sclerosis patients. Methods We conducted a retrospective study and sought multiple sclerosis patients with trigeminal neuralgia and controls in a local database. Multiple sclerosis lesions were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed a voxel-wise subtraction analysis. Secondly, we conducted a voxel-wise non-parametric analysis using the Liebermeister test. Results From 12,210 multiple sclerosis patient records screened, we identified 41 patients with trigeminal neuralgia. The voxel-wise subtraction analysis yielded associations between trigeminal neuralgia and multiple sclerosis lesions in the pontine trigeminal afferents, as well as larger supratentorial lesion clusters in the contralateral insula and hippocampus. The non-parametric statistical analysis using the Liebermeister test yielded similar areas to be associated with multiple sclerosis-related trigeminal neuralgia. Conclusions Our study confirms previous data on associations between multiple sclerosis-related trigeminal neuralgia and pontine lesions, and showed for the first time an association with lesions in the insular region, a region involved in pain processing and endogenous pain modulation.

Cortico-pontine theta carrier frequency phase shift across sleep/wake states following monoaminergic lesion in rat.

PubMed

Kalauzi, Aleksandar; Spasic, Sladjana; Petrovic, Jelena; Ciric, Jelena; Saponjic, Jelena

2012-06-01

This study was aimed to explore the sleep/wake states related cortico-pontine theta carrier frequency phase shift following a systemically induced chemical axotomy of the monoaminergic afferents within a brain of the freely moving rats. Our experiments were performed in 14 adult, male Sprague Dawley rats, chronically implanted for sleep recording. We recorded sleep during baseline condition, following sham injection (saline i.p. 1 ml/kg), and every week for 5 weeks following injection of the systemic neurotoxins (DSP-4 or PCA; 1 ml/kg, i.p.) for chemical axotomy of the locus coeruleus (LC) and dorsal raphe (DR) axon terminals. After sleep/wake states identification, FFT analysis was performed on 5 s epochs. Theta carrier frequency phase shift (∆Φ) was calculated for each epoch by averaging theta Fourier component phase shifts, and the ∆Φ values were plotted for each rat in control condition and 28 days following the monoaminergic lesions, as a time for permanently established DR or LC chemical axotomy. Calculated group averages have shown that ∆Φ increased between pons and cortex significantly in all sleep/wake states (Wake, NREM and REM) following the monoaminergic lesions, with respect to controls. Monoaminergic lesions established the pontine leading role in the brain theta oscillations during all sleep/wake states.

Coordination of eye and head components of movements evoked by stimulation of the paramedian pontine reticular formation.

PubMed

Gandhi, Neeraj J; Barton, Ellen J; Sparks, David L

2008-07-01

Constant frequency microstimulation of the paramedian pontine reticular formation (PPRF) in head-restrained monkeys evokes a constant velocity eye movement. Since the PPRF receives significant projections from structures that control coordinated eye-head movements, we asked whether stimulation of the pontine reticular formation in the head-unrestrained animal generates a combined eye-head movement or only an eye movement. Microstimulation of most sites yielded a constant-velocity gaze shift executed as a coordinated eye-head movement, although eye-only movements were evoked from some sites. The eye and head contributions to the stimulation-evoked movements varied across stimulation sites and were drastically different from the lawful relationship observed for visually-guided gaze shifts. These results indicate that the microstimulation activated elements that issued movement commands to the extraocular and, for most sites, neck motoneurons. In addition, the stimulation-evoked changes in gaze were similar in the head-restrained and head-unrestrained conditions despite the assortment of eye and head contributions, suggesting that the vestibulo-ocular reflex (VOR) gain must be near unity during the coordinated eye-head movements evoked by stimulation of the PPRF. These findings contrast the attenuation of VOR gain associated with visually-guided gaze shifts and suggest that the vestibulo-ocular pathway processes volitional and PPRF stimulation-evoked gaze shifts differently.

Ferritin heavy chain as a molecular imaging reporter gene in glioma xenografts.

PubMed

Cheng, Sen; Mi, Ruifang; Xu, Yu; Jin, Guishan; Zhang, Junwen; Zhou, Yiqiang; Chen, Zhengguang; Liu, Fusheng

2017-06-01

The development of glioma therapy in clinical practice (e.g., gene therapy) calls for efficiently visualizing and tracking glioma cells in vivo. Human ferritin heavy chain is a novel gene reporter in magnetic resonance imaging. This study proposes hFTH as a reporter gene for MR molecular imaging in glioma xenografts. Rat C6 glioma cells were infected by packaged lentivirus carrying hFTH and EGFP genes and obtained by fluorescence-activated cell sorting. The iron-loaded ability was analyzed by the total iron reagent kit. Glioma nude mouse models were established subcutaneously and intracranially. Then, in vivo tumor bioluminescence was performed via the IVIS spectrum imaging system. The MR imaging analysis was analyzed on a 7T animal MRI scanner. Finally, the expression of hFTH was analyzed by western blotting and histological analysis. Stable glioma cells carrying hFTH and EGFP reporter genes were successfully obtained. The intracellular iron concentration was increased without impairing the cell proliferation rate. Glioma cells overexpressing hFTH showed significantly decreased signal intensity on T 2 -weighted MRI both in vitro and in vivo. EGFP fluorescent imaging could also be detected in the subcutaneous and intracranial glioma xenografts. Moreover, the expression of the transferritin receptor was significantly increased in glioma cells carrying the hFTH reporter gene. Our study illustrated that hFTH generated cellular MR imaging contrast efficiently in glioma via regulating the expression of transferritin receptor. This might be a useful reporter gene in cell tracking and MR molecular imaging for glioma diagnosis, gene therapy and tumor metastasis.

Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations

ClinicalTrials.gov

2018-06-13

Advanced Malignant Solid Neoplasm; Glioblastoma; IDH1 Gene Mutation; IDH2 Gene Mutation; Recurrent Cholangiocarcinoma; Recurrent Glioma; Recurrent Malignant Solid Neoplasm; WHO Grade II Glioma; WHO Grade III Glioma

MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zhen, E-mail: lizhen7111@163.com; Liu, Yun-hui; Diao, Hong-yu

In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3′ untranslated region (3′UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation,more » migration and invasion by targeting hTERT. - Highlights: • MiR-661 was downregulated in glioma tissues and functional as a tumor suppressor. • MiR-661 modulates cell proliferation, invasion and migration of glioma cells. • MiR-661 directly target hTERT in glioma cells. • MiR-661 inhibits glioma cell tumorgenesis by targeting hTERT.« less

Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma.

PubMed

Song, Ye; Zheng, Shihao; Wang, Jizhou; Long, Hao; Fang, Luxiong; Wang, Gang; Li, Zhiyong; Que, Tianshi; Liu, Yi; Li, Yilei; Zhang, Xi'an; Fang, Weiyi; Qi, Songtao

2017-06-27

Gliomas are the most common form of malignant primary brain tumors with poor 5-year survival rate. Dysregulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was observed in gliomas, but the specific role and molecular mechanism of PLOD2 in glioma have not been reported yet. In this study, PLOD2 was found to be frequently up-regulated in glioma and could serve as an independent prognostic marker to identify patients with poor clinical outcome. Knockdown of PLOD2 inhibited proliferation, migration and invasion of glioma cells in vitro and in vivo. Mechanistically, inhibition of PLOD2 inactivated PI3K/AKT signaling pathway and thus regulated the expression of its downstream epithelial-mesenchymal transition (EMT)-associated regulators, including E-cadherin, vimentin, N-cadherin, β-catenin, snail and slug in glioma cells. Moreover, PLOD2 could be induced by hypoxia-inducible factor-1α (HIF-1α) via hypoxia, thereby promoting hypoxia-induced EMT in glioma cells. Our data suggests that PLOD2 may be a potential therapeutic target for patients with glioma.

Photodynamic therapy on the ultrastructure of glioma cell

NASA Astrophysics Data System (ADS)

Hu, Shaoshan; Zhang, Ruyou; Zheng, Yongri

2005-07-01

OBJECTIVE ：the main purpose of this experiment was to study the change of C6 glioma cells' ultrastructure treated by photodynamic therapy(PDT), observe the change of morphology METHOD ：Make the model of rat glioma by transplanted C6 glioma cells into caudate nucleus，treated the glioma rat by PDT after two weeks. Observed the difference of subcellular structure before and after PDT by electron microscope. RESULT ： Apoptosis and necrosis can be seen after treated by PDT in the C6 glioma, basal membrance damaged ，number of cellular organ of endothelial cell of blood capillary declined，tight junction of endothelial cell lengthen and the gap enlarge. The PDT has slightly effect on the nomorl rat"s subcellular structue. CONCLUSION: PDT can induce the apoptosis and necrosis of C6 glioma cell. The damage of the ultramicrostructure of mitochondria and endoplasmic reticulum was the foundmentol of the change. PDT initiate the damage of BBB of the C6 glioma cell and weeken the function、and makes it a useful way of treating the glioma combained with chemotherapy.

A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy

PubMed Central

Mikheev, Andrei M; Stoll, Elizabeth A; Mikheeva, Svetlana A; Maxwell, John-Patrick; Jankowski, Pawel P; Ray, Sutapa; Uo, Takuma; Morrison, Richard S; Horner, Philip J; Rostomily, Robert C

2010-01-01

Summary Human glioma incidence, malignancy and treatment resistance are directly proportional to patient age. Cell intrinsic factors are reported to contribute to human age-dependent glioma malignancy but suitable animal models to examine the role of aging are lacking. Here we developed an orthotopic syngeneic glioma model to test the hypothesis that the age of neural progenitor cells (NPCs), presumed cells of glioma origin, influences glioma malignancy. Gliomas generated from transformed donor 3-, 12-, and 18-month-old NPCs in same-aged adult hosts all formed highly invasive glial tumors that phenocopied the human disease. Survival analysis indicated increased malignancy of gliomas generated from older 12- and 18-month-old transformed NPCs compared with their 3-month counterparts (median survival of 38.5 and 42.5 vs. 77 days, respectively). This study showed for the first time that age of target cells at the time of transformation can affect malignancy and demonstrated the feasibility of a syngeneic model using transformed NPCs for future examination of the relative impacts of age-related cell intrinsic and cell-extrinsic factors in glioma malignancy. PMID:19489742

[The re-introduction of malaria in the Pontine Marshes and the Cassino district during the end of World War II. Biological warfare or global war tactics?].

PubMed

Sabbatani, Sergio; Fiorino, Sirio; Manfredi, Roberto

2013-12-01

After the fall of the Fascist regime on September 8, 1943, Italy was split into two parts: (i) the Southern regions where the King Victor Emanuel III and the military general staff escaped was under the control of English-American allied armies, and (ii) the northern regions comprising Lazio, Tuscany, Umbria, and Marche still under the control of the Germans. The German Wehrmacht, after suffering several defeats on Southern lines, established a new strengthened line of defence called the Gustav line, located south of Rome and crossing in the western portion the recently-drained Pontine Marshes. In his book published in 2006, Frank Snowden hypothesised that occupying German armies in 1943 had initiated a programme of re-flooding the Pontine plain as a biological warfare strategy to re-introduce malaria infection in the territories south of Rome, Such a plan was intended (i) to slow down the advance of English-American forces, and (ii) to punish Italians who abandoned their former allies. Other authors, including Annibale Folchi, Erhard Geissler, and Jeanne Guillemin, have disputed this hypothesis based on an analysis of recently-uncovered archive documents. What is not disputed is that the flooding of the Pontine and Roman plains in 1943 contributed to a severe malaria epidemic in 1944, which was associated with exceptionally high morbidity and mortality rates in the afflicted populations. Herein, we critically evaluate the evidence and arguments of whether the Wehrmacht specifically aimed to spread malaria as a novel biological warfare strategy in Italy during the Second World War. In our opinion, evidence for specific orders to deliberately spread malaria by the German army is lacking, although the strategy itself may have been considered by Nazis during the waning years of the war.

Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization

PubMed Central

Zhang, Hanwen; Zhang, Wenbin; Sun, Xuan; Dang, Ruoyu; Zhou, Rongmei; Bai, Hui; Ben, Jingjing; Zhu, Xudong; Zhang, Yan; Yang, Qing; Xu, Yong; Chen, Qi

2016-01-01

Macrophages enhance glioma development and progression by shaping the tumor microenvironment. Class A1 scavenger receptor (SR-A1), a pattern recognition receptor primarily expressed in macrophages, is up-regulated in many human solid tumors. We found that SR-A1 expression in 136 human gliomas was positively correlated with tumor grade (P<0.01), but not prognosis or tumor recurrence. SR-A1-expressing macrophages originated primarily from circulating monocytes attracted to tumor tissue, and were almost twice as numerous as resident microglia in glioma tissues (P<0.001). The effects of SR-A1 on glioma proliferation and invasion were assessed in vivo using an SR-A1-deficient murine orthotopic glioma model. SR-A1 deletion promoted M2-like tumor-associated macrophage (TAM) polarization in mice by activating STAT3 and STAT6, which resulted in robust orthotopic glioma proliferation and angiogenesis. Finally, we found that HSP70 might be an endogenous ligand that activates SR-A1-dependent anti-tumorigenic pathways in gliomas, although its expression does not appear informative for diagnostic purposes. Our findings demonstrate a relationship between TAMs, SR-A1 expression and glioma growth and provide new insights into the pathogenic role of TAMs in glioma. PMID:27367025

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro.

PubMed

Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

2013-08-06

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.

Significance of perivascular tumour cells defined by CD109 expression in progression of glioma.

PubMed

Shiraki, Yukihiro; Mii, Shinji; Enomoto, Atsushi; Momota, Hiroyuki; Han, Yi-Peng; Kato, Takuya; Ushida, Kaori; Kato, Akira; Asai, Naoya; Murakumo, Yoshiki; Aoki, Kosuke; Suzuki, Hiromichi; Ohka, Fumiharu; Wakabayashi, Toshihiko; Todo, Tomoki; Ogawa, Seishi; Natsume, Atsushi; Takahashi, Masahide

2017-12-01

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Methylation of the miR-126 gene associated with glioma progression.

PubMed

Cui, Hongwei; Mu, Yongping; Yu, Lei; Xi, Ya-guang; Matthiesen, Rune; Su, Xiulan; Sun, Wenjie

2016-04-01

Gliomas are the most common and the most malignant brain tumors, accouting for 45-55% of all intracranial tumors. The incidence of glioma worldwide is about 6-12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21-23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP-DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of miR-126 was found in 40% of glioma patients in our study (20/50 cases), resulting in significantly decreased miR-126 expression (0.1715 ± 0.1376; P < 0.05). Our results indicate that we verified successfully the miRNA-126 down-regulation phenomenon in patients with glioma which showed in the results of glioma tissue miRNAs chip and the miRNA-126 down-regulation through methylation in patients with glioma. So we could say that epigenetic modification is a crucial mechanism for controlling the expression of miR-126 in glioma.

The basilar pontine nuclei and the nucleus reticularis tegmenti pontis subserve distinct cerebrocerebellar pathways.

PubMed

Cicirata, Federico; Serapide, Maria Francesca; Parenti, Rosalba; Pantò, Maria Rosita; Zappalà, Agata; Nicotra, Annalisa; Cicero, Deborah

2005-01-01

Previous studies often considered the basilar pontine nuclei (BPN) and the nucleus reticularis tegmenti pontis (NRTP) as relays of a single cerebro-(ponto)-cerebellar pathway. Conversely, the different cortical afferences to the BPN and the NRTP, as well as the anatomical and functional features of the cerebellopetal projections from these pontine nuclei, support the different, and for some aspect, complementary arrangement of the cerebrocerebellar pathways relayed by the BPN or NRTP. Both the BPN and the NRTP are innervated from the cerebral cortex, but with regional prevalence. The NRTP is principally innervated from motor or sensori-motor areas while the BPN are principally innervated from sensory, mainly teloceptive, and associative area. Projections from sensory-motor areas were also traced to the BPN. The BPN and NRTP project to all parts of the cerebellar cortex with a similar pattern. In fact, from single areas of them projections were traced to set of sagittal stripes of the cerebellar cortex. In variance to such analogies, the projections to the cerebellar nuclei differed between those traced from the NRTP and from BPN. In fact, BPN and NRTP have private terminal areas in the cerebellar nuclei with relatively little overlaps. The BPN innervated the lateroventral part of the nucleus lateralis and the caudoventral aspect of the nucleus interpositalis posterioris. The NRTP principally innervated the mediodorsal part of the nucleus lateralis, the nucleus interpositalis anterioris, the nucleus medialis. Since the single cerebellar nuclei have their specific targets in the extracerebellar brain areas, it follows that the BPN and the NRTP, passing through their cerebellar nuclei relays, are devoted to control different brain areas and thus likely to play different functional roles. From single pontine regions (of both BPN and NRTP) projections were traced to the cerebellar cortex and to the cerebellar nuclei. In some cases these projections reached areas which are likely anatomically connected (by Purkinje axons). This pattern of the pontine projections was termed as coupled projection. In some other cases, the projections reached areas of the cerebellar cortex but not the nuclear regions innervated by them. We termed this as uncoupled projection. The existence of both coupled and uncoupled projections, open new vistas on the functional architecture of the pontocerebellar pathway. More in detail, this study showed the different quantitative and topographic distribution of the coupled and uncoupled projections visualized in the cerebellar projections from BPN and NRTP. All these evidences strongly support the anatomical and the functional differences that characterise the cerebrocerebellar pathways relayed by the BPN and the NRTP.

Development of the precerebellar nuclei in the rat: IV. The anterior precerebellar extramural migratory stream and the nucleus reticularis tegmenti pontis and the basal pontine gray.

PubMed

Altman, J; Bayer, S A

1987-03-22

Sequential thymidine radiograms from rats injected on days E16, E17, E18, and E19 and killed 2 hours after injection and at daily intervals up to day E22 were used to establish the site of origin, migratory route, and settling patterns of neurons of the nucleus reticularis tegmenti pontis and basal pontine gray. The nucleus reticularis tegmenti pontis neurons, which are produced predominantly on days E15 and E16, derive from the primary precerebellar neuroepithelium. These cells, unlike those of the lateral reticular and external cuneate nuclei, take an anteroventral subpial route, forming the anterior precerebellar extramural migratory stream. This migratory stream reaches the anterior pole of the pons by day E18. In rats injected on day E16 and killed on day E18 some of the cells that reach the pons are unlabeled, indicating that they represent the early component of neurons generated on day E15. The cells labeled on day E16 begin to settle in the pons on day E19, 3 days after their production. These cells, migrating in an orderly temporal sequence, form a posterodorsal-to-anteroventral gradient in the nucleus reticularis tegmenti pontis. Unlike the neurons of all the other precerebellar nuclei, the basal pontine gray neurons derive from the secondary precerebellar neuroepithelium. The secondary precerebellar neuroepithelium forms on day E16 as an outgrowth of the primary precerebellar neuroepithelium, and it remains mitotically active through day E19, spanning the entire period of basal pontine gray neurogenesis. The secondary precerebellar neuroepithelium is surrounded by a horizontal layer of postmitotic cells, representing the head-waters of the anterior precerebellar extramural migratory stream. In rats injected on day E18 and killed on day E19 the cells are labeled in the proximal half of the stream around the medulla but those closer to the pons are unlabeled, indicating an orderly sequence of migration. In rats injected on day E18 and killed on day E20 the labeled cells reach the pole of the pons. In the basal pontine gray the sequentially generated neurons settle in a precise order. The neurons generated on day E16 form a small core posteriorly and the neurons generated on days E17, E18, and E19 form regular concentric rings around the core in an inside-out sequence.

MicroRNA-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1.

PubMed

Quan, Junjie; Qu, Jianqiang; Zhou, Le

2017-09-01

Dysregulation of microRNAs (miRNAs) has been suggested to contribute to malignant progression of glioma. Previous studies have demonstrated that miR-539 is dysregulated in malignant progression of cancers. However, the potential role and mechanism of miR-539 in the progression of glioma remains unclear. In this study, we aimed to investigate the expression status and functional significance of miR-539 in glioma. We found that miR-539 expression was significantly decreased in glioma cell lines and tissues. Overexpression of miR-539 markedly inhibited glioma cell proliferation and invasion, while miR-539 suppression exhibited the opposite effect. Bioinformatics analysis and dual-luciferase reporter assays showed that miR-539 directly targeted the 3'-untranslated region of Disheveled-axin domain containing 1 (DIXDC1). DIXDC1 expression was negatively regualted by miR-539 overexpression. An inverse correlation between DIXDC1 mRNA expression and miR-539 expression was found in glioma specimens. Furthermore, knockdown of DIXC1 significantly inhibited proliferation, invasion and Wnt signaling in glioma cells. Overexpression of DIXDC1 partially reversed the inhibitory effect of miR-539 on glioma cell proliferation and invasion. Overall, these findings demonstrate that miR-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1. Our study suggests that the miR-539 may serve as a potential target for the clinical diagnosis and treatment of glioma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.

PubMed

Kim, Julius W; Kane, J Robert; Young, Jacob S; Chang, Alan L; Kanojia, Deepak; Morshed, Ramin A; Miska, Jason; Ahmed, Atique U; Balyasnikova, Irina V; Han, Yu; Zhang, Lingjiao; Curiel, David T; Lesniak, Maciej S

2015-09-01

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel.

PubMed

Zacher, Angela; Kaulich, Kerstin; Stepanow, Stefanie; Wolter, Marietta; Köhrer, Karl; Felsberg, Jörg; Malzkorn, Bastian; Reifenberger, Guido

2017-03-01

Current classification of gliomas is based on histological criteria according to the World Health Organization (WHO) classification of tumors of the central nervous system. Over the past years, characteristic genetic profiles have been identified in various glioma types. These can refine tumor diagnostics and provide important prognostic and predictive information. We report on the establishment and validation of gene panel next generation sequencing (NGS) for the molecular diagnostics of gliomas. We designed a glioma-tailored gene panel covering 660 amplicons derived from 20 genes frequently aberrant in different glioma types. Sensitivity and specificity of glioma gene panel NGS for detection of DNA sequence variants and copy number changes were validated by single gene analyses. NGS-based mutation detection was optimized for application on formalin-fixed paraffin-embedded tissue specimens including small stereotactic biopsy samples. NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification. Oligoastrocytic gliomas were genetically assigned to either of these groups. Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification. © 2016 International Society of Neuropathology.

S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages

PubMed Central

Wang, Huaqing; Zhang, Leying; Zhang, Ian Y.; Chen, Xuebo; Da Fonseca, Anna; Wu, Shihua; Ren, Hui; Badie, Sam; Sadeghi, Sam; Ouyang, Mao; Warden, Charles D.; Badie, Behnam

2013-01-01

Purpose S100B is member of a multigenic family of Ca2+-binding proteins that is overexpressed by gliomas. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAMs). Experimental Design We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors. Results Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, RAGE (receptor for advanced glycation end products), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that CCL2 was upregulated in S100Bhigh tumors. Furthermore, analysis of TCGA’s glioma data bank demonstrated a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. Conclusions These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. PMID:23719262

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.

PubMed

Hou, Huagang; Krishnamurthy Nemani, Venkata; Du, Gaixin; Montano, Ryan; Song, Rui; Gimi, Barjor; Swartz, Harold M; Eastman, Alan; Khan, Nadeem

2015-04-01

Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation. © 2014 UICC.

Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.

PubMed

Zhang, Xiaohui; Zhao, Fangbo; Zhang, Shujun; Song, Yichun

2017-04-01

Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p < 0.05). Ectopic E2-EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p < 0.01). The 5-year survival rate of glioma patients with high E2-EPF levels was shorter than in patients with low expression (p < 0.05). Furthermore, the 5-year survival rate of patients with ectopic E2-EPF was significantly shorter than patients with only nuclear E2-EPF (p < 0.01). These results suggest that higher E2-EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.

Increased rate of positive penicillin skin tests among patients with glioma: insights into the association between allergies and glioma risk.

PubMed

Han, Sheng; Huang, Yanming; Wang, Zixun; Li, Zhonghua; Qin, Xiaofei; Wu, Anhua

2014-11-01

Allergy and immunoglobulin E levels are inversely associated with glioma risk. Previous studies have focused on respiratory and food allergies, and little information is available regarding drug allergies. This study evaluated the rate of positive penicillin skin tests (PenSTs) and blood eosinophil counts in a large population of patients with glioma compared with nontumor controls to provide evidence for the relationship between drug allergies and glioma risk. A retrospective case-control study was conducted in patients diagnosed with glioma (n = 913) between January 2004 and June 2013. The study patients were matched with nontumor controls (n = 1091) for age, sex, and date of admission to the hospital. Preoperative results of the PenST and eosinophil counts were obtained, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression models, while a Kaplan-Meier analysis was used to assess overall survival. The percentage of positive PenSTs was higher among patients with glioma than in control subjects. The age-, sex-, and admission date-adjusted OR for positive versus negative PenSTs was 2.392 (95% CI 1.891-3.026). Eosinophil counts were also higher in glioma cases than in controls: the OR for eosinophil > 0.06 × 10(9)/L versus ≤ 0.06 × 10(9)/L was 1.923 (95% CI 1.608-2.301). There was no association between positive PenST/eosinophil counts and glioma grade or patient survival (n = 105). In contrast to previously reported relationships between allergy and glioma, in the present study a significantly higher rate of positive PenSTs and higher eosinophil counts were found in patients with glioma than in nontumor controls. These results suggest a complex relationship between allergies and glioma development.

L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor.

PubMed

Mohanan, Vishnu; Temburni, Murali K; Kappes, John C; Galileo, Deni S

2013-04-01

The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.

Human umbilical cord blood stem cells show PDGF-D–dependent glioma cell tropism in vitro and in vivo

PubMed Central

Gondi, Christopher S.; Veeravalli, Krishna Kumar; Gorantla, Bharathi; Dinh, Dzung H.; Fassett, Dan; Klopfenstein, Jeffrey D.; Gujrati, Meena; Rao, Jasti S.

2010-01-01

Despite advances in clinical therapies and technologies, the prognosis for patients with malignant glioma is poor. Neural stem cells (NSCs) have a chemotactic tropism toward glioma cells. The use of NSCs as carriers of therapeutic agents for gliomas is currently being explored. Here, we demonstrate that cells isolated from the umbilical cord blood show mesenchymal characteristics and can differentiate to adipocytes, osteocytes, and neural cells and show tropism toward cancer cells. We also show that these stem cells derived from the human umbilical cord blood (hUCB) induce apoptosis-like cell death in the glioma cell line SNB19 via Fas-mediated caspase-8 activation. From our glioma tropism studies, we have observed that hUCB cells show tropism toward glioma cells in vitro, in vivo, and ex vivo. We determined that this migration is partially dependent on the expression levels of platelet-derived growth factor (PDGF)-D from glioma cells and have observed that local concentration gradient of PDGF-D is sufficient to cause migration of hUCB cells toward the gradient as seen from our brain slice cultures. In our animal experiment studies, we observed that intracranially implanted SNB19 green fluorescent protein cells induced tropism of the hUCB cells toward themselves. In addition, the ability of these hUCBs to inhibit established intracranial tumors was also observed. We also determined that the migration of stem cells toward glioma cells was partially dependent on PDGF secreted by glioma cells and that the presence of PDGF-receptor (PDGFR) on hUCB is required for migration. Our results demonstrate that hUCB are capable of inducing apoptosis in human glioma cells and also show that glioma tropism and hUCB tropism toward glioma cells are partially dependent on the PDGF/PGGFR system. PMID:20406896

Expression of REST4 in human gliomas in vivo and influence of pioglitazone on REST in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Huan; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078; Gao, Zhangfeng

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which includingmore » glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma. - Highlights: • A specific isoform REST4 is expressed in glioma specimens in vivo. • REST4 will influence the mRNA level of REST in vivo. • Pioglitazone can inhibit proliferation and induce apoptosis of glioma cells. • The role of pioglitazone in anti-glioma may be mediated by down-regulating REST.« less

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P{sub 2} on cell migration and invasiveness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Young, Nicholas; Van Brocklyn, James R.

2007-05-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of five G-protein-coupled receptors, termed S1P{sub 1-5}. S1P stimulates growth and invasiveness of glioma cells, and high expression levels of the enzyme that forms S1P, sphingosine kinase-1, correlate with short survival of glioma patients. In this study we examined the mechanism of S1P stimulation of glioma cell proliferation and invasion by either overexpressing or knocking down, by RNA interference, S1P receptor expression in glioma cell lines. S1P{sub 1}, S1P{sub 2} and S1P{sub 3} all contribute positively to S1P-stimulated glioma cell proliferation, with S1P{sub 1} being the major contributor. Stimulationmore » of glioma cell proliferation by these receptors correlated with activation of ERK MAP kinase. S1P{sub 5} blocks glioma cell proliferation, and inhibits ERK activation. S1P{sub 1} and S1P{sub 3} enhance glioma cell migration and invasion. S1P{sub 2} inhibits migration through Rho activation, Rho kinase signaling and stress fiber formation, but unexpectedly, enhances glioma cell invasiveness by stimulating cell adhesion. S1P{sub 2} also potently enhances expression of the matricellular protein CCN1/Cyr61, which has been implicated in tumor cell adhesion, and invasion as well as tumor angiogenesis. A neutralizing antibody to CCN1 blocked S1P{sub 2}-stimulated glioma invasion. Thus, while S1P{sub 2} decreases glioma cell motility, it may enhance invasion through induction of proteins that modulate glioma cell interaction with the extracellular matrix.« less

Stimulation of glioma cell motility by expression, proteolysis, and release of the L1 neural cell recognition molecule.

PubMed

Yang, Muhua; Adla, Shalini; Temburni, Murali K; Patel, Vivek P; Lagow, Errin L; Brady, Owen A; Tian, Jing; Boulos, Magdy I; Galileo, Deni S

2009-10-29

Malignant glioma cells are particularly motile and can travel diffusely through the brain parenchyma, apparently without following anatomical structures to guide their migration. The neural adhesion/recognition protein L1 (L1CAM; CD171) has been implicated in contributing to stimulation of motility and metastasis of several non-neural cancer types. We explored the expression and function of L1 protein as a stimulator of glioma cell motility using human high-grade glioma surgical specimens and established rat and human glioma cell lines. L1 protein expression was found in 17 out of 18 human high-grade glioma surgical specimens by western blotting. L1 mRNA was found to be present in human U-87/LacZ and rat C6 and 9L glioma cell lines. The glioma cell lines were negative for surface full length L1 by flow cytometry and high resolution immunocytochemistry of live cells. However, fixed and permeablized cells exhibited positive staining as numerous intracellular puncta. Western blots of cell line extracts revealed L1 proteolysis into a large soluble ectodomain (~180 kDa) and a smaller transmembrane proteolytic fragment (~32 kDa). Exosomal vesicles released by the glioma cell lines were purified and contained both full-length L1 and the proteolyzed transmembrane fragment. Glioma cell lines expressed L1-binding alphavbeta5 integrin cell surface receptors. Quantitative time-lapse analyses showed that motility was reduced significantly in glioma cell lines by 1) infection with an antisense-L1 retroviral vector and 2) L1 ectodomain-binding antibodies. Our novel results support a model of autocrine/paracrine stimulation of cell motility in glioma cells by a cleaved L1 ectodomain and/or released exosomal vesicles containing L1. This mechanism could explain the diffuse migratory behavior of high-grade glioma cancer cells within the brain.

Stimulation of glioma cell motility by expression, proteolysis, and release of the L1 neural cell recognition molecule

PubMed Central

Yang, Muhua; Adla, Shalini; Temburni, Murali K; Patel, Vivek P; Lagow, Errin L; Brady, Owen A; Tian, Jing; Boulos, Magdy I; Galileo, Deni S

2009-01-01

Background Malignant glioma cells are particularly motile and can travel diffusely through the brain parenchyma, apparently without following anatomical structures to guide their migration. The neural adhesion/recognition protein L1 (L1CAM; CD171) has been implicated in contributing to stimulation of motility and metastasis of several non-neural cancer types. We explored the expression and function of L1 protein as a stimulator of glioma cell motility using human high-grade glioma surgical specimens and established rat and human glioma cell lines. Results L1 protein expression was found in 17 out of 18 human high-grade glioma surgical specimens by western blotting. L1 mRNA was found to be present in human U-87/LacZ and rat C6 and 9L glioma cell lines. The glioma cell lines were negative for surface full length L1 by flow cytometry and high resolution immunocytochemistry of live cells. However, fixed and permeablized cells exhibited positive staining as numerous intracellular puncta. Western blots of cell line extracts revealed L1 proteolysis into a large soluble ectodomain (~180 kDa) and a smaller transmembrane proteolytic fragment (~32 kDa). Exosomal vesicles released by the glioma cell lines were purified and contained both full-length L1 and the proteolyzed transmembrane fragment. Glioma cell lines expressed L1-binding αvβ5 integrin cell surface receptors. Quantitative time-lapse analyses showed that motility was reduced significantly in glioma cell lines by 1) infection with an antisense-L1 retroviral vector and 2) L1 ectodomain-binding antibodies. Conclusion Our novel results support a model of autocrine/paracrine stimulation of cell motility in glioma cells by a cleaved L1 ectodomain and/or released exosomal vesicles containing L1. This mechanism could explain the diffuse migratory behavior of high-grade glioma cancer cells within the brain. PMID:19874583

Spontaneous complete regression of a brain stem glioma pathologically diagnosed as a high-grade glioma.

PubMed

Ishihara, Masahiro; Yamamoto, Kazumi; Miwa, Hideaki; Nishi, Masaya

2017-12-01

Spontaneous regressions of brain stem gliomas are extremely rare. Only six cases have been reported in the literature. We describe the case of a patient who was diagnosed with a pontomedullary dorsal brain stem glioma at the age of 15 years. An open biopsy showed the presence of an anaplastic glioma. Because the patient and her parents refused conventional therapies, including radiation and chemotherapy, we followed up the patient by performing magnetic resonance imaging scans on her every 3 months. At 3 months after biopsy, we observed the radiological disappearance of her tumor. One year after biopsy, the tumor retained the spontaneous complete regression observed earlier. In this case report, we present the first report of the spontaneous complete regression of a brain stem glioma that was histologically proven to be a high-grade glioma and we believe that this regression was the natural progression of this case, as may be the scenario in a few other cases of brain stem gliomas.

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation.

PubMed

Xing, Yang; Ge, Yuqing; Liu, Chanjuan; Zhang, Xiaobiao; Jiang, Jianhai; Wei, Yuanyan

2016-06-14

Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma-initiating cell to initiate tumor formation. Although tunicamycin induces glioma-initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells.

Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma.

PubMed

Tang, Chunhai; Yang, Zhenxiu; Chen, Dongliang; Xie, Qinghai; Peng, Tao; Wu, Jingzhan; Qi, Songtao

2017-12-01

Aberrant expression of miR-130a is usually found in cancer studies; however, the role of miR-130a has seldom been reported in glioma. We explored miR-130a's function and the underlying mechanism in glioma. It was found that miR-130a expression was significantly down-regulated in glioma tissues and cell lines. Overexpression of miR-130a decreased glioma cell growth and invasion both in vitro and in vivo. We identified the oncogene HMGB2 as a downstream target of miR-130a by using luciferase and western blot assays. Knockdown of HMGB2 mimicked the effect of miR-130a in glioma cells. Taken together, our study demonstrate that miR-130a may function as a tumor suppressor in glioma and suggest that miR-130a is a potential therapeutic target for glioma patients. Copyright © 2017. Published by Elsevier Ltd.

Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

PubMed Central

Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

2011-01-01

Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

CREB1 regulates glucose transport of glioma cell line U87 by targeting GLUT1.

PubMed

Chen, Jiaying; Zhang, Can; Mi, Yang; Chen, Fuxue; Du, Dongshu

2017-12-01

Glioma is stemmed from the glial cells in the brain, which is accounted for about 45% of all intracranial tumors. The characteristic of glioma is invasive growth, as well as there is no obvious boundary between normal brain tissue and glioma tissue, so it is difficult to resect completely with worst prognosis. The metabolism of glioma is following the Warburg effect. Previous researches have shown that GLUT1, as a glucose transporter carrier, affected the Warburg effect, but the molecular mechanism is not very clear. CREB1 (cAMP responsive element-binding protein1) is involved in various biological processes, and relevant studies confirmed that CREB1 protein regulated the expression of GLUT1, thus mediating glucose transport in cells. Our experiments mainly reveal that the CREB1 could affect glucose transport in glioma cells by regulating the expression of GLUT1, which controlled the metabolism of glioma and affected the progression of glioma.

Integrated analysis of dynamic FET PET/CT parameters, histology, and methylation profiling of 44 gliomas.

PubMed

Röhrich, Manuel; Huang, Kristin; Schrimpf, Daniel; Albert, Nathalie L; Hielscher, Thomas; von Deimling, Andreas; Schüller, Ulrich; Dimitrakopoulou-Strauss, Antonia; Haberkorn, Uwe

2018-05-07

Dynamic 18 F-FET PET/CT is a powerful tool for the diagnosis of gliomas. 18 F-FET PET time-activity curves (TAC) allow differentiation between histological low-grade gliomas (LGG) and high-grade gliomas (HGG). Molecular methods such as epigenetic profiling are of rising importance for glioma grading and subclassification. Here, we analysed dynamic 18 F-FET PET data, and the histological and epigenetic features of 44 gliomas. Dynamic 18 F-FET PET was performed in 44 patients with newly diagnosed, untreated glioma: 10 WHO grade II glioma, 13 WHO grade III glioma and 21 glioblastoma (GBM). All patients underwent stereotactic biopsy or tumour resection after 18 F-FET PET imaging. As well as histological analysis of tissue samples, DNA was subjected to epigenetic analysis using the Illumina 850 K methylation array. TACs, standardized uptake values corrected for background uptake in healthy tissue (SUVmax/BG), time to peak (TTP) and kinetic modelling parameters were correlated with histological diagnoses and with epigenetic signatures. Multivariate analyses were performed to evaluate the diagnostic accuracy of 18 F-FET PET in relation to the tumour groups identified by histological and methylation-based analysis. Epigenetic profiling led to substantial tumour reclassification, with six grade II/III gliomas reclassified as GBM. Overlap of HGG-typical TACs and LGG-typical TACs was dramatically reduced when tumours were clustered on the basis of their methylation profile. SUVmax/BG values of GBM were higher than those of LGGs following both histological diagnosis and methylation-based diagnosis. The differences in TTP between GBMs and grade II/III gliomas were greater following methylation-based diagnosis than following histological diagnosis. Kinetic modeling showed that relative K1 and fractal dimension (FD) values significantly differed in histology- and methylation-based GBM and grade II/III glioma between those diagnosed histologically and those diagnosed by methylation analysis. Multivariate analysis revealed slightly greater diagnostic accuracy with methylation-based diagnosis. IDH-mutant gliomas and GBM subgroups tended to differ in their 18 F-FET PET kinetics. The status of dynamic 18 F-FET PET as a biologically and clinically relevant imaging modality is confirmed in the context of molecular glioma diagnosis.

Proprioceptor pathway development is dependent on Math1

NASA Technical Reports Server (NTRS)

Bermingham, N. A.; Hassan, B. A.; Wang, V. Y.; Fernandez, M.; Banfi, S.; Bellen, H. J.; Fritzsch, B.; Zoghbi, H. Y.

2001-01-01

The proprioceptive system provides continuous positional information on the limbs and body to the thalamus, cortex, pontine nucleus, and cerebellum. We showed previously that the basic helix-loop-helix transcription factor Math1 is essential for the development of certain components of the proprioceptive pathway, including inner-ear hair cells, cerebellar granule neurons, and the pontine nuclei. Here, we demonstrate that Math1 null embryos lack the D1 interneurons and that these interneurons give rise to a subset of proprioceptor interneurons and the spinocerebellar and cuneocerebellar tracts. We also identify three downstream genes of Math1 (Lh2A, Lh2B, and Barhl1) and establish that Math1 governs the development of multiple components of the proprioceptive pathway.

Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20

PubMed Central

Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

2015-01-01

Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as “331” selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

The epidemiology of glioma in adults: a “state of the science” review

PubMed Central

Ostrom, Quinn T.; Bauchet, Luc; Davis, Faith G.; Deltour, Isabelle; Fisher, James L.; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A.; Turner, Michelle C.; Walsh, Kyle M.; Wrensch, Margaret R.; Barnholtz-Sloan, Jill S.

2014-01-01

Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O6-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine–phosphate–guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults. PMID:24842956

CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells.

PubMed

Johansson, Elinn; Grassi, Elisa S; Pantazopoulou, Vasiliki; Tong, Bei; Lindgren, David; Berg, Tracy J; Pietras, Elin J; Axelson, Håkan; Pietras, Alexander

2017-08-15

Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A role for ion channels in perivascular glioma invasion

PubMed Central

Thompson, Emily G.

2017-01-01

Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuro-peptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials. PMID:27424110

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

PubMed Central

2013-01-01

Background Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. Methods The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. Results The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Conclusions Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma. PMID:23915425

Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

PubMed Central

Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

2016-01-01

Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma.

PubMed

Peeri, Noah C; Creed, Jordan H; Anic, Gabriella M; Thompson, Reid C; Olson, Jeffrey J; LaRocca, Renato V; Chowdhary, Sajeel A; Brockman, John D; Gerke, Travis A; Nabors, L Burton; Egan, Kathleen M

2018-05-16

Selenium is an essential trace element obtained through diet that plays a critical role in DNA synthesis and protection from oxidative damage. Selenium intake and polymorphisms in selenoproteins have been linked to the risk of certain cancers though data for glioma are sparse. In a case-control study of glioma, we examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathway with the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study. None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70). The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome. Copyright © 2018 Elsevier Ltd. All rights reserved.

MiR-188 Inhibits Glioma Cell Proliferation and Cell Cycle Progression through Targeting ß-catenin.

PubMed

Li, Nan; Shi, Hangyu; Zhang, Lu; Li, Xu; Gao, Lu; Zhang, Gang; Shi, Yongqiang; Guo, Shiwen

2017-12-21

MicroRNAs (miRNAs) play important roles in several human cancers. Although miR188 has been suggested to function as a tumor repressor in cancers, its precise role in glioma and the molecular mechanism remain unknown. In the present study, we investigated the effect of miR-188 on glioma and explored its relevant mechanisms. We found that the expression of miR-188 is dramatically downregulated in glioma tissues and cell lines. Subsequent investigation revealed that miR-188 expression was inversely correlated with ß-catenin expression in glioma tissue samples. Using a luciferase reporter assay, ß-catenin was determined to be a direct target of miR-188. Overexpression of miR-188 reduced ß-catenin expression at both the mRNA and protein levels, and inhibition of miR-188 increased ß-catenin expression. Moreover, we found that overexpression of miR-188 suppressed glioma cell proliferation and cell cycle G1-S transition, whereas inhibition of miR-188 promoted glioma cell proliferation. Importantly, silencing ß-catenin recapitulated the cellular and molecular effects seen upon miR-188 overexpression, which included inhibiting glioma cell proliferation and G1-S transition. Taken together, our results demonstrated that miR188 inhibits glioma cell proliferation by targeting ß-catenin, representing an effective therapeutic strategy for glioma.

MicroRNA-584-3p, a novel tumor suppressor and prognostic marker, reduces the migration and invasion of human glioma cells by targeting hypoxia-induced ROCK1

PubMed Central

Xue, Hao; Guo, Xing; Han, Xiao; Yan, Shaofeng; Zhang, Jinsen; Xu, Shugang; Li, Tong; Guo, Xiaofan; Zhang, Ping; Gao, Xiao; Liu, Qinglin; Li, Gang

2016-01-01

Here, we report that microRNA-584-3p (miR-584-3p) is up-regulated in hypoxic glioma cells and in high-grade human glioma tumors (WHO grades III–IV) relative to normoxic cells and to low-grade tumors (WHO grades I–II), respectively. The postoperative survival time was significantly prolonged in the high-grade glioma patients with high miR-584-3p expression compared with those with low miR-584-3p expression. miR-584-3p may function as a potent tumor suppressor and as a prognostic biomarker for malignant glioma. However, the molecular mechanisms underlying these properties remain poorly understood. Our mechanistic studies revealed that miR-584-3p suppressed the migration and invasion of glioma cells by disrupting hypoxia-induced stress fiber formation. Specifically, we have found that ROCK1 is a direct and functionally relevant target of miR-584-3p in glioma cells. Our results have demonstrated a tumor suppressive function of miR-584-3p in glioma, in which it inhibits the migration and invasion of tumor cells by antagonizing hypoxia-induced, ROCK1-dependent stress fiber formation. Our findings have potential implications for glioma gene therapy and suggest that miR-584-3p could represent a prognostic indicator for glioma. PMID:26715733

Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

PubMed

Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

2015-12-08

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. Copyright © 2015, American Association for the Advancement of Science.

Receptor-Mediated Drug Delivery Systems Targeting to Glioma

PubMed Central

Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

2015-01-01

Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications. PMID:28344260

Glioma Stem Cells and Immunotherapy for the Treatment of Malignant Gliomas

PubMed Central

Toda, Masahiro

2013-01-01

Stem cell research has led to the discovery of glioma stem cells (GSCs), and because these cells are resistant to chemotherapy and radiotherapy, analysis of their properties has been rapidly pursued for targeted treatment of malignant glioma. Recent studies have also revealed complex crosstalk between GSCs and their specialized environment (niche). Therefore, targeting not only GSCs but also their niche may be a principle for novel therapies of malignant glioma. One possible novel strategy for targeting GSCs and their niches is immunotherapy with different antitumor mechanism(s) from those of conventional therapy. Recent clinical studies of immunotherapy using peptide vaccines and antibodies have shown promising results. This review describes the recent findings related to GSCs and their niches, as well as immunotherapies for glioma, followed by discussion of immunotherapies that target GSCs for the treatment of malignant glioma. PMID:23762610

Glioma stem cells and immunotherapy for the treatment of malignant gliomas.

PubMed

Toda, Masahiro

2013-01-01

Stem cell research has led to the discovery of glioma stem cells (GSCs), and because these cells are resistant to chemotherapy and radiotherapy, analysis of their properties has been rapidly pursued for targeted treatment of malignant glioma. Recent studies have also revealed complex crosstalk between GSCs and their specialized environment (niche). Therefore, targeting not only GSCs but also their niche may be a principle for novel therapies of malignant glioma. One possible novel strategy for targeting GSCs and their niches is immunotherapy with different antitumor mechanism(s) from those of conventional therapy. Recent clinical studies of immunotherapy using peptide vaccines and antibodies have shown promising results. This review describes the recent findings related to GSCs and their niches, as well as immunotherapies for glioma, followed by discussion of immunotherapies that target GSCs for the treatment of malignant glioma.

TGF-β promotes glioma cell growth via activating Nodal expression through Smad and ERK1/2 pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jing; Liu, Su-zhi; Lin, Yan

Highlights: •TGF-β promoted Nodal expression in glioma cells. •TGF-β promoted Nodal expression via activating Smad and ERK1/2 pathways. •TGF-β promotes glioma cell growth via activating Nodal expression. -- Abstract: While there were certain studies focusing on the mechanism of TGF-β promoting the growth of glioma cells, the present work revealed another novel mechanism that TGF-β may promote glioma cell growth via enhancing Nodal expression. Our results showed that Nodal expression was significantly upregulated in glioma cells when TGF-β was added, whereas the TGF-β-induced Nodal expression was evidently inhibited by transfection Smad2 or Smad3 siRNAs, and the suppression was especially significantmore » when the Smad3 was downregulated. Another, the attenuation of TGF-β-induced Nodal expression was observed with blockade of the ERK1/2 pathway also. Further detection of the proliferation, apoptosis, and invasion of glioma cells indicated that Nodal overexpression promoted the proliferation and invasion of tumor cells and inhibited their apoptosis, resembling the effect of TGF-β addition. Downregulation of Nodal expression via transfection Nodal-specific siRNA in the presence of TGF-β weakened the promoting effect of the latter on glioma cells growth, and transfecting Nodal siRNA alone in the absence of exogenous TGF-β more profoundly inhibited the growth of glioma cells. These results demonstrated that while both TGF-β and Nodal promoted glioma cells growth, the former might exert such effect by enhancing Nodal expression, which may form a new target for glioma therapy.« less

Analysis of expression and prognostic significance of vimentin and the response to temozolomide in glioma patients.

PubMed

Lin, Lin; Wang, Guangzhi; Ming, Jianguang; Meng, Xiangqi; Han, Bo; Sun, Bo; Cai, Jinquan; Jiang, Chuanlu

2016-11-01

Gliomas are the most common primary intracranial malignant tumors in adults. Surgical resection followed by optional radiotherapy and chemotherapy is the current standard therapy for glioma patients. Vimentin, a protein of intermediate filament family, could maintain the cellular integrity and participate in several cell signal pathways to modulate the motility and invasion of cancer cells. The purpose of the present research was to identify the relationship between vimentin expression and clinical characteristics and detect the prognostic and predictive ability of vimentin in patients with glioma. To determine the expression of vimentin in glioma tissues, paraffin-embedded blocks from glioma patients by surgical resection were obtained and evaluated by immunohistochemistry. To further investigate the association of vimentin expression with survival, we employed mRNA expression of vimentin genes from the Chinese Glioma Genome Atlas (CGGA) and the GSE 16011 dataset. Kaplan-Meier analysis and Cox regression model were used to statistical analysis. We detected positive vimentin straining in 84 % of high-grade compared to 47 % in low-grade glioma patients. Additionally, vimentin mRNA expression was correlated with glioma grade in both CGGA and GSE16011 dataset. Patients with low vimentin expression have longer survival than high expression. In multivariate analysis, vimentin was an independent significant prognostic factor for high-grade glioma patients. We also identified that glioblastoma patients with low vimentin expression had a better response to temozolomide therapy. Vimentin expression has a significant association with tumor grade and overall survival of high-grade glioma patients. Low vimentin expression may benefit from temozolomide therapy.

Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

ClinicalTrials.gov

2013-10-07

Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Light-controlled inhibition of malignant glioma by opsin gene transfer

PubMed Central

Yang, F; Tu, J; Pan, J-Q; Luo, H-L; Liu, Y-H; Wan, J; Zhang, J; Wei, P-F; Jiang, T; Chen, Y-H; Wang, L-P

2013-01-01

Glioblastomas are aggressive cancers with low survival rates and poor prognosis because of their highly proliferative and invasive capacity. In the current study, we describe a new optogenetic strategy that selectively inhibits glioma cells through light-controlled membrane depolarization and cell death. Transfer of the engineered opsin ChETA (engineered Channelrhodopsin-2 variant) gene into primary human glioma cells or cell lines, but not normal astrocytes, unexpectedly decreased cell proliferation and increased mitochondria-dependent apoptosis, upon light stimulation. These optogenetic effects were mediated by membrane depolarization-induced reductions in cyclin expression and mitochondrial transmembrane potential. Importantly, the ChETA gene transfer and light illumination in mice significantly inhibited subcutaneous and intracranial glioma growth and increased the survival of the animals bearing the glioma. These results uncover an unexpected effect of opsin ion channels on glioma cells and offer the opportunity for the first time to treat glioma using a light-controllable optogenetic approach. PMID:24176851

Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment.

PubMed

Rizzo, Daniela; Ruggiero, Antonio; Martini, Maurizio; Rizzo, Valentina; Maurizi, Palma; Riccardi, Riccardo

2015-01-01

High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.

Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

PubMed Central

Rizzo, Daniela; Ruggiero, Antonio; Martini, Maurizio; Rizzo, Valentina; Maurizi, Palma; Riccardi, Riccardo

2015-01-01

High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas. PMID:26448930

Light-controlled inhibition of malignant glioma by opsin gene transfer.

PubMed

Yang, F; Tu, J; Pan, J-Q; Luo, H-L; Liu, Y-H; Wan, J; Zhang, J; Wei, P-F; Jiang, T; Chen, Y-H; Wang, L-P

2013-10-31

Glioblastomas are aggressive cancers with low survival rates and poor prognosis because of their highly proliferative and invasive capacity. In the current study, we describe a new optogenetic strategy that selectively inhibits glioma cells through light-controlled membrane depolarization and cell death. Transfer of the engineered opsin ChETA (engineered Channelrhodopsin-2 variant) gene into primary human glioma cells or cell lines, but not normal astrocytes, unexpectedly decreased cell proliferation and increased mitochondria-dependent apoptosis, upon light stimulation. These optogenetic effects were mediated by membrane depolarization-induced reductions in cyclin expression and mitochondrial transmembrane potential. Importantly, the ChETA gene transfer and light illumination in mice significantly inhibited subcutaneous and intracranial glioma growth and increased the survival of the animals bearing the glioma. These results uncover an unexpected effect of opsin ion channels on glioma cells and offer the opportunity for the first time to treat glioma using a light-controllable optogenetic approach.

Terahertz reflectometry imaging for low and high grade gliomas

NASA Astrophysics Data System (ADS)

Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

2016-10-01

Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.

IGFBP6 Regulates Cell Apoptosis and Migration in Glioma.

PubMed

Bei, Yuanqi; Huang, Qingfeng; Shen, Jianhong; Shi, Jinlong; Shen, Chaoyan; Xu, Peng; Chang, Hao; Xia, Xiaojie; Xu, Li; Ji, Bin; Chen, JianGuo

2017-07-01

The insulin-like growth factor binding protein 6 (IGFBP6), as an inhibitor of IGF-II actions, plays an important role in inhibiting survival and migration of tumor cells. In our study, we intended to demonstrate the biological function of IGFBP6 in the development of glioma and its clinical significance. Firstly, Western blot and immunohistochemistry revealed that the expression of IGFBP6 inversely correlated with glioma grade. Secondly, multivariate analysis with the Cox proportional hazards model and Kaplan-Meier analysis indicated that IGFBP6 could be an independent prognostic factor for the survival of glioma patients. In addition, overexpression of IGFBP6 induced glioma cell apoptosis, and depletion of IGFBP6 had the opposite action. Finally, overexpression of IGFBP6 inhibited migration of glioma cells, and depletion of IGFBP6 had the opposite action. Together our findings suggest that IGFBP6 might be an important regulator and prognostic factor for glioma.

Long Non-Coding RNA in Glioma: Target miRNA and Signaling Pathways.

PubMed

Dang, Yuan; Wei, Xudong; Xue, Laien; Wen, Fuli; Gu, Jianjun; Zheng, Heping

2018-06-01

Glioma is one of the most common and aggressive malignant tumors of the central nervous system. Here, we review and explore the use of long noncoding RNA (lncRNA) as a therapeutic strategy for the targeting of gliomas. LncRNA is a functional RNA molecule with no protein coding function and is involved in the occurrence and progression of glioma. It is reported that the activation of several signaling pathways, including the MAPK, p53, Wnt/β-catenin, PI3K/AKT/mTOR, and epithelial mesenchymal transformation (EMT) pathways, are involved in the regulation of gliomas. In addition, microRNAs in glioma may also interact with lncRNAs and affect tumor growth and progression. Therefore, the exploration of lncRNA participation in signaling pathway regulatory mechanisms and the determination of the interaction between lncRNA and miRNA may help to develop new effective therapies for the treatment of glioma.

Formononetin sensitizes glioma cells to doxorubicin through preventing EMT via inhibition of histone deacetylase 5.

PubMed

Liu, Quan; Sun, Yan; Zheng, Jie-Min; Yan, Xian-Lei; Chen, Hong-Mou; Chen, Jia-Kang; Huang, He-Qing

2015-01-01

Chemoresistance is a major obstacle to successful chemotherapy for glioma. Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus and possesses antitumorigenic properties. In the present study, we investigated the anti-proliferative effects of formononetin on human glioma cells, and further elucidated the molecular mechanism underlying the anti-tumor property. We found that formononetin enhanced doxorubicin cytotoxicity in glioma cells. Combined treatment with formononetin reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in tumor cells. Moreover, we found that formononetin treatment significantly decreased the expression of HDAC5. Overexpression of HDAC5 diminished the suppressive effects of formononetin on glioma cell viability. Furthermore, knockdown of HDAC5 by siRNA inhibited the doxorubicin-induced EMT in glioma cells. Taken together, these results demonstrated that formononetin-combined therapy may enhance the therapeutic efficacy of doxorubicin in glioma cells by preventing EMT through inhibition of HDAC5.

Formononetin sensitizes glioma cells to doxorubicin through preventing EMT via inhibition of histone deacetylase 5

PubMed Central

Liu, Quan; Sun, Yan; Zheng, Jie-Min; Yan, Xian-Lei; Chen, Hong-Mou; Chen, Jia-Kang; Huang, He-Qing

2015-01-01

Chemoresistance is a major obstacle to successful chemotherapy for glioma. Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus and possesses antitumorigenic properties. In the present study, we investigated the anti-proliferative effects of formononetin on human glioma cells, and further elucidated the molecular mechanism underlying the anti-tumor property. We found that formononetin enhanced doxorubicin cytotoxicity in glioma cells. Combined treatment with formononetin reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in tumor cells. Moreover, we found that formononetin treatment significantly decreased the expression of HDAC5. Overexpression of HDAC5 diminished the suppressive effects of formononetin on glioma cell viability. Furthermore, knockdown of HDAC5 by siRNA inhibited the doxorubicin-induced EMT in glioma cells. Taken together, these results demonstrated that formononetin-combined therapy may enhance the therapeutic efficacy of doxorubicin in glioma cells by preventing EMT through inhibition of HDAC5. PMID:26261519

Attention dysfunction of postoperative patients with glioma.

PubMed

Fang, Dazhao; Jiang, Jian; Sun, Xiaoyang; Wang, Weijie; Dong, Nan; Fu, Xianhua; Pang, Cong; Chen, Xingui; Ding, Lianshu

2014-10-15

Attention dysfunction has been observed among many kinds of nervous system diseases, including glioma. This study aimed to investigate the correlation between glioma localization, malignancy, postoperative recovery time and attention deficit. A total of 45 patients with glioma who underwent surgical resection and 18 healthy volunteers were enrolled. The attention network test, digital span test, color trail test II and Stroop test were used to detect the characteristics of attention deficit. Orientation network dysfunction was detected in the parietal lobe tumor group, and execution network deficit was detected in both the frontal and parietal lobe groups, while no significant difference was detected in the temporal lobe group compared to healthy controls. The high-grade glioma group (grade III-IV) exhibited more serious functional impairment than the low-grade group (grade I-II). No significant correlation was observed between postoperative recovery time and attention impairment. High-grade glioma patients suffer more severe attention impairment. In addition, the frontal and parietal lobe glioma patients suffer attention dysfunction in dissimilar manner. These findings will provide important guidance on the care of glioma patients after therapy.

Dobesilate diminishes activation of the mitogen - activated protein kinase ERK1/2 in glioma cells

PubMed Central

Cuevas, P; Diaz-González, Diana; Garcia-Martin-Córdova, C; Sánchez, I; Lozano, Rosa Maria; Giménez-Gallego, G; Dujovny, M

2006-01-01

Fibroblast growth factors (FGFs) and their receptors, regularly expressed at high levels in gliomas, are further upregulated during the transition of the tumor from low- to high-grade malignancy, and are essential for glioma progression. FGFs induce upregulation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured glioma cells, which suggests that MAPK pathway participates in the FGF-dependent glioma development. Recently, it has been shown that dobesilate, an inhibitor of FGF mitogenic activity, shows antiproliferative and proapoptotic activities in glioma cell cultures. Accordingly, it should be expected this new synthetic FGF inhibitor to affect the activation levels of MAPK. Here we report that immunocytochemical and Western blot data unequivocally show that treatment of cell cultures with dobesilate causes a significant decrease of the intracellular levels of ERK1/2 activation, one of the components of the MAPK signalling cascade. This finding supports an important role for dobesilate in glioma growth, suggesting that dobesilate should be a treatment to be born in mind for glioma management. PMID:16563234

Development of a Hypoxic Radiosensitizer-Prodrug Liposome Delivery DNA Repair Inhibitor Dbait Combination with Radiotherapy for Glioma Therapy.

PubMed

Liu, Hongmei; Cai, Yifan; Zhang, Yafei; Xie, Yandong; Qiu, Hui; Hua, Lei; Liu, Xuejiao; Li, Yuling; Lu, Jun; Zhang, Longzhen; Yu, Rutong

2017-06-01

Gliomas are highly radioresistant tumors, mainly due to hypoxia in the core region of the gliomas and efficient DNA double-strand break repair. However, the design of a radiosensitizer incorporating the two above mechanisms is difficult and has rarely been reported. Thus, this study develops a hypoxic radiosensitizer-prodrug liposome (MLP) to deliver the DNA repair inhibitor Dbait (MLP/Dbait) to achieve the simultaneous entry of radiosensitizers with two different mechanisms into the glioma. MLP/Dbait effectively sensitizes glioma cells to X-ray radiotherapy (RT). Histological and microscopic examinations of dissected brain tissue confirm that MLP effectively delivers Dbait into the glioma. Furthermore, the combination of MLP/Dbait with RT significantly inhibits growth of the glioma, as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a Dbait delivery system to enhance the effect of RT on glioma, owing to the synergistic effects of the two different radiosensitizers. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Up-regulation of plakophilin-2 is correlated with the progression of glioma.

PubMed

Zhang, Degeng; Qian, Yuxia; Liu, Xiaoxing; Yu, Hong; Zhao, Niangao; Wu, Zhengdong

2017-06-01

Glioma is the most common type of primary brain tumor in the CNS. Due to its poor prognosis and high mortality rates, it is urgent to find out more effective therapies. Plakophilin-2 (PKP2) is a widespread desmosomal plaque protein. Recently, the important roles of PKP2 in the proliferation and migration of cancer cells and tumor progression has been shown. However, the expression and potential function of PKP2 in glioma was still unclear. In this study, we demonstrated that PKP2 protein expression level was increased in glioma tissues compared with normal brain tissues, and its level was significantly associated with the Ki-67 expression and WHO grade by Western blot analysis and immunohistochemistry. Clinically, high PKP2 expression was tightly related to poor prognosis of glioma patients. Interestingly, we found that down-regulated PKP2 expression was shown to inhibit the migration of cells in glioma. Moreover, cell counting kit (CCK)-8 and colony formation analyses proved that reduced expression of PKP2 could weaken glioma cell proliferation. Taken together, these data uncover a potential role for PKP2 in the pathogenic process of glioma, suggesting that PKP2 may be a promising therapeutic target of glioma. © 2017 Japanese Society of Neuropathology.

Upregulation of long noncoding RNA HOXA-AS3 promotes tumor progression and predicts poor prognosis in glioma

PubMed Central

Wu, Fan; Zhang, Chuanbao; Cai, Jinquan; Yang, Fan; Liang, Tingyu; Yan, Xiaoyan; Wang, Haoyuan; Wang, Wen; Chen, Jing; Jiang, Tao

2017-01-01

Long noncoding RNAs (lncRNAs) have recently emerged as new potentially promising therapeutic targets in many cancers. However, their prognostic value and biological functions associated with glioma remain to be elucidated. Here, High-throughput RNAseq was performed to detect the expression profiles of lncRNAs in 325 human glioma tissues. It was shown that a novel lncRNA HOXA-AS3 was one of the most significantly upregulated lncRNAs in glioma tissues. Quantitative PCR further verified the increased expression of HOXA-AS3 in patient samples and glioma cell lines. Uni and Multivariate Cox regression analysis revealed that HOXA-AS3 was an independent prognostic factor in glioma patients. Gene set enrichment analysis indicated that the gene sets correlated with HOXA-AS3 expression were involved in cell cycle progression and E2F targets. Functionally, HOXA-AS3 silencing resulted in proliferation arrest by altering cell cycle progression and promoting cell apoptosis, and impaired cell migration in glioma cells. Furthermore, the growth-inhibiting effect of HOXA-AS3 knockdown was also demonstrated in Xenograft mouse model. Our results highlight the important role of HOXA-AS3 in glioma progression, and indicate that HOXA-AS3 may be served as a valuable prognostic biomarker for glioma. PMID:28881797

Clinical Significance of SASH1 Expression in Glioma.

PubMed

Yang, Liu; Zhang, Haitao; Yao, Qi; Yan, Yingying; Wu, Ronghua; Liu, Mei

2015-01-01

SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher's exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma.

Handedness and the risk of glioma.

PubMed

Miller, Briana; Peeri, Noah C; Nabors, Louis Burt; Creed, Jordan H; Thompson, Zachary J; Rozmeski, Carrie M; LaRocca, Renato V; Chowdhary, Sajeel; Olson, Jeffrey J; Thompson, Reid C; Egan, Kathleen M

2018-05-01

Gliomas are the most common type of malignant primary brain tumor and few risk factors have been linked to their development. Handedness has been associated with several pathologic neurological conditions such as schizophrenia, autism, and epilepsy, but few studies have evaluated a connection between handedness and risk of glioma. In this study, we examined the relationship between handedness and glioma risk in a large case-control study (1849 glioma cases and 1354 healthy controls) and a prospective cohort study (326,475 subjects with 375 incident gliomas). In the case-control study, we found a significant inverse association between left handedness and glioma risk, with left-handed persons exhibiting a 35% reduction in the risk of developing glioma [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51-0.83] after adjustment for age, gender, race, education, and state of residence; similar inverse associations were observed for GBM (OR = 0.69, 95% CI 0.52-0.91), and non-GBM (OR = 0.59, 95% CI 0.42-0.82) subgroups. The association was consistent in both males and females, and across age strata, and was observed in both glioblastoma and in lower grade tumors. In the prospective cohort study, we found no association between handedness and glioma risk (hazards ratio = 0.92, 95% CI 0.67-1.28) adjusting for age, gender, and race. Further studies on this association may help to elucidate mechanisms of pathogenesis in glioma.

Epstein–Barr Virus in Gliomas: Cause, Association, or Artifact?

PubMed Central

Akhtar, Saghir; Vranic, Semir; Cyprian, Farhan Sachal; Al Moustafa, Ala-Eddin

2018-01-01

Gliomas are the most common malignant brain tumors and account for around 60% of all primary central nervous system cancers. Glioblastoma multiforme (GBM) is a grade IV glioma associated with a poor outcome despite recent advances in chemotherapy. The etiology of gliomas is unknown, but neurotropic viruses including the Epstein–Barr virus (EBV) that is transmitted via salivary and genital fluids have been implicated recently. EBV is a member of the gamma herpes simplex family of DNA viruses that is known to cause infectious mononucleosis (glandular fever) and is strongly linked with the oncogenesis of several cancers, including B-cell lymphomas, nasopharyngeal, and gastric carcinomas. The fact that EBV is thought to be the causative agent for primary central nervous system (CNS) lymphomas in immune-deficient patients has led to its investigations in other brain tumors including gliomas. Here, we provide a review of the clinical literature pertaining to EBV in gliomas and discuss the possibilities of this virus being simply associative, causative, or even an experimental artifact. We searched the PubMed/MEDLINE databases using the following key words such as: glioma(s), glioblastoma multiforme, brain tumors/cancers, EBV, and neurotropic viruses. Our literature analysis indicates conflicting results on the presence and role of EBV in gliomas. Further comprehensive studies are needed to fully implicate EBV in gliomagenesis and oncomodulation. Understanding the role of EBV and other oncoviruses in the etiology of gliomas, would likely open up new avenues for the treatment and management of these, often fatal, CNS tumors. PMID:29732319

A Novel Candidate Molecule in Pathological Grading Of Gliomas: ELABELA.

PubMed

Artas, Gokhan; Ozturk, Sait; Kuloglu, Tuncay; Dagli, Adile Ferda; Gonen, Murat; Artas, Hakan; Aydin, Suleyman; Erol, Fatih Serhat

2018-04-06

This study aimed to investigate the possible role of ELABELA (ELA) in the histopathological grading of gliomas. We retrospectively assessed pathological specimens of patients who underwent surgery for intracranial space-occupying lesions. Only primary glioma specimens were included in this study. We enrolled 11 patients histologically diagnosed with low-grade glioma and 22 patients with high-grade glioma. The ELA antibody was applied to 4-6-µm-thick sections obtained from paraffin blocks. Histoscores were calculated using the distribution and intensity of staining immunoreactivity. An independent sample t-test was used for two-point inter-group assessments, whereas one-way analysis of variance was used for the other assessments. P 0.05 was considered statistically significant. The histoscores of the control brain, low-grade glioma, and high-grade glioma tissues were found to be 0.08, 0.37, and 0.92, respectively. The difference in ELA immunoreactivity between the control brain tissue and glioma tissue was statistically significant (p 0.05). In addition, a statistically significant increase was observed in ELA immunoreactivity in high-grade glioma tissues compared with that in low-grade glioma tissues (p 0.05). ELA has an angiogenetic role in the progression of glial tumors. ELA, which is an endogenous ligand of the apelin receptor, activates the apelinergic system and causes the progression of glial tumors. Further studies with a large number of patients are necessary to investigate the angiogenetic role of ELA in glial tumors.

Comprehensive analysis of the functional microRNA–mRNA regulatory network identifies miRNA signatures associated with glioma malignant progression

PubMed Central

Li, Yongsheng; Xu, Juan; Chen, Hong; Bai, Jing; Li, Shengli; Zhao, Zheng; Shao, Tingting; Jiang, Tao; Ren, Huan; Kang, Chunsheng; Li, Xia

2013-01-01

Glioma is the most common and fatal primary brain tumour with poor prognosis; however, the functional roles of miRNAs in glioma malignant progression are insufficiently understood. Here, we used an integrated approach to identify miRNA functional targets during glioma malignant progression by combining the paired expression profiles of miRNAs and mRNAs across 160 Chinese glioma patients, and further constructed the functional miRNA–mRNA regulatory network. As a result, most tumour-suppressive miRNAs in glioma progression were newly discovered, whose functions were widely involved in gliomagenesis. Moreover, three miRNA signatures, with different combinations of hub miRNAs (regulations≥30) were constructed, which could independently predict the survival of patients with all gliomas, high-grade glioma and glioblastoma. Our network-based method increased the ability to identify the prognostic biomarkers, when compared with the traditional method and random conditions. Hsa-miR-524-5p and hsa-miR-628-5p, shared by these three signatures, acted as protective factors and their expression decreased gradually during glioma progression. Functional analysis of these miRNA signatures highlighted their critical roles in cell cycle and cell proliferation in glioblastoma malignant progression, especially hsa-miR-524-5p and hsa-miR-628-5p exhibited dominant regulatory activities. Therefore, network-based biomarkers are expected to be more effective and provide deep insights into the molecular mechanism of glioma malignant progression. PMID:24194606

The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

PubMed

Yin, Haoyuan; Shao, Ying; Chen, Xuan

2017-01-01

To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P < 0.05). Downregulated the expression of CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

Tissue Proteome Analysis of Different Grades of Human Gliomas Provides Major Cues for Glioma Pathogenesis.

PubMed

Gollapalli, Kishore; Ghantasala, Saicharan; Atak, Apurva; Rapole, Srikanth; Moiyadi, Aliasgar; Epari, Sridhar; Srivastava, Sanjeeva

2017-05-01

Gliomas are heterogeneous and most commonly occurring brain tumors. Blood-brain barrier restricts the entry of brain tumor proteins into blood stream thus limiting the usage of serum or plasma for proteomic analysis. Our study aimed at understanding the molecular basis of aggressiveness of various grades of brain tumors using isobaric tagging for relative and absolute quantification (iTRAQ) based mass spectrometry. Tissue proteomic analysis of various grades of gliomas was performed using four-plex iTRAQ. We labeled five sets (each set consists of control, grade-II, III, and IV tumor samples) of individual glioma patients using iTRAQ reagents. Significantly altered proteins were subjected to bioinformatics analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID). Various metabolic pathways like glycolysis, TCA-cycle, electron transport chain, lactate metabolism, and blood coagulation pathways were majorly observed to be perturbed in gliomas. Most of the identified proteins involved in redox reactions, protein folding, pre-messenger RNA (mRNA) processing, antiapoptosis, and blood coagulation were found to be upregulated in gliomas. Transcriptomics data of glioblastoma multiforme (GBM), low-grade gliomas (LGGs), and controls were downloaded from The Cancer Genome Atlas (TCGA) data portal and further analyzed using BRB-Array tools. Expression levels of a few significantly altered proteins like lactate dehydrogenase, alpha-1 antitrypsin, fibrinogen alpha chain, nucleophosmin, annexin A5, thioredoxin, ferritin light chain, thymosin beta-4-like protein 3, superoxide dismutase-2, and peroxiredoxin-1 and 6 showed a positive correlation with increasing grade of gliomas thereby offering an insight into molecular basis behind their aggressive nature. Several proteins identified in different grades of gliomas are potential grade-specific markers, and perturbed pathways provide comprehensive overview of molecular cues involved in glioma pathogenesis.

Long noncoding RNA FTX is upregulated in gliomas and promotes proliferation and invasion of glioma cells by negatively regulating miR-342-3p.

PubMed

Zhang, Weiguang; Bi, Yunke; Li, Jianhua; Peng, Fei; Li, Hui; Li, Chenguang; Wang, Laizang; Ren, Fubin; Xie, Chen; Wang, Pengwei; Liang, Weiwei; Wang, Zhi; Zhu, Dan

2017-04-01

Gliomas remain a major public health challenge, posing a high risk for brain tumor-related morbidity and mortality. However, the mechanisms that drive the development of gliomas remain largely unknown. Emerging evidence has shown that long noncoding RNAs are key factors in glioma pathogenesis. qRT-PCR analysis was used to assess the expression of FTX and miR-342-3p in the different stages of gliomas in tissues. Bioinformatics tool DIANA and TargetSCan were used to predict the targets of FTX and miR-342-3p, respectively. Pearson's correlation analysis was performed to test the correlation between the expression levels of FTX, miR-342-3p, and astrocyte-elevated gene-1 (AEG-1). To examine the role of FTX in regulating proliferation and invasion of glioma cells, specific siRNA was used to knockdown FTX, and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and transwell assays were performed. Furthermore, rescue experiments were performed to further confirm the regulation of miR-342-3p by FTX. We then found that the expression of FTX and miR-342-3p was associated with progression of gliomas. FTX directly inhibited the expression of miR-342-3p, which subsequently regulates the expression of AEG-1. Collectively, FTX is critical for proliferation and invasion of glioma cells by regulating miR-342-3p and AEG-1. Our findings indicate that FTX and miR-342-3p may serve as a biomarker of glioma diagnosis, and offer potential novel therapeutic targets of treatment of gliomas.

Difference of language cortex reorganization between cerebral arteriovenous malformations, cavernous malformations, and gliomas: a functional MRI study.

PubMed

Deng, Xiaofeng; Xu, Long; Zhang, Yan; Wang, Bo; Wang, Shuo; Zhao, Yuanli; Cao, Yong; Zhang, Dong; Wang, Rong; Ye, Xun; Wu, Jun; Zhao, Jizong

2016-04-01

The authors attempted to demonstrate the difference in language cortex reorganization between cerebral malformations (AVMs), cavernous malformations (CMs), and gliomas by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Clinical and imaging data of 27 AVM patients (AVM-L group), 29 CM patients (CM-L group), and 20 glioma patients (Glioma-L group) were retrospectively reviewed, with lesions overlying the left inferior frontal gyrus (Broca area). As a control, patients with lesions involving the right inferior frontal gyrus were also enrolled, including 14 AVM patients (AVM-R group), 20 CM patients (CM-R group), and 14 glioma patients (Glioma-R group). All patients were right-handed. Lateralization indices (LI) of BOLD signal activations were calculated separately for Broca and Wernicke areas. In AVM-L group, right-sided lateralization of BOLD signals was observed in 10 patients (37.0%), including 6 in the Broca area alone, 1 in the Wernicke area alone, and 3 in both areas. Three patients (10.3%) of CM-L group showed right-sided lateralization in both Broca and Wernicke areas, and 1 patient (5.0%) of Glioma-L group had right-sided lateralization in the Wernicke area alone. A significant difference of right-sided lateralization was observed between the AVM-L group and CM-L group (P = 0.018) and also between the AVM-L group and Glioma-L group (P = 0.027). No patient in AVM-R, CM-R, or Glioma-R groups showed right-sided lateralization. Language cortex reorganization may occur in AVM, CM, and glioma patients when the traditional language cortex was involved by lesions, but the potential of reorganization for CM and glioma patients seems to be insufficient compared with AVM patients.

Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness

PubMed Central

Emdad, Luni; Janjic, Aleksandar; Alzubi, Mohammad A.; Hu, Bin; Santhekadur, Prasanna K.; Menezes, Mitchell E.; Shen, Xue-Ning; Das, Swadesh K.; Sarkar, Devanand; Fisher, Paul B.

2015-01-01

Background Malignant glioma is an aggressive cancer requiring new therapeutic targets. MicroRNAs (miRNAs) regulate gene expression post transcriptionally and are implicated in cancer development and progression. Deregulated expressions of several miRNAs, specifically hsa-miR-184, correlate with glioma development. Methods Bioinformatic approaches were used to identify potential miR-184-regulated target genes involved in malignant glioma progression. This strategy identified a multifunctional nuclease, SND1, known to be overexpressed in multiple cancers, including breast, colon, and hepatocellular carcinoma, as a putative direct miR-184 target gene. SND1 levels were evaluated in patient tumor samples and human-derived cell lines. We analyzed invasion and signaling in vitro through SND1 gain-of-function and loss-of-function. An orthotopic xenograft model with primary glioma cells demonstrated a role of miR-184/SND1 in glioma pathogenesis in vivo. Results SND1 is highly expressed in human glioma tissue and inversely correlated with miR-184 expression. Transfection of glioma cells with a miR-184 mimic inhibited invasion, suppressed colony formation, and reduced anchorage-independent growth in soft agar. Similar phenotypes were evident when SND1 was knocked down with siRNA. Additionally, knockdown (KD) of SND1 induced senescence and improved the chemoresistant properties of malignant glioma cells. In an orthotopic xenograft model, KD of SND1 or transfection with a miR-184 mimic induced a less invasive tumor phenotype and significantly improved survival of tumor bearing mice. Conclusions Our study is the first to show a novel regulatory role of SND1, a direct target of miR-184, in glioma progression, suggesting that the miR-184/SND1 axis may be a useful diagnostic and therapeutic tool for malignant glioma. PMID:25216670

Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance.

PubMed

Hegazy, Ahmed M; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A E; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi

2016-10-07

Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon

A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in themore » malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133{sup +} cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.« less

The Long Noncoding RNA TP73-AS1 Interacted with miR-124 to Modulate Glioma Growth by Targeting Inhibitor of Apoptosis-Stimulating Protein of p53.

PubMed

Xiao, Shuai; Wang, Rensheng; Wu, Xiangwei; Liu, Wen; Ma, Shanshan

2018-02-01

P73 antisense RNA 1T (non-protein coding), known as TP73-AS1 or PDAM, is a long noncoding RNA (lncRNA), which may regulate apoptosis by regulation of p53-dependent antiapoptotic genes. An abnormal change of TP73-AS1 expression was noticed in cancers. The effects of TP73-AS1 in brain glioma growth and the underlying mechanism remain unclear so far. In this study, the effect of TP73-AS1 in human brain glioma cell lines and clinical tumor samples was detected so as to reveal its role and function. In this study, TP73-AS1 was specifically upregulated in brain glioma cell lines and promoted glioma cell growth through targeting miR-124. TP73-AS1 knocking down suppressed human brain glioma cell proliferation, invasion, and metastasis in vitro. The inhibitory effect of TP73-AS1 knocking down on glioma cell proliferation and invasion could partly be restored by miR-124 inhibition. In addition, miR-124-dependent inhibitor of apoptosis-stimulating protein of p53 (iASPP) regulation was required in TP73-AS1-induced brain glioma cell growth. Data from this study revealed that TP73-AS1 inhibited the brain glioma growth and metastasis as a competing endogenous RNA (ceRNA) through miR-124-dependent iASPP regulation. In conclusion, we regarded TP73-AS1 as an oncogenic lncRNA promoting brain glioma proliferation and metastasis and a potential target for human brain glioma treatment.

In vivo detection of inducible nitric oxide synthase in rodent gliomas.

PubMed

Towner, Rheal A; Smith, Nataliya; Doblas, Sabrina; Garteiser, Philippe; Watanabe, Yasuko; He, Ting; Saunders, Debra; Herlea, Oana; Silasi-Mansat, Robert; Lupu, Florea

2010-03-01

Increased iNOS expression is often found in brain tumors, such as gliomas. The goal of this study was to develop and assess a novel molecular MRI (mMRI) probe for in vivo detection of iNOS in rodent models for gliomas (intracerebral implantation of rat C6 or RG2 cells or ethyl nitrosourea-induced glioma). The probe we used incorporated a Gd-DTPA (gadolinium(III) complex of diethylenetriamine-N,N,N',N'',N''-pentaacetate) backbone with albumin and biotin moieties and covalent binding of an anti-iNOS antibody (Ab) to albumin (anti-iNOS probe). We used mMRI with the anti-iNOS probe to detect in vivo iNOS levels in gliomas. Nonimmune normal rat IgG coupled to albumin-Gd-DTPA-biotin was used as a control nonspecific contrast agent. By targeting the biotin component of the anti-iNOS probe with streptavidin Cy3, fluorescence imaging confirmed the specificity of the probe for iNOS in glioma tissue. iNOS levels in glioma tumors were also confirmed via Western blots and immunohistochemistry. The presence of plasma membrane-associated iNOS in glioma cells was established by transmission electron microscopy and gold-labeled anti-iNOS Ab. The more aggressive RG2 glioma was not found to have higher levels of iNOS compared to C6. Differences in glioma vascularization and blood-brain barrier permeability between the C6 and the RG2 gliomas are discussed. In vivo assessment of iNOS levels associated with tumor development is quite feasible in heterogeneous tissues with mMRI. (c) 2009 Elsevier Inc. All rights reserved.

S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages.

PubMed

Wang, Huaqing; Zhang, Leying; Zhang, Ian Y; Chen, Xuebo; Da Fonseca, Anna; Wu, Shihua; Ren, Hui; Badie, Sam; Sadeghi, Sam; Ouyang, Mao; Warden, Charles D; Badie, Behnam

2013-07-15

S100B is member of a multigenic family of Ca(2+)-binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM). We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100B(high)) or underexpressed (S100B(low)) S100B and compared their growth characteristics to intracranial wild-type (S100B(wt)) tumors. Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100B(low) tumors, S100B(wt) and S100B(high) intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100B(high) tumors. Furthermore, analysis of The Cancer Genome Atlas's glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy.

In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor.

PubMed

Badie, B; Schartner, J; Klaver, J; Vorpahl, J

1999-05-01

Considered as immune effector cells of the central nervous system, microglia represent a major component of the inflammatory cells found in malignant gliomas. Although their role in brain tumor biology is unclear, accumulation of microglia in malignant brain tumors may be mediated through active secretion of cytokines by glioma cells. Because hepatocyte growth factor/scatter factor (HGF/SF) has been shown to modulate glioma motility through an autocrine mechanism, and because microglia have been reported to express the HGF/SF receptor Met, we hypothesized that microglia recruitment by gliomas may also occur through the secretion of HGF/SF. The effect of glioma cells in augmenting BV-2 murine microglia motility was studied by using an in vitro Boyden chamber migration assay. To determine the chemokines involved in microglia migration, neutralizing monoclonal antibodies against monocyte chemotactic protein-1 and HGF/SF were tested. Immunoblotting was used to check for the expression of HGF/SF by glioma cells, and the expression of Met by BV-2 cells was examined by flow cytometry. BV-2 migration was noted within 7 hours of incubation with both human (U251 MG and U373 MG) and murine (GL261) glioma cell lines. This migration corresponded to HGF/SF secretion by glioma cells and was completely inhibited by neutralizing monoclonal antibody against HGF/SF, but not monocyte chemotactic protein-1. Exposure of BV-2 cells to recombinant HGF/SF, but not monocyte chemotactic protein-1, resulted in their migration and down-regulation of Met in a dose-dependent fashion. HGF/SF, which plays a role in glioma motility and mitogenesis, may also act as a chemokine for microglia and may be responsible for the microglia infiltration in malignant gliomas. This active recruitment of microglia may play an important role in glioma biology.

T11TS immunotherapy repairs PI3K-AKT signaling in T-cells: Clues toward enhanced T-cell survival in rat glioma model.

PubMed

Chaudhuri, Suhnrita; Singh, Manoj K; Bhattacharya, Debanjan; Datta, Ankur; Hazra, Iman; Mondal, Somnath; Faruk Sk Md, Omar; Ronsard, Larance; Ghosh, Tushar K; Chaudhuri, Swapna

2018-02-01

Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes. © 2017 Wiley Periodicals, Inc.

MicroRNA-675 promotes glioma cell proliferation and motility by negatively regulating retinoblastoma 1.

PubMed

Zheng, Yungui; Lu, Xiaowen; Xu, Liepeng; Chen, Zhe; Li, Qinxi; Yuan, Jun

2017-11-01

Previous studies indicated that microRNA (miR)-675 and its precursor lncRNA H19 were both overexpressed in glioma tissues, and H19 might play an oncogenic role. To investigate the involvement of miR-675 in gliomas and its underlying mechanisms, we here collected candidate target genes of miR-675-5p from miRTarBase (http://mirtarbase.mbc.nctu.edu.tw/, Release 6.0), which contains the experimentally validated microRNA-target interactions. Then, regulatory effects of miR-675 on its target genes were validated using clinical samples and glioma cell lines. Involvement of the miR-675-target axis deregulation in cell proliferation, migration and invasion of glioma was demonstrated by both gain- and loss-of-function experiments. As a result, retinoblastoma 1 (RB1) was identified as a candidate target gene of miR-675-5p. Expression levels of miR-675-5p in glioma tissues and cells were negatively correlated with RB1 expression at both mRNA and protein levels. Importantly, deregulation of the miR-675-5p-RB1 axis was significantly associated with advanced World Health Organization (WHO) grade and low Karnofsky performance score (KPS) score of glioma patients. Luciferase reporter assay verified that RB1 was a direct target gene of miR-675 in glioma cells. Functionally, miR-675 promoted glioma cell proliferation, migration and invasion. Notably, simulation of RB1 antagonized the effects induced by miR-675 up-regulation in glioma cells. In conclusion, our data suggest that miR-675 may be a key negative regulator of RB1 and the imbalance of the miR-675-RB1 axis may be clinically associated with aggressive progression of glioma patients. In addition, miR-675 may act as an oncogenic miRNA in glioma cells via regulating its target gene RB1. Copyright © 2017 Elsevier Inc. All rights reserved.

Mobile phone use and glioma risk: A systematic review and meta-analysis.

PubMed

Yang, Ming; Guo, WenWen; Yang, ChunSheng; Tang, JianQin; Huang, Qian; Feng, ShouXin; Jiang, AiJun; Xu, XiFeng; Jiang, Guan

2017-01-01

Many studies have previously investigated the potential association between mobile phone use and the risk of glioma. However, results from these individual studies are inconclusive and controversial. The objective of our study was to investigate the potential association between mobile phone use and subsequent glioma risk using meta-analysis. We performed a systematic search of the Science Citation Index Embase and PubMed databases for studies reporting relevant data on mobile phone use and glioma in 1980-2016. The data were extracted and measured in terms of the odds ratio (OR) and 95% confidence interval (CI) using the random effects model. Subgroup analyses were also carried out. This meta-analysis eventually included 11 studies comprising a total 6028 cases and 11488 controls. There was a significant positive association between long-term mobile phone use (minimum, 10 years) and glioma (OR = 1.44, 95% CI = 1.08-1.91). And there was a significant positive association between long-term ipsilateral mobile phone use and the risk of glioma (OR = 1.46, 95% CI = 1.12-1.92). Long-term mobile phone use was associated with 2.22 times greater odds of low-grade glioma occurrence (OR = 2.22, 95% CI = 1.69-2.92). Mobile phone use of any duration was not associated with the odds of high-grade glioma (OR = 0.81, 95% CI = 0.72-0.92). Contralateral mobile phone use was not associated with glioma regardless of the duration of use. Similarly, this association was not observed when the analysis was limited to high-grade glioma. Our results suggest that long-term mobile phone use may be associated with an increased risk of glioma. There was also an association between mobile phone use and low-grade glioma in the regular use or long-term use subgroups. However, current evidence is of poor quality and limited quantity. It is therefore necessary to conduct large sample, high quality research or better characterization of any potential association between long-term ipsilateral mobile phone use and glioma risk.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

PubMed

Brat, Daniel J; Verhaak, Roel G W; Aldape, Kenneth D; Yung, W K Alfred; Salama, Sofie R; Cooper, Lee A D; Rheinbay, Esther; Miller, C Ryan; Vitucci, Mark; Morozova, Olena; Robertson, A Gordon; Noushmehr, Houtan; Laird, Peter W; Cherniack, Andrew D; Akbani, Rehan; Huse, Jason T; Ciriello, Giovanni; Poisson, Laila M; Barnholtz-Sloan, Jill S; Berger, Mitchel S; Brennan, Cameron; Colen, Rivka R; Colman, Howard; Flanders, Adam E; Giannini, Caterina; Grifford, Mia; Iavarone, Antonio; Jain, Rajan; Joseph, Isaac; Kim, Jaegil; Kasaian, Katayoon; Mikkelsen, Tom; Murray, Bradley A; O'Neill, Brian Patrick; Pachter, Lior; Parsons, Donald W; Sougnez, Carrie; Sulman, Erik P; Vandenberg, Scott R; Van Meir, Erwin G; von Deimling, Andreas; Zhang, Hailei; Crain, Daniel; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron; Bowen, Jay; Dicostanzo, Katie; Gastier-Foster, Julie; Leraas, Kristen M; Lichtenberg, Tara M; Pierson, Christopher R; Ramirez, Nilsa C; Taylor, Cynthia; Weaver, Stephanie; Wise, Lisa; Zmuda, Erik; Davidsen, Tanja; Demchok, John A; Eley, Greg; Ferguson, Martin L; Hutter, Carolyn M; Mills Shaw, Kenna R; Ozenberger, Bradley A; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Jensen, Mark A; Liu, Jia; Pihl, Todd; Raman, Rohini; Wan, Yunhu; Wu, Ye; Ally, Adrian; Auman, J Todd; Balasundaram, Miruna; Balu, Saianand; Baylin, Stephen B; Beroukhim, Rameen; Bootwalla, Moiz S; Bowlby, Reanne; Bristow, Christopher A; Brooks, Denise; Butterfield, Yaron; Carlsen, Rebecca; Carter, Scott; Chin, Lynda; Chu, Andy; Chuah, Eric; Cibulskis, Kristian; Clarke, Amanda; Coetzee, Simon G; Dhalla, Noreen; Fennell, Tim; Fisher, Sheila; Gabriel, Stacey; Getz, Gad; Gibbs, Richard; Guin, Ranabir; Hadjipanayis, Angela; Hayes, D Neil; Hinoue, Toshinori; Hoadley, Katherine; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven; Jones, Corbin D; Kucherlapati, Raju; Lai, Phillip H; Lander, Eric; Lee, Semin; Lichtenstein, Lee; Ma, Yussanne; Maglinte, Dennis T; Mahadeshwar, Harshad S; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew L; Mieczkowski, Piotr A; Moore, Richard A; Mose, Lisle E; Mungall, Andrew J; Pantazi, Angeliki; Parfenov, Michael; Park, Peter J; Parker, Joel S; Perou, Charles M; Protopopov, Alexei; Ren, Xiaojia; Roach, Jeffrey; Sabedot, Thaís S; Schein, Jacqueline; Schumacher, Steven E; Seidman, Jonathan G; Seth, Sahil; Shen, Hui; Simons, Janae V; Sipahimalani, Payal; Soloway, Matthew G; Song, Xingzhi; Sun, Huandong; Tabak, Barbara; Tam, Angela; Tan, Donghui; Tang, Jiabin; Thiessen, Nina; Triche, Timothy; Van Den Berg, David J; Veluvolu, Umadevi; Waring, Scot; Weisenberger, Daniel J; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Xu, Andrew W; Yang, Lixing; Zack, Travis I; Zhang, Jianhua; Aksoy, B Arman; Arachchi, Harindra; Benz, Chris; Bernard, Brady; Carlin, Daniel; Cho, Juok; DiCara, Daniel; Frazer, Scott; Fuller, Gregory N; Gao, JianJiong; Gehlenborg, Nils; Haussler, David; Heiman, David I; Iype, Lisa; Jacobsen, Anders; Ju, Zhenlin; Katzman, Sol; Kim, Hoon; Knijnenburg, Theo; Kreisberg, Richard Bailey; Lawrence, Michael S; Lee, William; Leinonen, Kalle; Lin, Pei; Ling, Shiyun; Liu, Wenbin; Liu, Yingchun; Liu, Yuexin; Lu, Yiling; Mills, Gordon; Ng, Sam; Noble, Michael S; Paull, Evan; Rao, Arvind; Reynolds, Sheila; Saksena, Gordon; Sanborn, Zack; Sander, Chris; Schultz, Nikolaus; Senbabaoglu, Yasin; Shen, Ronglai; Shmulevich, Ilya; Sinha, Rileen; Stuart, Josh; Sumer, S Onur; Sun, Yichao; Tasman, Natalie; Taylor, Barry S; Voet, Doug; Weinhold, Nils; Weinstein, John N; Yang, Da; Yoshihara, Kosuke; Zheng, Siyuan; Zhang, Wei; Zou, Lihua; Abel, Ty; Sadeghi, Sara; Cohen, Mark L; Eschbacher, Jenny; Hattab, Eyas M; Raghunathan, Aditya; Schniederjan, Matthew J; Aziz, Dina; Barnett, Gene; Barrett, Wendi; Bigner, Darell D; Boice, Lori; Brewer, Cathy; Calatozzolo, Chiara; Campos, Benito; Carlotti, Carlos Gilberto; Chan, Timothy A; Cuppini, Lucia; Curley, Erin; Cuzzubbo, Stefania; Devine, Karen; DiMeco, Francesco; Duell, Rebecca; Elder, J Bradley; Fehrenbach, Ashley; Finocchiaro, Gaetano; Friedman, William; Fulop, Jordonna; Gardner, Johanna; Hermes, Beth; Herold-Mende, Christel; Jungk, Christine; Kendler, Ady; Lehman, Norman L; Lipp, Eric; Liu, Ouida; Mandt, Randy; McGraw, Mary; Mclendon, Roger; McPherson, Christopher; Neder, Luciano; Nguyen, Phuong; Noss, Ardene; Nunziata, Raffaele; Ostrom, Quinn T; Palmer, Cheryl; Perin, Alessandro; Pollo, Bianca; Potapov, Alexander; Potapova, Olga; Rathmell, W Kimryn; Rotin, Daniil; Scarpace, Lisa; Schilero, Cathy; Senecal, Kelly; Shimmel, Kristen; Shurkhay, Vsevolod; Sifri, Suzanne; Singh, Rosy; Sloan, Andrew E; Smolenski, Kathy; Staugaitis, Susan M; Steele, Ruth; Thorne, Leigh; Tirapelli, Daniela P C; Unterberg, Andreas; Vallurupalli, Mahitha; Wang, Yun; Warnick, Ronald; Williams, Felicia; Wolinsky, Yingli; Bell, Sue; Rosenberg, Mara; Stewart, Chip; Huang, Franklin; Grimsby, Jonna L; Radenbaugh, Amie J; Zhang, Jianan

2015-06-25

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Mobile phone use and glioma risk: A systematic review and meta-analysis

PubMed Central

Tang, JianQin; Huang, Qian; Feng, ShouXin; Jiang, AiJun; Xu, XiFeng; Jiang, Guan

2017-01-01

Objective Many studies have previously investigated the potential association between mobile phone use and the risk of glioma. However, results from these individual studies are inconclusive and controversial. The objective of our study was to investigate the potential association between mobile phone use and subsequent glioma risk using meta-analysis. Methods We performed a systematic search of the Science Citation Index Embase and PubMed databases for studies reporting relevant data on mobile phone use and glioma in 1980–2016. The data were extracted and measured in terms of the odds ratio (OR) and 95% confidence interval (CI) using the random effects model. Subgroup analyses were also carried out. This meta-analysis eventually included 11 studies comprising a total 6028 cases and 11488 controls. Results There was a significant positive association between long-term mobile phone use (minimum, 10 years) and glioma (OR = 1.44, 95% CI = 1.08–1.91). And there was a significant positive association between long-term ipsilateral mobile phone use and the risk of glioma (OR = 1.46, 95% CI = 1.12–1.92). Long-term mobile phone use was associated with 2.22 times greater odds of low-grade glioma occurrence (OR = 2.22, 95% CI = 1.69–2.92). Mobile phone use of any duration was not associated with the odds of high-grade glioma (OR = 0.81, 95% CI = 0.72–0.92). Contralateral mobile phone use was not associated with glioma regardless of the duration of use. Similarly, this association was not observed when the analysis was limited to high-grade glioma. Conclusions Our results suggest that long-term mobile phone use may be associated with an increased risk of glioma. There was also an association between mobile phone use and low-grade glioma in the regular use or long-term use subgroups. However, current evidence is of poor quality and limited quantity. It is therefore necessary to conduct large sample, high quality research or better characterization of any potential association between long-term ipsilateral mobile phone use and glioma risk. PMID:28472042

RTEL1 tagging SNPs and haplotypes were associated with glioma development.

PubMed

Li, Gang; Jin, Tianbo; Liang, Hongjuan; Zhang, Zhiguo; He, Shiming; Tu, Yanyang; Yang, Haixia; Geng, Tingting; Cui, Guangbin; Chen, Chao; Gao, Guodong

2013-05-17

As glioma ranks as the first most prevalent solid tumors in primary central nervous system, certain single-nucleotide polymorphisms (SNPs) may be related to increased glioma risk, and have implications in carcinogenesis. The present case-control study was carried out to elucidate how common variants contribute to glioma susceptibility. Ten candidate tagging SNPs (tSNPs) were selected from seven genes whose polymorphisms have been proven by classical literatures and reliable databases to be tended to relate with gliomas, and with the minor allele frequency (MAF)>5% in the HapMap Asian population. The selected tSNPs were genotyped in 629 glioma patients and 645 controls from a Han Chinese population using the multiplexed SNP MassEXTEND assay calibrated. Two significant tSNPs in RTEL1 gene were observed to be associated with glioma risk (rs6010620, P=0.0016, OR: 1.32, 95% CI: 1.11-1.56; rs2297440, P=0.001, OR: 1.33, 95% CI: 1.12-1.58) by χ2 test. It was identified the genotype "GG" of rs6010620 acted as the protective genotype for glioma (OR, 0.46; 95% CI, 0.31-0.7; P=0.0002), while the genotype "CC" of rs2297440 as the protective genotype in glioma (OR, 0.47; 95% CI, 0.31-0.71; P=0.0003). Furthermore, haplotype "GCT" in RTEL1 gene was found to be associated with risk of glioma (OR, 0.7; 95% CI, 0.57-0.86; Fisher's P=0.0005; Pearson's P=0.0005), and haplotype "ATT" was detected to be associated with risk of glioma (OR, 1.32; 95% CI, 1.12-1.57; Fisher's P=0.0013; Pearson's P=0.0013). Two single variants, the genotypes of "GG" of rs6010620 and "CC" of rs2297440 (rs6010620 and rs2297440) in the RTEL1 gene, together with two haplotypes of GCT and ATT, were identified to be associated with glioma development. And it might be used to evaluate the glioma development risks to screen the above RTEL1 tagging SNPs and haplotypes. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1993021136961998.

German flooding of the Pontine Marshes in World War II.

PubMed

Geissler, Erhard; Guillemin, Jeanne

2010-03-01

The German army's 1943 flooding of the Pontine Marshes south of Rome, which later caused a sharp rise in malaria cases among Italian civilians, has recently been described by historian Frank Snowden as a unique instance of biological warfare and bioterrorism in the European theater of war and, consequently, as a violation of the 1925 Geneva Protocol prohibiting chemical and biological warfare. We argue that archival documents fail to support this allegation, on several counts. As a matter of historical record, Hitler prohibited German biological weapons (BW) development and consistently adhered to the Geneva Protocol. Rather than biological warfare against civilians, the Wehrmacht used flooding, land mines, and the destruction of vital infrastructure to obstruct the Allied advance. To protect its own troops in the area, the German army sought to contain the increased mosquito breeding likely to be caused by the flooding. Italians returning to the Pontine Marshes after the German retreat in 1944 suffered malaria as a result of environmental destruction, which was banned by the 1899 and 1907 Hague Conventions and by subsequent treaties. In contrast, a state's violation of the Geneva Protocol, whether past or present, involves the use of germ weapons and, by inference, a state-level capability. Any allegation of such a serious violation demands credible evidence that meets high scientific and legal standards of proof.

Advanced and amplified BOLD fluctuations in high-grade gliomas.

PubMed

Gupta, Lalit; Gupta, Rakesh K; Postma, Alida A; Sahoo, Prativa; Gupta, Pradeep K; Patir, Rana; Ahlawat, Sunita; Saha, Indrajit; Backes, Walter H

2018-06-01

Glioma grade along with patient's age and general health are used for treatment planning and prognosis. To characterize and quantify the spontaneous blood oxygen level-dependent (BOLD) fluctuations in gliomas using measures based on T2*-weighted signal time-series and to distinguish between high- and low-grade gliomas. Retrospective. Twenty-one patients with high-grade and 13 patients with low-grade gliomas confirmed on histology were investigated. Dynamic T2*-weighted (multislice single-shot echo-planar-imaging) magnetic resonance imaging (MRI) was performed on a 3T system with an 8-element receive-only head coil to measure the BOLD fluctuations. In addition, a dynamic T 1 -weighted (3D fast field echo) dynamic contrast-enhanced (DCE) perfusion scan was performed. Three BOLD measures were determined: the temporal shift (TS), amplitude of low frequency fluctuations (ALFF), and regional homogeneity (ReHo). DCE perfusion-based cerebral blood volume (CBV) and time-to-peak (TTP) maps were concurrently evaluated for comparison. An analysis-of-variance test was first used. When the test appeared significant, post-hoc analysis was performed using analysis-of-covariance with age as covariate. Logistic regression and receiver-operator characteristic curve analysis were also performed. TS was significantly advanced in high-grade gliomas compared to the contralateral cortex (P = 0.01) and low-grade gliomas (P = 0.009). In high-grade gliomas, ALFF and CBV were significantly higher than the contralateral cortex (P = 0.041 and P = 0.008, respectively) and low-grade gliomas (P = 0.036 and P = 0.01, respectively). ReHo and TTP did not show significant differences between high- and low-grade gliomas (P = 0.46 and P = 0.42, respectively). The area-under-curve was above 0.7 only for the TS, ALFF, and CBV measures. Advanced and amplified hemodynamic fluctuations manifest in high-grade gliomas, but not in low-grade gliomas, and can be assessed using BOLD measures. Preliminary results showed that quantification of spontaneous fluctuations has potential for hemodynamic characterization of gliomas and distinguishing between high- and low-grade gliomas. 4 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:1616-1625. © 2017 International Society for Magnetic Resonance in Medicine.

Setting the Stage for Personalized Treatment of Glioma | Center for Cancer Research

Cancer.gov

Gliomas, the most common type of primary brain tumors in adults, arise from different types of glial cells, which support and protect the neurons of the central nervous system. How a patient’s glioma is treated depends in part on the type of glial cell from which the tumor developed. Classification of gliomas has traditionally been done by microscopic analysis of tumor sections. This process is subjective and prone to inconsistencies, which may explain in part the wide-ranging and often suboptimal responses of gliomas to treatment.  

Focal brainstem gliomas

PubMed Central

Sabbagh, Abdulrahman J.; Alaqeel, Ahmed M.

2015-01-01

Improved neuronavigation guidance as well as intraoperative imaging and neurophysiologic monitoring technologies have enhanced the ability of neurosurgeons to resect focal brainstem gliomas. In contrast, diffuse brainstem gliomas are considered to be inoperable lesions. This article is a continuation of an article that discussed brainstem glioma diagnostics, imaging, and classification. Here, we address open surgical treatment of and approaches to focal, dorsally exophytic, and cervicomedullary brainstem gliomas. Intraoperative neuronavigation, intraoperative neurophysiologic monitoring, as well as intraoperative imaging are discussed as adjunctive measures to help render these procedures safer, more acute, and closer to achieving surgical goals. PMID:25864061

The biology and mathematical modelling of glioma invasion: a review

PubMed Central

Talkenberger, K.; Seifert, M.; Klink, B.; Hawkins-Daarud, A.; Swanson, K. R.; Hatzikirou, H.

2017-01-01

Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion. PMID:29118112

Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside

NASA Astrophysics Data System (ADS)

Liu, Heng; Zhang, Jun; Chen, Xiao; Du, Xue-Song; Zhang, Jin-Long; Liu, Gang; Zhang, Wei-Guo

2016-04-01

Gliomas are the most common primary brain tumors and have a very dismal prognosis. However, recent advancements in nanomedicine and nanotechnology provide opportunities for personalized treatment regimens to improve the poor prognosis of patients suffering from glioma. This comprehensive review starts with an outline of the current status facing glioma. It then provides an overview of the state-of-the-art applications of iron oxide nanoparticles (IONPs) to glioma diagnostics and therapeutics, including MR contrast enhancement, drug delivery, cell labeling and tracking, magnetic hyperthermia treatment and magnetic particle imaging. It also addresses current challenges associated with the biological barriers and IONP design with an emphasis on recent advances and innovative approaches for glioma targeting strategies. Opportunities for future development are highlighted.

Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside.

PubMed

Liu, Heng; Zhang, Jun; Chen, Xiao; Du, Xue-Song; Zhang, Jin-Long; Liu, Gang; Zhang, Wei-Guo

2016-04-21

Gliomas are the most common primary brain tumors and have a very dismal prognosis. However, recent advancements in nanomedicine and nanotechnology provide opportunities for personalized treatment regimens to improve the poor prognosis of patients suffering from glioma. This comprehensive review starts with an outline of the current status facing glioma. It then provides an overview of the state-of-the-art applications of iron oxide nanoparticles (IONPs) to glioma diagnostics and therapeutics, including MR contrast enhancement, drug delivery, cell labeling and tracking, magnetic hyperthermia treatment and magnetic particle imaging. It also addresses current challenges associated with the biological barriers and IONP design with an emphasis on recent advances and innovative approaches for glioma targeting strategies. Opportunities for future development are highlighted.

Extra-axial medulloblastoma in cerebello-pontine angle: A report of a rare case with literature review.

PubMed

Bahrami, Eshagh; Bakhti, Sahar; Fereshtehnejad, Seyed-Mohammad; Parvaresh, Mansour; Khani, Mohammad Reza

2014-01-01

Medulloblastoma is quite uncommon in the adult population and even rarer in extra-axial site in cerebello-pontine (CP) angle. In this report, a 23-year-old male patient with a two month history of deafness, nausea, vomiting and ataxia is presented. Clinical and radiological findings demonstrated a heterogeneously enhanced extra-axial lesion in the right CP angle. Total excision was performed and the histopathological features of medulloblastoma were confirmed. After surgery, the patient had no neurological deficit and the audiometric findings were improved. In addition, he underwent adjuant radiotherapy and no sign of metastatic mass was observed in follow-up spinal cord MRI. Although extremely rare, medulloblastoma must be considered in the differential diagnosis of extra-axial CP angle lesions.

Extra-axial medulloblastoma in cerebello-pontine angle: A report of a rare case with literature review

PubMed Central

Bahrami, Eshagh; Bakhti, Sahar; Fereshtehnejad, Seyed-Mohammad; Parvaresh, Mansour; Khani, Mohammad Reza

2014-01-01

Medulloblastoma is quite uncommon in the adult population and even rarer in extra-axial site in cerebello-pontine (CP) angle. In this report, a 23-year-old male patient with a two month history of deafness, nausea, vomiting and ataxia is presented. Clinical and radiological findings demonstrated a heterogeneously enhanced extra-axial lesion in the right CP angle. Total excision was performed and the histopathological features of medulloblastoma were confirmed. After surgery, the patient had no neurological deficit and the audiometric findings were improved. In addition, he underwent adjuant radiotherapy and no sign of metastatic mass was observed in follow-up spinal cord MRI. Although extremely rare, medulloblastoma must be considered in the differential diagnosis of extra-axial CP angle lesions. PMID:25405123

Contrasting expressions of aggressive behavior released by lesions of the central nucleus of the amygdala during wakefulness and rapid eye movement sleep without atonia in cats.

PubMed

Zagrodzka, J; Hedberg, C E; Mann, G L; Morrison, A R

1998-06-01

Whether damage to the central nucleus of the amygdala (Ace) contributes to the predatorylike attack sometimes observed in rapid eye movement sleep without atonia (REM-A), created in cats by bilateral pontine lesions, was examined. Such lesions eliminate REM sleep skeletal muscle atonia and release elaborate behavior. Unilateral damage to the Ace alone increased affective defensive aggressive behavior toward humans and conspecifics without altering predatory behavior in wakefulness. Pontine lesions added at loci normally not leading to aggression induced predatorylike attacks in REM-A as well as the waking affective defense. Alterations of autonomic activity, the absence of relevant environmental stimuli in REM-A, or both may explain the state-related differences.

TCGA_LowerGradeGliomas

Cancer.gov

TCGA researchers analyzed nearly 300 cases of diffuse low- and intermediate-grade gliomas, which together comprise lower-grade gliomas. LGGs occur mainly in adults and include astrocytomas, oligodendrogliomas and oligoastrocytomas.

Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade.

PubMed

Dejaegher, Joost; Verschuere, Tina; Vercalsteren, Ellen; Boon, Louis; Cremer, Jonathan; Sciot, Raf; Van Gool, Stefaan W; De Vleeschouwer, Steven

2017-11-01

Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas. © 2017 UICC.

Long non-coding RNA ENST00462717 suppresses the proliferation, survival, and migration by inhibiting MDM2/MAPK pathway in glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Aiqin; Meng, Mingzhu; Zhao, Xiuhe

Gliomas are the most common and aggressive primary malignant tumor in the central nervous system, and requires new biomarkers and therapeutic methods. Long noncoding RNAs (lncRNAs) are important factors in numerous human diseases, including cancer. But studies on lncRNAs and gliomas are limited. In this study, we investigated the expression patterns of lncRNAs in 3 pairs of glioma samples and adjacent non-tumor tissues via microarray and selected the most down-regulated lnc00462717 to further verify its roles in glioma. We observed that decreased lnc00462717 expression was associated with the malignant status in glioma. In vitro experiment demonstrated that lnc00462717 overexpression suppressed gliomamore » cell proliferation, survival and migration while knockdown of lnc00462717 had an opposite result. Moreover, we identified MDM2 as a direct target of lnc00462717 and lnc00462717 played a role by partially regulating the MDM2/MAPK pathway. In conclusion, lnc00462717 may function in suppressing glioma cell proliferation, survival, migration and may potentially serve as a novel biomarker and therapeutic target for glioma. - Highlights: • Using microarray to investigate the expression patterns of lncRNAs in glioma. • Selecting the most down-regulated lnc00462717 via microarray to verify its roles. • Identifying MDM2 as a direct target of lnc00462717. • The mechanism of lnc00462717 regulating the MDM2/MAPK pathway. • lnc00462717 serve as a novel biomarker and therapeutic target for treating glioma.« less

Potential of MR spectroscopy for assessment of glioma grading.

PubMed

Bulik, Martin; Jancalek, Radim; Vanicek, Jiri; Skoch, Antonin; Mechl, Marek

2013-02-01

Magnetic resonance spectroscopy (MRS) is an imaging diagnostic method based that allows non-invasive measurement of metabolites in tissues. There are a number of metabolites that can be identified by standard brain proton MRS but only a few of them has a clinical significance in diagnosis of gliomas including N-acetylaspartate, choline, creatine, myo-inositol, lactate, and lipids. In this review, we describe potential of MRS for grading of gliomas. Low-grade gliomas are generally characterized by a relatively high concentration of N-acetylaspartate, low level of choline and absence of lactate and lipids. The increase in creatine concentration indicates low-grade gliomas with earlier progression and malignant transformation. Progression in grade of a glioma is reflected in the progressive decrease in the N-acetylaspartate and myo-inositol levels on the one hand and elevation in choline level up to grade III on the other. Malignant transformation of the glial tumors is also accompanied by the presence of lactate and lipids in MR spectra of grade III but mainly grade IV gliomas. It follows that MRS is a helpful method for detection of glioma regions with aggressive growth or upgrading due to favorable correlation of the choline and N-acetylaspartate levels with histopathological proliferation index Ki-67. Thus, magnetic resonance spectroscopy is also a suitable method for the targeting of brain biopsies. Gliomas of each grade have some specific MRS features that can be used for improvement of the diagnostic value of conventional magnetic resonance imaging in non-invasive assessment of glioma grade. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Histogram analysis of diffusion kurtosis imaging derived maps may distinguish between low and high grade gliomas before surgery.

PubMed

Qi, Xi-Xun; Shi, Da-Fa; Ren, Si-Xie; Zhang, Su-Ya; Li, Long; Li, Qing-Chang; Guan, Li-Ming

2018-04-01

To investigate the value of histogram analysis of diffusion kurtosis imaging (DKI) maps in the evaluation of glioma grading. A total of 39 glioma patients who underwent preoperative magnetic resonance imaging (MRI) were classified into low-grade (13 cases) and high-grade (26 cases) glioma groups. Parametric DKI maps were derived, and histogram metrics between low- and high-grade gliomas were analysed. The optimum diagnostic thresholds of the parameters, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were achieved using a receiver operating characteristic (ROC). Significant differences were observed not only in 12 metrics of histogram DKI parameters (P<0.05), but also in mean diffusivity (MD) and mean kurtosis (MK) values, including age as a covariate (F=19.127, P<0.001 and F=20.894, P<0.001, respectively), between low- and high-grade gliomas. Mean MK was the best independent predictor of differentiating glioma grades (B=18.934, 22.237 adjusted for age, P<0.05). The partial correlation coefficient between fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA) was 0.675 (P<0.001). The AUC of the mean MK, sensitivity, and specificity were 0.925, 88.5% and 84.6%, respectively. DKI parameters can effectively distinguish between low- and high-grade gliomas. Mean MK is the best independent predictor of differentiating glioma grades. • DKI is a new and important method. • DKI can provide additional information on microstructural architecture. • Histogram analysis of DKI may be more effective in glioma grading.

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features

PubMed Central

Hu, Yu-Chuan; Li, Gang; Yang, Yang; Han, Yu; Sun, Ying-Zhi; Liu, Zhi-Cheng; Tian, Qiang; Han, Zi-Yang; Liu, Le-De; Hu, Bin-Quan; Qiu, Zi-Yu; Wang, Wen; Cui, Guang-Bin

2017-01-01

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization. PMID:28599282

Zn{sup 2+} induces apoptosis in human highly metastatic SHG-44 glioma cells, through inhibiting activity of the voltage-gated proton channel Hv1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yifan; Zhang, Shangrong; Li, Shu Jie, E-mail: shujieli@nankai.edu.cn

Highlights: •Hv1 is expressed in highly metastatic glioma cell. •Zn{sup 2+} ions induces apoptosis in highly metastatic glioma cells. •Zn{sup 2+} ions markedly inhibit proton secretion. •Zn{sup 2+} ions reduce the gelatinase activity. •Inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth. -- Abstract: In contrast to the voltage-gated K{sup +} channels, the voltage-gated proton channel Hv1 contains a voltage-sensor domain but lacks a pore domain. Here, we showed that Hv1 is expressed in the highly metastatic glioma cell SHG-44, but lowly in the poorly metastatic glioma cell U-251. Inhibition of Hv1 activity by 140more » μM zinc chloride induces apoptosis in the human highly metastatic glioma cells. Zn{sup 2+} ions markedly inhibit proton secretion, and reduce the gelatinase activity in the highly metastatic glioma cells. In vivo, the glioma tumor sizes of the implantation of the SHG-44 xenografts in nude mice that were injected zinc chloride solution, were dramatically smaller than that in the controlled groups. The results demonstrated that the inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity. Our results suggest that Zn{sup 2+} ions may be used as a potential anti-glioma drug for glioma therapy.« less

Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis.

PubMed

Laffaire, Julien; Everhard, Sibille; Idbaih, Ahmed; Crinière, Emmanuelle; Marie, Yannick; de Reyniès, Aurelien; Schiappa, Renaud; Mokhtari, Karima; Hoang-Xuan, Khê; Sanson, Marc; Delattre, Jean-Yves; Thillet, Joëlle; Ducray, François

2011-01-01

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis.

Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis

PubMed Central

Laffaire, Julien; Everhard, Sibille; Idbaih, Ahmed; Crinière, Emmanuelle; Marie, Yannick; de Reyniès, Aurelien; Schiappa, Renaud; Mokhtari, Karima; Hoang-Xuan, Khê; Sanson, Marc; Delattre, Jean-Yves; Thillet, Joëlle; Ducray, François

2011-01-01

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis. PMID:20926426

Meta-analysis of diffusion metrics for the prediction of tumor grade in gliomas.

PubMed

Miloushev, V Z; Chow, D S; Filippi, C G

2015-02-01

Diffusion tensor metrics are potential in vivo quantitative neuroimaging biomarkers for the characterization of brain tumor subtype. This meta-analysis analyzes the ability of mean diffusivity and fractional anisotropy to distinguish low-grade from high-grade gliomas in the identifiable tumor core and the region of peripheral edema. A meta-analysis of articles with mean diffusivity and fractional anisotropy data for World Health Organization low-grade (I, II) and high-grade (III, IV) gliomas, between 2000 and 2013, was performed. Pooled data were analyzed by using the odds ratio and mean difference. Receiver operating characteristic analysis was performed for patient-level data. The minimum mean diffusivity of high-grade gliomas was decreased compared with low-grade gliomas. High-grade gliomas had decreased average mean diffusivity values compared with low-grade gliomas in the tumor core and increased average mean diffusivity values in the peripheral region. High-grade gliomas had increased FA values compared with low-grade gliomas in the tumor core, decreased values in the peripheral region, and a decreased fractional anisotropy difference between the tumor core and peripheral region. The minimum mean diffusivity differs significantly with respect to the World Health Organization grade of gliomas. Statistically significant effects of tumor grade on average mean diffusivity and fractional anisotropy were observed, supporting the concept that high-grade tumors are more destructive and infiltrative than low-grade tumors. Considerable heterogeneity within the literature may be due to systematic factors in addition to underlying lesion heterogeneity. © 2015 by American Journal of Neuroradiology.

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features.

PubMed

Zhang, Xin; Yan, Lin-Feng; Hu, Yu-Chuan; Li, Gang; Yang, Yang; Han, Yu; Sun, Ying-Zhi; Liu, Zhi-Cheng; Tian, Qiang; Han, Zi-Yang; Liu, Le-De; Hu, Bin-Quan; Qiu, Zi-Yu; Wang, Wen; Cui, Guang-Bin

2017-07-18

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization.

Monocyte-derived cells of the brain and malignant gliomas: the double face of Janus.

PubMed

Kushchayev, Sergiy V; Kushchayeva, Yevgeniya S; Wiener, Philip C; Scheck, Adrienne C; Badie, Behnam; Preul, Mark C

2014-12-01

Monocyte-derived cells of the brain (MDCB) are a diverse group of functional immune cells that are also highly abundant in gliomas. There is growing evidence that MDCB play essential roles in the pathogenesis of gliomas. The aim of this review was to collate and systematize contemporary knowledge about these cells as they relate to glioma progression and antiglioblastoma therapeutic modalities with a view toward improved effectiveness of therapy. We reviewed relevant studies to construct a summary of different MDCB subpopulations in steady state and in malignant gliomas and discuss their role in the development of malignant gliomas and potential future therapies. Current studies suggest that MDCB subsets display different phenotypes and differentiation potentials depending on their milieu in the brain and exposure to tumoral influences. MDCB possess specific and unique functions, including those that are protumoral and those that are antitumoral. Elucidating the role of mononuclear-derived cells associated with gliomas is crucial in designing novel immunotherapy strategies. Much progress is needed to characterize markers to identify cell subsets and their specific regulatory roles. Investigation of MDCB can be clinically relevant. Specific MDCB populations potentially can be used for glioma therapy as a target or as cell vehicles that might deliver cytotoxic substances or processes to the glioma microenvironment. Copyright © 2014 Elsevier Inc. All rights reserved.

MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian, Yuan; Hao, Shaobo; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052

We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brainmore » tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin. - Highlights: • Let-7b and let-7i are downregulated in glioma cell lines. • IKBKE is a target gene of let-7b/i. • Let-7b/i inhibit the invasion and migration of glioma cells. • Let-7b/i upregulate E-cadherin by downregulating IKBKE.« less

GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis.

PubMed

Xu, Hui; Sun, Lili; Zheng, Yanwen; Yu, Shuye; Ou-Yang, Jia; Han, Hui; Dai, Xingliang; Yu, Xiaoting; Li, Ming; Lan, Qing

2018-01-01

Guanylate binding proteins (GBPs) are interferon-inducible large GTPases and play a crucial role in cell-autonomous immunity. However, the biology function of GBPs in cancer remains elusive. GBP3 is specifically expressed in adult brain. Here we show that GBP3 is highly elevated in human glioma tumors and glioma cell lines. Overexpression of GBP3 dramatically increased glioma cell proliferation whereas silencing GBP3 by RNA interference produced opposite effects. We further showed that GBP3 expression was able to induce sequestosome-1(SQSTM1, also named p62) expression and activate extracellular signal-regulated kinase (ERK1/2). The SQSTM1-ERK1/2 signaling cascade was essential for GBP3-promoted cell growth because depletion of SQSTM1 markedly reduced the phosphorylated ERK1/2 levels and GBP3-mediated cell growth, and inhibition of mitogen-activated protein kinase/ERK kinase abolished GBP3-induced glioma cell proliferation. Consistently, GBP3 overexpression significantly promoted glioma tumor growth in vivo and its expression was inversely correlated with the survival rate of glioma patients. Taken together, these results for the first time suggest that GBP3 contributes to the proliferation of glioma cells via regulating SQSTM1-ERK1/2 pathway, and GBP3 might represent as a new potential therapeutic target against glioma. Copyright © 2017 Elsevier Inc. All rights reserved.

Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ge, Yuqing; Zhou, Fengbiao; Chen, Hong

2010-07-09

Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was amore » positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.« less

Clinical Significance of SASH1 Expression in Glioma

PubMed Central

Yang, Liu; Zhang, Haitao; Yao, Qi; Yan, Yingying; Wu, Ronghua; Liu, Mei

2015-01-01

Objective. SAM and SH3 domain containing 1 (SASH1) is a recently discovered tumor suppressor gene. The role of SASH1 in glioma has not yet been described. We investigated SASH1 expression in glioma cases to determine its clinical significance on glioma pathogenesis and prognosis. Methods. We produced tissue microarrays using 121 patient-derived glioma samples and 30 patient-derived nontumor cerebral samples. Immunohistochemistry and Western blotting were used to evaluate SASH1 expression. We used Fisher's exact tests to determine relationships between SASH1 expression and clinicopathological characteristics; Cox regression analysis to evaluate the independency of different SASH1 expression; Kaplan-Meier analysis to determine any correlation of SASH1 expression with survival rate. Results. SASH1 expression was closely correlated with the WHO glioma grade. Of the 121 cases, 66.9% with low SASH1 expression were mostly grade III-IV cases, whereas 33.1% with high SASH1 expression were mostly grades I-II. Kaplan-Meier analysis revealed a significant positive correlation between SASH1 expression and postoperative survival. Conclusions. SASH1 was widely expressed in normal and low-grade glioma tissues. SASH1 expression strongly correlated with glioma grades, showing higher expression at a lower grade, which decreased significantly as grade increased. Furthermore, SASH1 expression was positively correlated with better postoperative survival in patients with glioma. PMID:26424902

Association of sequence variants on chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) with glioma susceptibility in a Chinese population.

PubMed

Chen, Hongyan; Chen, Yuanyuan; Zhao, Yao; Fan, Weiwei; Zhou, Keke; Liu, Yanhong; Zhou, Liangfu; Mao, Ying; Wei, Qingyi; Xu, Jianfeng; Lu, Daru

2011-04-15

Two genome-wide association studies of glioma in European populations identified 14 genetic variants strongly associated with risk of glioma, but it is unknown whether these variants are associated with glioma risk in Asian populations. The authors genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma (glioblastoma; n = 312), in a Chinese population (2004-2009). Overall, the authors identified 3 susceptibility loci for glioma risk at 20q13.33 (RTEL1 rs6010620 (P = 2.79 × 10(-6))), 11q23.3 (PHLDB1 rs498872 (P = 3.8 × 10(-6))), and 5p15.33 (TERT rs2736100 (P = 3.69 × 10(-4))) in this study population; these loci were also associated with glioblastoma risk (20q13.33: RTEL1 rs6010620 (P = 3.57 × 10(-7)); 11q23.3: PHLDB1 rs498872 (P = 7.24 × 10(-3)); 5p15.33: TERT rs2736100 and TERT rs2736098 (P = 1.21 × 10(-4) and P = 2.84 × 10(-4), respectively)). This study provides further evidence for 3 glioma susceptibility regions at 20q13.33, 11q23.3, and 5p15.33 in Chinese populations.

History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC).

PubMed

Amirian, E Susan; Scheurer, Michael E; Zhou, Renke; Wrensch, Margaret R; Armstrong, Georgina N; Lachance, Daniel; Olson, Sara H; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Jenkins, Robert B; Bernstein, Jonine L; Merrell, Ryan T; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Melin, Beatrice S; Bondy, Melissa L

2016-06-01

Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Comparative magnetic resonance imaging findings between gliomas and presumed cerebrovascular accidents in dogs.

PubMed

Cervera, Vicente; Mai, Wilfried; Vite, Charles H; Johnson, Victoria; Dayrell-Hart, Betsy; Seiler, Gabriela S

2011-01-01

Cerebrovascular accidents, or strokes, and gliomas are common intraaxial brain lesions in dogs. An accurate differentiation of these two lesions is necessary for prognosis and treatment decisions. The magnetic resonance (MR) imaging characteristics of 21 dogs with a presumed cerebrovascular accident and 17 with a glioma were compared. MR imaging findings were reviewed retrospectively by three observers unaware of the final diagnosis. Statistically significant differences between the appearance of gliomas and cerebrovascular accidents were identified based on lesion location, size, mass effect, perilesional edema, and appearance of the apparent diffusion coefficient map. Gliomas were predominantly located in the cerebrum (76%) compared with presumed cerebrovascular accidents that were located mainly in the cerebellum, thalamus, caudate nucleus, midbrain, and brainstem (76%). Gliomas were significantly larger compared with presumed cerebrovascular accidents and more commonly associated with mass effect and perilesional edema. Wedge-shaped lesions were seen only in 19% of presumed cerebrovascular accidents. Between the three observers, 10-47% of the presumed cerebrovascular accidents were misdiagnosed as gliomas, and 0-12% of the gliomas were misdiagnosed as cerebrovascular accidents. Diffusion weighted imaging increased the accuracy of the diagnosis for both lesions. Agreement between observers was moderate (kappa = 0.48, P < 0.01).

The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas.

PubMed

Ma, Huihui; Wang, Zhen; Hu, Lei; Zhang, Shangrong; Zhao, Chenggang; Yang, Haoran; Wang, Hongzhi; Fang, Zhiyou; Wu, Lijun; Chen, Xueran

2018-02-19

More than 40% of glioma patients have tumors that harbor PTEN (phosphatase and tensin homologue deleted on chromosome ten) mutations; this disease is associated with poor therapeutic resistance and outcome. Such mutations are linked to increased cell survival and growth, decreased apoptosis, and drug resistance; thus, new therapeutic strategies focusing on inhibiting glioma tumorigenesis and progression are urgently needed. Melatonin, an indolamine produced and secreted predominantly by the pineal gland, mediates a variety of physiological functions and possesses antioxidant and antitumor properties. Here, we analyzed the relationship between PTEN and the inhibitory effect of melatonin in primary human glioma cells and cultured glioma cell lines. The results showed that melatonin can inhibit glioma cell growth both in culture and in vivo. This inhibition was associated with PTEN levels, which significantly correlated with the expression level of MT1 in patients. In fact, c-fos-mediated MT1 was shown to be a key modulator of the effect of melatonin on gliomas that harbor wild type PTEN. Taken together, these data suggest that melatonin-MT1 receptor complexes represent a potential target for the treatment of glioma. Copyright © 2018 Elsevier Inc. All rights reserved.

Advances in the molecular genetics of gliomas - implications for classification and therapy.

PubMed

Reifenberger, Guido; Wirsching, Hans-Georg; Knobbe-Thomsen, Christiane B; Weller, Michael

2017-07-01

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

PAQR3 inhibits the proliferation, migration and invasion in human glioma cells.

PubMed

Tang, Shi-Lei; Gao, Yuan-Lin; Hu, Wen-Zhong

2017-08-01

Progestin and AdipoQ Receptor 3 (PAQR3), a member of the PAQR family, is down-regulated in several types of cancers and has been closely associated with tumor progression and development. However, little is known about the functions of PAQR3 in the tumorigenesis of human glioma. Therefore, in this report, we investigated the role of PAQR3 in human glioma. Our results showed that the expression of PAQR3 was significantly reduced in human glioma tissues and cell lines. PAQR3 overexpression inhibited the proliferation of glioma cells in vitro and attenuated tumor xenograft growth in vivo. In addition, PAQR3 overexpression suppressed the migration and invasion of glioma cells, as well as prevented the EMT process. Mechanistic studies demonstrated that PAQR3 overexpression significantly down-regulated the levels of phosphorylated PI3K and Akt in U251 cells. In conclusion, these results demonstrated that PAQR3 inhibited the proliferation, migration and invasion in glioma cells, at least in part, through the inactivation of PI3K/Akt signaling pathway. Therefore, PAQR3 may be a therapeutic target for the treatment of glioma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell.

PubMed

Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

2015-01-01

Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p < 0.05). The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated.

EMMPRIN Is an Independent Negative Prognostic Factor for Patients with Astrocytic Glioma

PubMed Central

Chen, Yu; Cai, Min; Dong, Hailong; Xiong, Lize

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). It has been proved to be associated with tumor invasion and metastasis in various human malignancies. In our study, the protein expression level of EMMPRIN in 306 cases of astrocytic glioma is investigated by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of EMMPRIN with clinicopathological characteristics and prognosis of patients. It was proved that EMMPRIN protein expression was increased in glioma compared with that in normal brain tissue. Moreover, EMMPRIN immunohistochemical staining was correlated with WHO grade and Karnofsky performance score for strong positive EMMPRIN staining is more frequently detected in glioma of advanced grade or low KPS score. It is also demonstrated that EMMPRIN could be an independent negative prognostic factor in glioma for patients with glioma of strong EMMPRIN staining tend to have high risk of death. These results proved that EMMPRIN is associated with prognosis of glioma, which may also suggest the potential role of EMMPRIN in glioma management. PMID:23516431

EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.

PubMed

Tian, Li; Zhang, Yang; Chen, Yu; Cai, Min; Dong, Hailong; Xiong, Lize

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). It has been proved to be associated with tumor invasion and metastasis in various human malignancies. In our study, the protein expression level of EMMPRIN in 306 cases of astrocytic glioma is investigated by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of EMMPRIN with clinicopathological characteristics and prognosis of patients. It was proved that EMMPRIN protein expression was increased in glioma compared with that in normal brain tissue. Moreover, EMMPRIN immunohistochemical staining was correlated with WHO grade and Karnofsky performance score for strong positive EMMPRIN staining is more frequently detected in glioma of advanced grade or low KPS score. It is also demonstrated that EMMPRIN could be an independent negative prognostic factor in glioma for patients with glioma of strong EMMPRIN staining tend to have high risk of death. These results proved that EMMPRIN is associated with prognosis of glioma, which may also suggest the potential role of EMMPRIN in glioma management.

High-grade glioma diffusive modeling using statistical tissue information and diffusion tensors extracted from atlases.

PubMed

Roniotis, Alexandros; Manikis, Georgios C; Sakkalis, Vangelis; Zervakis, Michalis E; Karatzanis, Ioannis; Marias, Kostas

2012-03-01

Glioma, especially glioblastoma, is a leading cause of brain cancer fatality involving highly invasive and neoplastic growth. Diffusive models of glioma growth use variations of the diffusion-reaction equation in order to simulate the invasive patterns of glioma cells by approximating the spatiotemporal change of glioma cell concentration. The most advanced diffusive models take into consideration the heterogeneous velocity of glioma in gray and white matter, by using two different discrete diffusion coefficients in these areas. Moreover, by using diffusion tensor imaging (DTI), they simulate the anisotropic migration of glioma cells, which is facilitated along white fibers, assuming diffusion tensors with different diffusion coefficients along each candidate direction of growth. Our study extends this concept by fully exploiting the proportions of white and gray matter extracted by normal brain atlases, rather than discretizing diffusion coefficients. Moreover, the proportions of white and gray matter, as well as the diffusion tensors, are extracted by the respective atlases; thus, no DTI processing is needed. Finally, we applied this novel glioma growth model on real data and the results indicate that prognostication rates can be improved. © 2012 IEEE

A choline derivate-modified nanoprobe for glioma diagnosis using MRI

NASA Astrophysics Data System (ADS)

Li, Jianfeng; Huang, Shixian; Shao, Kun; Liu, Yang; An, Sai; Kuang, Yuyang; Guo, Yubo; Ma, Haojun; Wang, Xuxia; Jiang, Chen

2013-04-01

Gadolinium (Gd) chelate contrast-enhanced magnetic resonance imaging (MRI) is a preferred method of glioma detection and preoperative localisation because it offers high spatial resolution and non-invasive deep tissue penetration. Gd-based contrast agents, such as Gd-diethyltriaminepentaacetic acid (DTPA-Gd, Magnevist), are widely used clinically for tumor diagnosis. However, the Gd-based MRI approach is limited for patients with glioma who have an uncompromised blood-brain barrier (BBB). Moreover, the rapid renal clearance and non-specificity of such contrast agents further hinders their prevalence. We present a choline derivate (CD)-modified nanoprobe with BBB permeability, glioma specificity and a long blood half-life. Specific accumulation of the nanoprobe in gliomas and subsequent MRI contrast enhancement are demonstrated in vitro in U87 MG cells and in vivo in a xenograft nude model. BBB and glioma dual targeting by this nanoprobe may facilitate precise detection of gliomas with an uncompromised BBB and may offer better preoperative and intraoperative tumor localization.

The role of myosin II in glioma invasion: A mathematical model

PubMed Central

Lee, Wanho; Lim, Sookkyung; Kim, Yangjin

2017-01-01

Gliomas are malignant tumors that are commonly observed in primary brain cancer. Glioma cells migrate through a dense network of normal cells in microenvironment and spread long distances within brain. In this paper we present a two-dimensional multiscale model in which a glioma cell is surrounded by normal cells and its migration is controlled by cell-mechanical components in the microenvironment via the regulation of myosin II in response to chemoattractants. Our simulation results show that the myosin II plays a key role in the deformation of the cell nucleus as the glioma cell passes through the narrow intercellular space smaller than its nuclear diameter. We also demonstrate that the coordination of biochemical and mechanical components within the cell enables a glioma cell to take the mode of amoeboid migration. This study sheds lights on the understanding of glioma infiltration through the narrow intercellular spaces and may provide a potential approach for the development of anti-invasion strategies via the injection of chemoattractants for localization. PMID:28166231

Serum immunoreactivity of cancer/testis antigen OY-TES-1 and its tissues expression in glioma.

PubMed

Li, Xisheng; Yan, Jun; Fan, Rong; Luo, Bin; Zhang, Qingmei; Lin, Yongda; Zhou, Sufang; Luo, Guorong; Xie, Xiaoxun; Xiao, Shaowen

2017-05-01

OY-TES-1 is a member of the cancer/testis antigen family that is expressed in healthy testis tissue and certain types of cancerous tissue. The present study aimed to analyze the expression pattern of OY-TES-1 and serum anti-OY-TES-1 antibody concentration in patients with glioma. OY-TES-1 mRNA was detected in 28/36 (78%) of glioma cases using conventional reverse transcription polymerase chain reaction (RT-PCR) analysis. RT-quantitative-PCR revealed that OY-TES-1 was expressed at a higher level in glioma tissues compared with normal adult tissues (with the exception of testis tissue). Anti-OY-TES-1 antibodies were present in the serum of 5/36 (14%) of patients with glioma, but absent in all the serum samples from 107 healthy donors. Immunohistochemical analysis demonstrated that OY-TES-1 protein was expressed in all glioma tissues from patients with anti-OY-TES-1 antibody seropositivity. These results suggest that OY-TES-1 is a novel candidate for glioma immunotherapy.

Genetic Alterations in Glioma

PubMed Central

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. PMID:24212656

Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

PubMed

Ceccarelli, Michele; Barthel, Floris P; Malta, Tathiane M; Sabedot, Thais S; Salama, Sofie R; Murray, Bradley A; Morozova, Olena; Newton, Yulia; Radenbaugh, Amie; Pagnotta, Stefano M; Anjum, Samreen; Wang, Jiguang; Manyam, Ganiraju; Zoppoli, Pietro; Ling, Shiyun; Rao, Arjun A; Grifford, Mia; Cherniack, Andrew D; Zhang, Hailei; Poisson, Laila; Carlotti, Carlos Gilberto; Tirapelli, Daniela Pretti da Cunha; Rao, Arvind; Mikkelsen, Tom; Lau, Ching C; Yung, W K Alfred; Rabadan, Raul; Huse, Jason; Brat, Daniel J; Lehman, Norman L; Barnholtz-Sloan, Jill S; Zheng, Siyuan; Hess, Kenneth; Rao, Ganesh; Meyerson, Matthew; Beroukhim, Rameen; Cooper, Lee; Akbani, Rehan; Wrensch, Margaret; Haussler, David; Aldape, Kenneth D; Laird, Peter W; Gutmann, David H; Noushmehr, Houtan; Iavarone, Antonio; Verhaak, Roel G W

2016-01-28

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapid Intraoperative Molecular Characterization of Glioma

PubMed Central

Shankar, Ganesh M.; Francis, Joshua M.; Rinne, Mikael L.; Ramkissoon, Shakti H.; Huang, Franklin W.; Venteicher, Andrew S.; Akama-Garren, Elliot H.; Kang, Yun Jee; Lelic, Nina; Kim, James C.; Brown, Loreal E.; Charbonneau, Sarah K.; Golby, Alexandra J.; Pedamallu, Chandra Sekhar; Hoang, Mai P.; Sullivan, Ryan J.; Cherniack, Andrew D.; Garraway, Levi A.; Stemmer-Rachamimov, Anat; Reardon, David A.; Wen, Patrick Y.; Brastianos, Priscilla K.; Curry, William T.; Barker, Fred G.; Hahn, William C.; Nahed, Brian V.; Ligon, Keith L.; Louis, David N.; Cahill, Daniel P.; Meyerson, Matthew

2016-01-01

IMPORTANCE Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations. PMID:26181761

Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.

PubMed

Li, Ningning; Zhang, Ying; Sidlauskas, Kastytis; Ellis, Matthew; Evans, Ian; Frankel, Paul; Lau, Joanne; El-Hassan, Tedani; Guglielmi, Loredana; Broni, Jessica; Richard-Loendt, Angela; Brandner, Sebastian

2018-05-03

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

A role for intracellular zinc in glioma alteration of neuronal chloride equilibrium

PubMed Central

Di Angelantonio, S; Murana, E; Cocco, S; Scala, F; Bertollini, C; Molinari, M G; Lauro, C; Bregestovski, P; Limatola, C; Ragozzino, D

2014-01-01

Glioma patients commonly suffer from epileptic seizures. However, the mechanisms of glioma-associated epilepsy are far to be completely understood. Using glioma-neurons co-cultures, we found that tumor cells are able to deeply influence neuronal chloride homeostasis, by depolarizing the reversal potential of γ-aminobutyric acid (GABA)-evoked currents (EGABA). EGABA depolarizing shift is due to zinc-dependent reduction of neuronal KCC2 activity and requires glutamate release from glioma cells. Consistently, intracellular zinc loading rapidly depolarizes EGABA in mouse hippocampal neurons, through the Src/Trk pathway and this effect is promptly reverted upon zinc chelation. This study provides a possible molecular mechanism linking glioma invasion to excitation/inhibition imbalance and epileptic seizures, through the zinc–mediated disruption of neuronal chloride homeostasis. PMID:25356870

Resonant Raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588 cm-1 mode

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhou, Lixin; Zhu, Ke; Liu, Yulong; Zhang, Lin; Boydston-White, Susie; Cheng, Gangge; Pu, Yang; Bidyut, Das; Alfano, Robert R.

2015-03-01

RR spectra of brain normal tissue, gliomas in low grade I and II, and malignant glioma tumors in grade III and IV were measured using a confocal micro Raman spectrometer. This report focus on the relative contents of tryptophan (W) in various grades of brain glioma tumors by the intrinsic molecular resonance Raman (RR) spectroscopy method using the 1588cm-1 of tryptophan mode by 532 nm excitation. The RR spectra of key fingerprints of tryptophan, with a main vibrational mode at 1588cm-1 (W8b), were observed. It was found that tryptophan contribution was accumulated in grade I to IV gliomas and the mode of 1588cm-1 in grade III and IV malignant gliomas were enhanced by resonance.

Glioma

MedlinePlus

... cells are called mixed gliomas. Tumors such as “optic nerve glioma” and “brain stem glioma” are named ... Oligodendroglioma: Click here to learn more about oligodendroglioma. Optic Glioma: These tumors may involve any part of ...

RTEL1 tagging SNPs and haplotypes were associated with glioma development

PubMed Central

2013-01-01

Abstract As glioma ranks as the first most prevalent solid tumors in primary central nervous system, certain single-nucleotide polymorphisms (SNPs) may be related to increased glioma risk, and have implications in carcinogenesis. The present case–control study was carried out to elucidate how common variants contribute to glioma susceptibility. Ten candidate tagging SNPs (tSNPs) were selected from seven genes whose polymorphisms have been proven by classical literatures and reliable databases to be tended to relate with gliomas, and with the minor allele frequency (MAF) > 5% in the HapMap Asian population. The selected tSNPs were genotyped in 629 glioma patients and 645 controls from a Han Chinese population using the multiplexed SNP MassEXTEND assay calibrated. Two significant tSNPs in RTEL1 gene were observed to be associated with glioma risk (rs6010620, P = 0.0016, OR: 1.32, 95% CI: 1.11-1.56; rs2297440, P = 0.001, OR: 1.33, 95% CI: 1.12-1.58) by χ2 test. It was identified the genotype “GG” of rs6010620 acted as the protective genotype for glioma (OR, 0.46; 95% CI, 0.31-0.7; P = 0.0002), while the genotype “CC” of rs2297440 as the protective genotype in glioma (OR, 0.47; 95% CI, 0.31-0.71; P = 0.0003). Furthermore, haplotype “GCT” in RTEL1 gene was found to be associated with risk of glioma (OR, 0.7; 95% CI, 0.57-0.86; Fisher’s P = 0.0005; Pearson’s P = 0.0005), and haplotype “ATT” was detected to be associated with risk of glioma (OR, 1.32; 95% CI, 1.12-1.57; Fisher’s P = 0.0013; Pearson’s P = 0.0013). Two single variants, the genotypes of “GG” of rs6010620 and “CC” of rs2297440 (rs6010620 and rs2297440) in the RTEL1 gene, together with two haplotypes of GCT and ATT, were identified to be associated with glioma development. And it might be used to evaluate the glioma development risks to screen the above RTEL1 tagging SNPs and haplotypes. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1993021136961998 PMID:23683922

Setting the Stage for Personalized Treatment of Glioma | Center for Cancer Research

Cancer.gov

Gliomas, the most common type of primary brain tumors in adults, arise from different types of glial cells, which support and protect the neurons of the central nervous system. How a patient’s glioma is treated depends in part on the type of glial cell from which the tumor developed. Classification of gliomas has traditionally been done by microscopic analysis of tumor

TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway.

PubMed

Zheng, Jian; Liu, Xiaobai; Xue, Yixue; Gong, Wei; Ma, Jun; Xi, Zhuo; Que, Zhongyou; Liu, Yunhui

2017-02-20

Circular RNAs are a subgroup of non-coding RNAs and generated by a mammalian genome. Herein, the expression and function of circular RNA circ-TTBK2 were investigated in human glioma cells. Fluorescence in situ hybridization and quantitative real-time PCR were conducted to profile the cell distribution and expression of circ-TTBK2 and microRNA-217 (miR-217) in glioma tissues and cells. Immunohistochemical and western blot were used to determine the expression of HNF1β and Derlin-1 in glioma tissues and cells. Stable knockdown of circ-TTBK2 or overexpression of miR-217 glioma cell lines (U87 and U251) were established to explore the function of circ-TTBK2 and miR-217 in glioma cells. Further, luciferase reports and RNA immunoprecipitation were used to investigate the correlation between circ-TTBK2 and miR-217. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate circ-TTBK2 and miR-217 function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between HNF1β and Derlin-1. We found that circ-TTBK2 was upregulated in glioma tissues and cell lines, while linear TTBK2 was not dysregulated in glioma tissues and cells. Enhanced expression of circ-TTBK2 promoted cell proliferation, migration, and invasion, while inhibited apoptosis. MiR-217 was downregulated in glioma tissues and cell lines. We also found that circ-TTBK2, but not linear TTBK2, acted as miR-217 sponge in a sequence-specific manner. In addition, upregulated circ-TTBK2 decreased miR-217 expression and there was a reciprocal negative feedback between them in an Argonaute2-dependent manner. Moreover, reintroduction of miR-217 significantly reversed circ-TTBK2-mediated promotion of glioma progression. HNF1β was a direct target of miR-217, and played oncogenic role in glioma cells. Remarkably, circ-TTBK2 knockdown combined with miR-217 overexpression led to tumor regression in vivo. These results demonstrated a novel role circ-TTBK2 in the glioma progression.

MR Imaging-derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas.

PubMed

Stadlbauer, Andreas; Zimmermann, Max; Kitzwögerer, Melitta; Oberndorfer, Stefan; Rössler, Karl; Dörfler, Arnd; Buchfelder, Michael; Heinz, Gertraud

2017-06-01

Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty-three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO 2 ]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO 2 was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO 2 showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time. © RSNA, 2016 Online supplemental material is available for this article.

[A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma].

PubMed

Tonoyan, A S; Pronin, I N; Pitshelauri, D I; Shishkina, L V; Fadeeva, L M; Pogosbekyan, E L; Zakharova, N E; Shults, E I; Khachanova, N V; Kornienko, V N; Potapov, A A

2015-01-01

The aim of the study was to assess the capabilities of diffusion kurtosis imaging (DKI) in diagnosis of the glioma proliferative activity and to evaluate a relationship between the glioma proliferative activity index and diffusion parameters of the contralateral normal appearing white matter (CNAWM). The study included 47 patients with newly diagnosed brain gliomas (23 low grade, 13 grade III, and 11 grade IV gliomas). We determined a relationship between absolute and normalized parameters of the diffusion tensor (mean (MD), axial (AD), and radial (RD) diffusivities; fractional (FA) and relative (RA) anisotropies) and diffusion kurtosis (mean (MK), axial (AK), and radial (RK) kurtosis; kurtosis anisotropy (KA)) and the proliferative activity index in the most malignant glioma parts (p<0.05). We also established a relationship between the tensor and kurtosis parameters of CNAWM and the glioma proliferative activity index (p<0.05). The correlation between all the absolute and normalized diffusion parameters and the glioma proliferative activity index, except absolute and normalized FA and RA values, was found to be statistically significant (p<0.05). Kurtosis (MK, AK, and RK) and anisotropy (KA, FA, RA) values increased, and diffusivity (MD, AD, RD) values decreased as the glioma proliferative activity index increased. A strong correlation between the proliferative activity index and absolute RK (r=0,71; p=0.000001) and normalized values of MK (r=0.8; p=0.000001), AK (r=0.71; p=0.000001), RK (r=0.81; p=0.000001), and RD (r=-0.71; p=0.000001) was found. A weak, but statistically significant correlation between the glioma proliferative activity index and diffusion values RK (r=-0.36; p=0.014), KA (r=-0.39; p=0.007), RD (r=0.35; p=0.017), FA (r=-0.42; p=0.003), and RA (r=-0.41; p=0.004) of CNAWM was found. DKI has good capabilities to detect immunohistochemical changes in gliomas. DKI demonstrated a high sensitivity in detection of microstructural changes in the contralateral normal appearing white matter in patients with brain gliomas.

MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

PubMed

Lee, Hae Kyung; Bier, Ariel; Cazacu, Simona; Finniss, Susan; Xiang, Cunli; Twito, Hodaya; Poisson, Laila M; Mikkelsen, Tom; Slavin, Shimon; Jacoby, Elad; Yalon, Michal; Toren, Amos; Rempel, Sandra A; Brodie, Chaya

2013-01-01

Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

Hyperplasia of Pericytes Is One of the Main Characteristics of Microvascular Architecture in Malignant Glioma

PubMed Central

Sun, Huiqin; Guo, Deyu; Su, Yongping; Yu, Dongmei; Wang, Qingliang; Wang, Tao; Zhou, Qing; Ran, Xinze; Zou, Zhongmin

2014-01-01

Objectives To investigate the role of pericytes in constructing the malformed microvessels (MVs) and participating microvascular architecture heterogeneity of glioma. Methods Forty human glioma tissue samples (WHO grade II-IV) were included in present study. Observation of blood vessel patterns, quantitative analysis of endothelial cells (ECs)- and pericyte-labeled MVs and comparison between malignant grades based on single- or double-immunohistochemical staining. The MV number density (MVND), microvascular pericyte number density (MPND), and microvascular pericyte area density (MPAD) were calculated. The expression of PDGFβ was also scored after immunostaining. Results In grade II glioma, most of tumor MVs were the thin-wall CD34+ vessels with near normal morphology. In addition to thin-wall CD34+ MVs, more thick-wall MVs were found in grade III glioma, which often showed α-SMA positive. Most of MVs in grade IV glioma were in the form of plexus, curled cell cords and glomeruloid microvascular proliferation while the α-SMA+ cells were the main components. The MVs usually showed disordered arrangement, loose connection and active cell proliferation as shown by Ki67 and α-SMA coexpression. With the increase of glioma grades, the α-SMA+ MVND, CD34+ MVND and MPND were significantly augmented although the increase of CD34+ MVND but not MPAD was statistically insignificant between grade III and IV. It was interesting that some vessel-like structures only consist of α-SMA+ cells, assuming the guiding role of pericytes in angiogenesis. The expression level of PDGFβ was upregulated and directly correlated with the MPND in different glioma grades. Conclusion Hyperplasia of pericytes was one of the significant characteristics of malignant glioma and locally proliferated pericytes were the main constituent of MVs in high grade glioma. The pathological characteristics of pericytes could be used as indexes of malignant grades of glioma. PMID:25478951

Local image variance of 7 Tesla SWI is a new technique for preoperative characterization of diffusely infiltrating gliomas: correlation with tumour grade and IDH1 mutational status.

PubMed

Grabner, Günther; Kiesel, Barbara; Wöhrer, Adelheid; Millesi, Matthias; Wurzer, Aygül; Göd, Sabine; Mallouhi, Ammar; Knosp, Engelbert; Marosi, Christine; Trattnig, Siegfried; Wolfsberger, Stefan; Preusser, Matthias; Widhalm, Georg

2017-04-01

To investigate the value of local image variance (LIV) as a new technique for quantification of hypointense microvascular susceptibility-weighted imaging (SWI) structures at 7 Tesla for preoperative glioma characterization. Adult patients with neuroradiologically suspected diffusely infiltrating gliomas were prospectively recruited and 7 Tesla SWI was performed in addition to standard imaging. After tumour segmentation, quantification of intratumoural SWI hypointensities was conducted by the SWI-LIV technique. Following surgery, the histopathological tumour grade and isocitrate dehydrogenase 1 (IDH1)-R132H mutational status was determined and SWI-LIV values were compared between low-grade gliomas (LGG) and high-grade gliomas (HGG), IDH1-R132H negative and positive tumours, as well as gliomas with significant and non-significant contrast-enhancement (CE) on MRI. In 30 patients, 9 LGG and 21 HGG were diagnosed. The calculation of SWI-LIV values was feasible in all tumours. Significantly higher mean SWI-LIV values were found in HGG compared to LGG (92.7 versus 30.8; p < 0.0001), IDH1-R132H negative compared to IDH1-R132H positive gliomas (109.9 versus 38.3; p < 0.0001) and tumours with significant CE compared to non-significant CE (120.1 versus 39.0; p < 0.0001). Our data indicate that 7 Tesla SWI-LIV might improve preoperative characterization of diffusely infiltrating gliomas and thus optimize patient management by quantification of hypointense microvascular structures. • 7 Tesla local image variance helps to quantify hypointense susceptibility-weighted imaging structures. • SWI-LIV is significantly increased in high-grade and IDH1-R132H negative gliomas. • SWI-LIV is a promising technique for improved preoperative glioma characterization. • Preoperative management of diffusely infiltrating gliomas will be optimized.

ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients.

PubMed

Pandith, Arshad A; Qasim, Iqbal; Zahoor, Wani; Shah, Parveen; Bhat, Abdul R

2018-01-10

ACE I/D and MTHFR C677T gene polymorphisms can be seen as candidate genes for glioma on the basis of their biological functions and their involvement in different cancers. The aim of this study was to analyze potential association and overall survival between MTHFR C677T and ACE I/D polymorphism in glioma patients in our population. We tested genotype distribution of 112 glioma patients against 141 cancer-free controls from the same region. Kaplan-Meier survival analysis was performed to evaluate overall survival of patients for both genes. No significant differences were found among MTHFR C677T wild type C and variant genotypes CT/TT with glioma patients. In ACE, the distribution of variant ID and DD was found to be significantly higher in glioma cases as compared to controls (p<0.0001). ACE DD genotypes were highly presented in glioma cases 26.8% versus 10.6% in controls (p<0.0001) and conferred 5-fold risk for predisposition in glioma cases. Per copy D allele frequency was found higher in cases than in controls (0.54 versus 0.25: p<0.0001). Interestingly we found a significant overall survival (with log rank p<0.01) in patients who presented with ACE DD genotypes had the least estimated overall survival of 13.4months in comparison to 21. 7 and 17.6months for ACE II and I/D genotypes respectively. We conclude ACE I/D polymorphism plays a vital role in predisposition of higher risk for glioma. We also suggest that ACE DD genotypes may act as an important predictive biomarker for overall survival of glioma patients. Copyright © 2017. Published by Elsevier B.V.

MiR-320 inhibits the growth of glioma cells through downregulating PBX3.

PubMed

Pan, Cuicui; Gao, Hua; Zheng, Ni; Gao, Qi; Si, Yuanquan; Zhao, Yueran

2017-09-21

MiR-320 is downregulated in multiple cancers, including glioma and acts as tumor suppressor through inhibiting tumor cells proliferation and inducing apoptosis. PBX3 (Pre-B cell leukemia homeobox 3), a putative target gene of miR-320, has been reported to be upregulated in various tumors and promote tumor cell growth through regulating MAKP/ERK pathway. This study aimed to verify whether miR-320 influences glioma cells growth through regulating PBX3. Twenty-four human glioma and paired adjacent nontumorous tissues were collected for determination of miR-320 and PBX3 expression using RT-qPCR and western blot assays. Luciferase reporter assay was performed to verify the interaction between miR-320 and its targeting sequence in the 3' UTR of PBX3 in glioma cells U87 and U251. Increased miR-320 level in U87 and U251 cells was achieved through miR-320 mimic transfection and the effect of which on glioma cells growth, proliferation, cell cycle, apoptosis and activation of Raf-1/MAPK pathway was determined using MTT, colony formation, flow cytometry and western blot assays. PBX3 knockdown was performed using shPBX3 and the influence on MAPK pathway activation was evaluated. MiR-320 downregulation and PBX3 upregulation was found in glioma tissues. Luciferase reporter assays identified miR-320 directly blinds to the 3' UTR of PBX3 in glioma cells. MiR-320 mimic transfection suppressed glioma cells proliferation, and induced cell cycle arrest and apoptosis. Both miR-320 overexpression and PBX3 knockdown inhibited Raf-1/MAPK activation. MiR-320 may suppress glioma cells growth and induced apoptosis through the PBX3/Raf-1/MAPK axis, and miR-320 oligonucleotides may be a potential cancer therapeutic for glioma.

Repression of the expression of PPP3CC by ZEB1 confers activation of NF-κB and contributes to invasion and growth in glioma cells.

PubMed

Wang, Hongquan; Zhao, Shuli; Chen, Bo; Fu, Chuhua; Dang, Yanwei; Fang, Peihai; Wang, Jun; Wang, Ning; Liu, Lijun

2018-02-01

Gliomas are highly malignant brain tumors. Aberrant activation of NF-κB plays a crucial role in tumor progression. ELISA assay was used to detect NF-κB activity in glimoas cells with different treatments. PPP3CC expression was evaluated by qRT-PCR and western blot assay. Kaplan-Meier analysis estimated the overall survival rates according to the protein level of PPP3CC. Transwell and MTS assay were performed to determine cell invasion and growth. Chromatin immunoprecipitation combined with luciferase reporter assays illustrated the transcriptional regulation of PPP3CC. We showed that PPP3CC decrease was responsible for constitutive activation of NF-κB in gliomas. Restored PPP3CC expression inhibited activation of NF-κB. PPP3CC was frequently decreased in gliomas and that repression of the expression of PPP3CC correlated glioma progression. The ectopic expression of PPP3CC inhibited the invasive potential of glioma cells, and inhibited glioma cells proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E-box-binding homeobox 1(ZEB1) was increased in gliomas and was negatively correlated with clinical outcomes of glioma patients. ZEB1 inversely correlated with the expression of PPP3CC. ZEB1 was also confirmed to physically bind to the PPP3CC promoter. ZEB1 knockdown resulted in an increase in the expression of PPP3CC and elevation of PPP3CC promoter activity in glioma cells. These findings indicated that the down-regulation of PPP3CC by ZEB1 resulted in activation of NF-κB is a critical oncogenic event in gliomas. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas

PubMed Central

2014-01-01

Background Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. Methods We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. Results FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients’ sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. Conclusions The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study. PMID:24946857

Association between adult height, genetic susceptibility and risk of glioma

PubMed Central

Kitahara, Cari M; Wang, Sophia S; Melin, Beatrice S; Wang, Zhaoming; Braganza, Melissa; Inskip, Peter D; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E; Buring, Julie E; Carreón, Tania; Feychting, Maria; Gapstur, Susan M; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Henriksson, Roger; Hsing, Ann W; Johansen, Christoffer; Linet, Martha S; McKean-Cowdin, Roberta; Michaud, Dominique S; Peters, Ulrike; Purdue, Mark P; Rothman, Nathaniel; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Stevens, Victoria L; Visvanathan, Kala; Waters, Martha A; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Hoover, Robert; Fraumeni, Joseph F; Chatterjee, Nilanjan; Yeager, Meredith; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2012-01-01

Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Results Among men, we found a positive association between height and glioma risk (≥190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. PMID:22933650

Association between adult height, genetic susceptibility and risk of glioma.

PubMed

Kitahara, Cari M; Wang, Sophia S; Melin, Beatrice S; Wang, Zhaoming; Braganza, Melissa; Inskip, Peter D; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E; Buring, Julie E; Carreón, Tania; Feychting, Maria; Gapstur, Susan M; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Henriksson, Roger; Hsing, Ann W; Johansen, Christoffer; Linet, Martha S; McKean-Cowdin, Roberta; Michaud, Dominique S; Peters, Ulrike; Purdue, Mark P; Rothman, Nathaniel; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Stevens, Victoria L; Visvanathan, Kala; Waters, Martha A; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Hoover, Robert; Fraumeni, Joseph F; Chatterjee, Nilanjan; Yeager, Meredith; Chanock, Stephen J; Hartge, Patricia; Rajaraman, Preetha

2012-08-01

Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Among men, we found a positive association between height and glioma risk (≥ 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (≥ 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.

14-3-3β exerts glioma-promoting effects and is associated with malignant progression and poor prognosis in patients with glioma.

PubMed

Liu, Liang; Liu, Zhixiong; Wang, Hao; Chen, Long; Ruan, Fuqiang; Zhang, Jihui; Hu, Yi; Luo, Hengshan; Wen, Shuai

2018-03-01

Glioma is a type of tumor that affects the central nervous system. It has been demonstrated that 14-3-3β, a protein that is mainly concentrated in the brain, serves an important role in tumor regulation. However, the mechanism of action of 14-3-3β that underlies the pathogenesis of glioma remains to be elucidated. In the present study, 14-3-3β was silenced by RNA interference in the human glioma cell line U373-MG. Following knockdown of 14-3-3β, the proliferation, colony formation, cell cycle progression, migration and invasion of U373-MG cells were significantly decreased (P<0.01), whereas cell apoptosis was increased (P<0.01). Furthermore, in a tumor xenograft experiment, silencing 14-3-3β significantly inhibited the in vivo tumor growth of U373-MG cells (P<0.01). The results demonstrated that 14-3-3β levels were significantly higher in human glioma tissues compared with normal brain tissues (P<0.01) and high 14-3-3β expression was significantly associated with advanced pathological grade (P<0.03) and low Karnofsky performance scale (P<0.003). Patients with glioma who had high 14-3-3β levels had a significantly shorter survival time compared with those with low expression of 14-3-3β (P=0.031), suggesting that 14-3-3β may be an effective predictor of the prognosis of patients with glioma. The results of the present study indicate that 14-3-3β serves an oncogenic role in glioma, suggesting that 14-3-3β may have potential as a promising therapeutic target for glioma.

Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas.

PubMed

Wang, Peng-Fei; Cai, Hong-Qing; Zhang, Chuan-Bao; Li, Yan-Michael; Liu, Xiang; Wan, Jing-Hai; Jiang, Tao; Li, Shou-Wei; Yan, Chang-Xiang

2018-05-15

Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling. Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures. PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8 + T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas. PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies.

Liposome-based glioma targeted drug delivery enabled by stable peptide ligands.

PubMed

Wei, Xiaoli; Gao, Jie; Zhan, Changyou; Xie, Cao; Chai, Zhilan; Ran, Danni; Ying, Man; Zheng, Ping; Lu, Weiyue

2015-11-28

The treatment of glioma is one of the most challenging tasks in clinic. As an intracranial tumor, glioma exhibits many distinctive characteristics from other tumors. In particular, various barriers including enzymatic barriers in the blood and brain capillary endothelial cells, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) rigorously prevent drug and drug delivery systems from reaching the tumor site. To tackle this dilemma, we developed a liposomal formulation to circumvent multiple-barriers by modifying the liposome surface with proteolytically stable peptides, (D)CDX and c(RGDyK). (D)CDX is a D-peptide ligand of nicotine acetylcholine receptors (nAChRs) on the BBB, and c(RGDyK) is a ligand of integrin highly expressed on the BBTB and glioma cells. Lysosomal compartments of brain capillary endothelial cells are implicated in the transcytosis of those liposomes. However, both peptide ligands displayed exceptional stability in lysosomal homogenate, ensuring that intact ligands could exert subsequent exocytosis from brain capillary endothelial cells and glioma targeting. In the cellular uptake studies, dually labeled liposomes could target both brain capillary endothelial cells and tumor cells, effectively traversing the BBB and BBTB monolayers, overcoming enzymatic barrier and targeting three-dimensional tumor spheroids. Its targeting ability to intracranial glioma was further verified in vivo by ex vivo imaging and histological studies. As a result, doxorubicin liposomes modified with both (D)CDX and c(RGDyK) presented better anti-glioma effect with prolonged median survival of nude mice bearing glioma than did unmodified liposomes and liposomes modified with individual peptide ligand. In conclusion, the liposome suggested in the present study could effectively overcome multi-barriers and accomplish glioma targeted drug delivery, validating its potential value in improving the therapeutic efficacy of doxorubicin for glioma. Copyright © 2015 Elsevier B.V. All rights reserved.

Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Xiaopeng; Du, Jie; Hua, Song

Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly,more » combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.« less

4'-Acetoamido-4-hydroxychalcone, a chalcone derivative, inhibits glioma growth and invasion through regulation of the tropomyosin 1 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ku, Bo Mi; Ryu, Hyung Won; Lee, Yeon Kyung

2010-11-19

Research highlights: {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) has anti-cancer property for glioma. {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) increased tropomyosin expreesion through activattion of PKA signaling. {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) inhibits glioma cell migration and invasion. {yields} In vivo administration of 4'-acetoamido-4-hydroxychalcone (AHC) reduced tumor growth. -- Abstract: Chalcones are precursors of flavonoids and have been shown to have anti-cancer activity. Here, we identify the synthetic chalcone derivative 4'-acetoamido-4-hydroxychalcone (AHC) as a potential therapeutic agent for the treatment of glioma. Treatment with AHC reduced glioma cell invasion, migration, and colony formation in a concentration-dependent manner. In addition, AHC inhibited vascular endothelial growth factor-induced migration, invasion, andmore » tube formation in HUVECs. To determine the mechanism underlying the inhibitory effect of AHC on glioma cell invasion and migration, we investigated the effect of AHC on the gene expression change and found that AHC affects actin dynamics in U87MG glioma cells. In actin cytoskeleton regulating system, AHC increased tropomyosin expression and stress fiber formation, probably through activation of PKA. Suppression of tropomyosin expression by siRNA or treatment with the PKA inhibitor H89 reduced the inhibitory effects of AHC on glioma cell invasion and migration. In vivo experiments also showed that AHC inhibited tumor growth in a xenograft mouse tumor model. Together, these data suggest that the synthetic chalcone derivative AHC has potent anti-cancer activity through inhibition of glioma proliferation, invasion, and angiogenesis and is therefore a potential chemotherapeutic candidate for the treatment of glioma.« less

Guanosine promotes cytotoxicity via adenosine receptors and induces apoptosis in temozolomide-treated A172 glioma cells.

PubMed

Oliveira, Karen A; Dal-Cim, Tharine A; Lopes, Flávia G; Nedel, Cláudia B; Tasca, Carla Inês

2017-09-01

Gliomas are a malignant tumor group whose patients have survival rates around 12 months. Among the treatments are the alkylating agents as temozolomide (TMZ), although gliomas have shown multiple resistance mechanisms for chemotherapy. Guanosine (GUO) is an endogenous nucleoside involved in extracellular signaling that presents neuroprotective effects and also shows the effect of inducing differentiation in cancer cells. The chemotherapy allied to adjuvant drugs are being suggested as a novel approach in gliomas treatment. In this way, this study evaluated whether GUO presented cytotoxic effects on human glioma cells as well as GUO effects in association with a classical chemotherapeutic compound, TMZ. Classical parameters of tumor aggressiveness, as alterations on cell viability, type of cell death, migration, and parameters of glutamatergic transmission, were evaluated. GUO (500 and 1000 μM) decreases the A172 glioma cell viability after 24, 48, or 72 h of treatment. TMZ alone or GUO plus TMZ also reduced glioma cell viability similarly. GUO combined with TMZ showed a potentiation effect of increasing apoptosis in A172 glioma cells, and a similar pattern was observed in reducing mitochondrial membrane potential. GUO per se did not elevate the acidic vesicular organelles occurrence, but TMZ or GUO plus TMZ increased this autophagy hallmark. GUO did not alter glutamate transport per se, but it prevented TMZ-induced glutamate release. GUO or TMZ did not alter glutamine synthetase activity. Pharmacological blockade of glutamate receptors did not change GUO effect on glioma viability. GUO cytotoxicity was partially prevented by adenosine receptor (A 1 R and A 2A R) ligands. These results point to a cytotoxic effect of GUO on A172 glioma cells and suggest an anticancer effect of GUO as a putative adjuvant treatment, whose mechanism needs to be unraveled.

In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma.

PubMed

Khurshed, Mohammed; Molenaar, Remco J; Lenting, Krissie; Leenders, William P; van Noorden, Cornelis J F

2017-07-25

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic rewiring that is not fully understood. We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type (IDH1WT) versus 399 IDH1MUT low-grade glioma and 157 IDH1WT versus 9 IDH1MUT glioblastoma samples. In both glioma types, IDH1WT was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1MUT glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle. In vitro, we observed that IDH1MUT cancer cells have a higher basal respiration compared to IDH1WT cancer cells and inhibition of the IDH1MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis. Our findings indicate that IDH1WT glioma have a typical Warburg phenotype whereas in IDH1MUT glioma the TCA cycle, rather than glycolytic lactate production, is the predominant metabolic pathway. Our data further suggest that the TCA in IDH1MUT glioma is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. This metabolic rewiring may be a basis for novel therapies for IDH1MUT and IDH1WT glioma.

miR-218 inhibits the invasive ability of glioma cells by direct downregulation of IKK-{beta}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Libing, E-mail: lb.song1@gmail.com; Huang, Quan; Chen, Kun

2010-11-05

Research highlights: {yields} miR-218 is markedly downregulated in glioma cell lines and in primary glioma tissues. {yields} Upregulation of miR-218 dramatically reduces the invasive ability of glioma cells. {yields} Ectopic expression of miR-218 inactivates IKK-{beta}/NF-{kappa}B signaling pathway. {yields} miR-218 directly targets the 3'-untranslated region (3'-UTR) of IKK-{beta}. -- Abstract: Aberrant activation of nuclear factor-kappa B (NF-{kappa}B) pathway has been proven to play important roles in the development and progression of cancers. Activation of NF-{kappa}B via the classical pathway is modulated by I{kappa}Bs kinase (IKK-{beta}). However, the mechanism underlying the epigenetic regulation of IKK-{beta}/NF-{kappa}B pathway remains largely unknown. In this study,more » we found that the expression level of miR-218 was markedly downregulated in glioma cell lines and in human primary glioma tissues. Upregulation of miR-218 dramatically reduced the migratory speed and invasive ability of glioma cells. Furthermore, we showed that ectopically expressing miR-218 in glioma cells resulted in downregulation of matrix metalloproteinase-9 (MMP-9) and reduction in NF-{kappa}B transactivity at a transcriptional level, but inhibition of miR-218 enhanced the expression of MMP-9 and transcriptional activity of NF-{kappa}B. Moreover, we showed that miR-218 inactivated the NF-{kappa}B pathway through downregulating IKK-{beta} expression by directly targeting the 3'-untranslated region (3'-UTR) of IKK-{beta}. Taken together, our results suggest that miR-218 plays an important role in preventing the invasiveness of glioma cells, and our results present a novel mechanism of miRNA-mediated direct suppression of IKK-{beta}/NF-{kappa}B pathway in gliomas.« less

BRAF Mutation is Associated with an Improved Survival in Glioma-a Systematic Review and Meta-analysis.

PubMed

Vuong, Huy Gia; Altibi, Ahmed M A; Duong, Uyen N P; Ngo, Hanh T T; Pham, Thong Quang; Fung, Kar-Ming; Hassell, Lewis

2018-05-01

Newly emerged molecular markers in gliomas provide prognostic values beyond the capabilities of histologic classification. BRAF mutation, especially BRAF V600E, is common in a subset of gliomas and may represent a potential prognostic marker. The aim of our study is to investigate the potential use of BRAF mutations on prognosis of glioma patients. Four electronic databases were searched for potential articles, including PubMed, Scopus, ISI Web of Science, and Virtual Health Library (VHL). Data of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were directly obtained from original papers or indirectly estimated from Kaplan Meier curve (KMC). A random effect model weighted by inverse variance method was used to calculate the pooled HR. From 705 articles, we finally included 11 articles with 1308 glioma patients for the final analysis. The overall estimates showed that BRAF V600E was associated with an improved overall survival (OS) in glioma patients (HR = 0.60; 95% CI = 0.44-0.80). Results for progression-free survival (PFS), however, were not statistically significant (HR = 1.39; 95% CI = 0.82-2.34). In subgroup analyses, BRAF V600E showed its effect in improving survival in pediatric and young adult gliomas (under 35 years) but did not have prognostic value in old adult. Additionally, BRAF V600E was only associated with a favorable prognosis in lower grade glioma. Our meta-analysis provides evidence that BRAF mutation has a favorable prognostic impact in gliomas and its prognostic value might be dependent on patient age and tumor grade. This mutation can be used as a prognostic factor in glioma but additional studies are required to clarify its prognostic value taking into account other confounding factors.

Revealing the potential pathogenesis of glioma by utilizing a glioma associated protein-protein interaction network.

PubMed

Pan, Weiran; Li, Gang; Yang, Xiaoxiao; Miao, Jinming

2015-04-01

This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate < 0.0005). Furthermore, 16 known glioma related genes were abstracted from Genetic Association Database. After mapping 8,890 DEGs and 16 known glioma related genes to Human Protein Reference Database, a glioma associated protein-protein interaction network (GAPN) was constructed. In addition, 51 sub-networks in GAPN were screened out through Molecular Complex Detection (score ≥ 1), and sub-network 1 was found to have the closest interaction (score = 3). What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value < 0.05) was performed, and DEGs involved in sub-network 1 and 2, such as BRMS1L and CCNA1, were predicted to regulate cell growth, cell cycle, and DNA replication via interacting with known glioma related genes. Finally, the overlaps of DEGs and human essential, housekeeping, tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.

Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

ClinicalTrials.gov

2017-10-23

Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

18F-FDOPA PET/CT or PET/MRI in Measuring Tumors in Patients With Newly-Diagnosed or Recurrent Gliomas

ClinicalTrials.gov

2017-01-30

Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Oligoastrocytoma; Recurrent Childhood Oligodendroglioma; Recurrent Childhood Pilomyxoid Astrocytoma; Recurrent Childhood Protoplasmic Astrocytoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligoastrocytoma; Untreated Childhood Anaplastic Oligodendroglioma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebellar Astrocytoma; Untreated Childhood Cerebral Astrocytoma; Untreated Childhood Diffuse Astrocytoma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Gemistocytic Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliomatosis Cerebri; Untreated Childhood Gliosarcoma; Untreated Childhood Oligoastrocytoma; Untreated Childhood Oligodendroglioma; Untreated Childhood Pilomyxoid Astrocytoma; Untreated Childhood Protoplasmic Astrocytoma; Untreated Childhood Subependymal Giant Cell Astrocytoma; Untreated Childhood Visual Pathway and Hypothalamic Glioma; Untreated Childhood Visual Pathway Glioma

The immunohistochemical expression of calcitonin receptor-like receptor (CRLR) in human gliomas

PubMed Central

Benes, L; Kappus, C; McGregor, G P; Bertalanffy, H; Mennel, H D; Hagner, S

2004-01-01

Background: Gliomas are the most common primary tumours of the central nervous system and exhibit rapid growth that is associated with neovascularisation. Adrenomedullin is an important tumour survival factor in human carcinogenesis. It has growth promoting effects on gliomas, and blockade of its actions has been experimentally shown to reduce the growth of glioma tissues and cell lines. There is some evidence that the calcitonin receptor-like receptor (CRLR) mediates the tumorigenic actions of adrenomedullin. Aim: To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin. Methods: Biopsies from 95 human gliomas of varying grade were processed for immunohistochemical analysis using a previously developed and characterised antibody to CRLR. Results: All tumour specimens were positive for CRLR. As previously found in normal peripheral tissues, CRLR immunostaining was particularly intense in the endothelial cells. This was evident in all the various vascular conformations that were observed, and which are typical of gliomas. In addition, clear immunostaining of tumour cells with astrocyte morphology was observed. These were preferentially localised around vessels. Conclusions: This study has shown for the first time that the CRLR protein is present in human glioma tissue. The expression of the receptor in endothelial cells and in astrocytic tumour cells is consistent with the evidence that its endogenous ligand, adrenomedullin, may influence glioma growth by means of both direct mitogenic and indirect angiogenic effects. CRLR may be a valuable target for effective therapeutic intervention in these malignant tumours. PMID:14747444

The immunohistochemical expression of calcitonin receptor-like receptor (CRLR) in human gliomas.

PubMed

Benes, L; Kappus, C; McGregor, G P; Bertalanffy, H; Mennel, H D; Hagner, S

2004-02-01

Gliomas are the most common primary tumours of the central nervous system and exhibit rapid growth that is associated with neovascularisation. Adrenomedullin is an important tumour survival factor in human carcinogenesis. It has growth promoting effects on gliomas, and blockade of its actions has been experimentally shown to reduce the growth of glioma tissues and cell lines. There is some evidence that the calcitonin receptor-like receptor (CRLR) mediates the tumorigenic actions of adrenomedullin. To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin. Biopsies from 95 human gliomas of varying grade were processed for immunohistochemical analysis using a previously developed and characterised antibody to CRLR. All tumour specimens were positive for CRLR. As previously found in normal peripheral tissues, CRLR immunostaining was particularly intense in the endothelial cells. This was evident in all the various vascular conformations that were observed, and which are typical of gliomas. In addition, clear immunostaining of tumour cells with astrocyte morphology was observed. These were preferentially localised around vessels. This study has shown for the first time that the CRLR protein is present in human glioma tissue. The expression of the receptor in endothelial cells and in astrocytic tumour cells is consistent with the evidence that its endogenous ligand, adrenomedullin, may influence glioma growth by means of both direct mitogenic and indirect angiogenic effects. CRLR may be a valuable target for effective therapeutic intervention in these malignant tumours.

Cholera Toxin Subunit B Enabled Multifunctional Glioma-Targeted Drug Delivery.

PubMed

Guan, Juan; Zhang, Zui; Hu, Xuefeng; Yang, Yang; Chai, Zhilan; Liu, Xiaoqin; Liu, Jican; Gao, Bo; Lu, Weiyue; Qian, Jun; Zhan, Changyou

2017-12-01

Glioma is among the most formidable brain cancers due to location in the brain. Cholera toxin subunit B (CTB) is investigated to facilitate multifunctional glioma-targeted drug delivery by targeting the glycosphingolipid GM1 expressed in the blood-brain barrier (BBB), neovasulature, and glioma cells. When modified on the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CTB-NPs), CTB fully retains its bioactivity after 24 h incubation in the fresh mouse plasma. The formed protein corona (PC) of CTB-NP and plain PLGA nanoparticles (NP) after incubation in plasma is analyzed using liquid chromatography tandem massspectrometry (nano-LC-MS/MS). CTB modification does not alter the protein components of the formed PC, macrophage phagocytosis, or pharmacokinetic profiles. CTB-NP can efficiently penetrate the in vitro BBB model and target glioma cells and human umbilical vascular endothelial cells. Paclitaxel is loaded in NP (NP/PTX) and CTB-NP (CTB-NP/PTX), and their antiglioma effects are assessed in nude mice bearing intracranial glioma. CTB-NP/PTX can efficiently induce apoptosis of intracranial glioma cells and ablate neovasulature in vivo, resulting in significant prolongation of survival of nude mice bearing intracranial glioma (34 d) in comparison to those treated with NP/PTX (29 d), Taxol (24 d), and saline (21 d). The present study suggests a potential multifunctional glioma-targeted drug delivery system enabled by cholera toxin subunit B. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

CRNDE Promotes Malignant Progression of Glioma by Attenuating miR-384/PIWIL4/STAT3 Axis

PubMed Central

Zheng, Jian; Liu, Xiaobai; Wang, Ping; Xue, Yixue; Ma, Jun; Qu, Chengbin; Liu, Yunhui

2016-01-01

Colorectal neoplasia differentially expressed (CRNDE) is the most upregulated long noncoding RNA (lncRNA) in glioma. Herein, the function and potential molecular mechanisms of CRNDE and miR-384 were illustrated in glioma cells. CRNDE overexpression facilitated cell proliferation, migration, and invasion, while inhibited glioma cells apoptosis. Quantitative real-time polymerase chain reaction (PCR) demonstrated that miR-384 was downregulated in human glioma tissues and glioma cell lines. Moreover, restoration of miR-384 exerted tumor-suppressive functions. In addition, the expression of miR-384 was negatively correlated with CRNDE expression. A binding region between CRNDE and miR-384 was confirmed using luciferase assays. Moreover, CRNDE promoted cell malignant behavior by decreasing miR-384 expression. At the molecular level, treatment by CRNDE knockdown or miR-384 overexpression resulted in a decrease of piwi-like RNA-mediated gene silencing 4 (PIWIL4) protein. Besides, PIWIL4 was identified as a target of miR-384 and plays an oncogenic role in glioma. Similarly, downstream proteins of PIWIL4 such as STAT3, cyclin D1, VEGFA, SLUG, MMP-9, caspase 3, Bcl-2, and bcl-xL were modulated when treated with miR-384 and PIWIL4. Remarkably, CRNDE knockdown combined with miR-384 overexpression led to tumor regression in vivo. Overall, these results depicted a novel pathway mediated by CRNDE in glioma, which may be a potential application for glioma therapy. PMID:27058823

High expression of B7-H6 in human glioma tissues promotes tumor progression.

PubMed

Jiang, Tianwei; Wu, Wei; Zhang, Huasheng; Zhang, Xiangsheng; Zhang, Dingding; Wang, Qiang; Huang, Lei; Wang, Ye; Hang, Chunhua

2017-06-06

B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.

STAT3 Activation Promotes Oncolytic HSV1 Replication in Glioma Cells

PubMed Central

Okemoto, Kazuo; Wagner, Benjamin; Meisen, Hans; Haseley, Amy; Kaur, Balveen; Chiocca, Ennio Antonio

2013-01-01

Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy. PMID:23936533

The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

PubMed

Ryken, Timothy C; Parney, Ian; Buatti, John; Kalkanis, Steven N; Olson, Jeffrey J

2015-12-01

(1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? These recommendations apply to adults with newly diagnosed diffuse LGG. OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4-64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors-see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy.

Subjective Quality of Life in Persons with Low-Grade Glioma and Their Next of Kin

ERIC Educational Resources Information Center

Edvardsson, Tanja I.; Ahlstrom, Gerd I.

2009-01-01

Patients with low-grade glioma have a longer survival than patients with highly malignant glioma, and for this reason questions of quality of life (QoL) are of particular importance to such patients as well as to their next of kin. No studies have been found in which both adult patients with low-grade glioma and their next of kin have estimated…

Glioma Selectivity of Magnetically Targeted Nanoparticles: A Role of Abnormal Tumor Hydrodynamics

PubMed Central

Chertok, Beata; David, Allan E.; Huang, Yongzhuo; Yang, Victor C.

2007-01-01

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma-versus contralateral brain-relevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting. PMID:17628157

MeCP2 overexpression inhibits proliferation, migration and invasion of C6 glioma by modulating ERK signaling and gene expression.

PubMed

Sharma, Kedarlal; Singh, Juhi; Frost, Emma E; Pillai, Prakash P

2018-05-01

MethylCpG binding protein-2 (MeCP2) is an epigenetic regulator and essential for brain development. MeCP2 mutations are associated with a spectrum of neuro-developmental disorders that vary depending on the patient gender, most notably Rett Syndrome. MeCP2 is essential for normal neuronal maturation, and glial cell function in the brain. Besides, its role in neurodevelopmental disorders, MeCP2 is involved in many cancers such as breast, colorectal, lung, liver, and prostate cancer. Glioma is the most lethal form of brain cancer. Studies have shown that dysfunctional epigenetic regulation plays a crucial role in glioma progression. Further, previous studies have suggested a role for MeCP2 in glioma pathogenesis. In this study, we show that MeCP2 may play a critical role in the suppression of glioma progression. Stable overexpression of MeCP2in C6 glioma cells inhibits proliferation, migration, invasion, and adhesion. Moreover, MeCP2 overexpression inhibits pERKand BDNF expression while inducing GFAP expression in C6 glioma. These findings suggest that MeCP2 may play a crucial role in suppression of glioma progression. Copyright © 2018 Elsevier B.V. All rights reserved.

Histogram analysis of T2*-based pharmacokinetic imaging in cerebral glioma grading.

PubMed

Liu, Hua-Shan; Chiang, Shih-Wei; Chung, Hsiao-Wen; Tsai, Ping-Huei; Hsu, Fei-Ting; Cho, Nai-Yu; Wang, Chao-Ying; Chou, Ming-Chung; Chen, Cheng-Yu

2018-03-01

To investigate the feasibility of histogram analysis of the T2*-based permeability parameter volume transfer constant (K trans ) for glioma grading and to explore the diagnostic performance of the histogram analysis of K trans and blood plasma volume (v p ). We recruited 31 and 11 patients with high- and low-grade gliomas, respectively. The histogram parameters of K trans and v p , derived from the first-pass pharmacokinetic modeling based on the T2* dynamic susceptibility-weighted contrast-enhanced perfusion-weighted magnetic resonance imaging (T2* DSC-PW-MRI) from the entire tumor volume, were evaluated for differentiating glioma grades. Histogram parameters of K trans and v p showed significant differences between high- and low-grade gliomas and exhibited significant correlations with tumor grades. The mean K trans derived from the T2* DSC-PW-MRI had the highest sensitivity and specificity for differentiating high-grade gliomas from low-grade gliomas compared with other histogram parameters of K trans and v p . Histogram analysis of T2*-based pharmacokinetic imaging is useful for cerebral glioma grading. The histogram parameters of the entire tumor K trans measurement can provide increased accuracy with additional information regarding microvascular permeability changes for identifying high-grade brain tumors. Copyright © 2017 Elsevier B.V. All rights reserved.

Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

PubMed

Malta, Tathiane M; de Souza, Camila F; Sabedot, Thais S; Silva, Tiago C; Mosella, Maritza S; Kalkanis, Steven N; Snyder, James; Castro, Ana Valeria B; Noushmehr, Houtan

2018-04-09

Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.

Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression

PubMed Central

Roy, Ananya; Attarha, Sanaz; Weishaupt, Holger; Edqvist, Per-Henrik; Swartling, Fredrik J.; Bergqvist, Michael; Siebzehnrubl, Florian A.; Smits, Anja; Pontén, Fredrik; Tchougounova, Elena

2017-01-01

Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin. In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients. PMID:28445977

miR-141-3p functions as a tumor suppressor modulating activating transcription factor 5 in glioma.

PubMed

Wang, Mengyuan; Hu, Ming; Li, Zhaohua; Qian, Dongmeng; Wang, Bin; Liu, David X

2017-09-02

Glioma is the most common malignant primary brain tumor which arises from the central nervous system. Our studies reported that an anti-apoptotic factor, activating transcription factor 5 (ATF5), is highly expressed in malignant glioma specimens and cell lines. Downregulation by dominant-negetive ATF5 could repress glioma cell proliferation and accelerate apoptosis. Here, we further investigate the upstream factor which regulates ATF5 expression. Bioinformatic analysis showed that ATF5 was a potential target of miR-141-3p. Luciferase reporter assay verified that miR-141-3p specifically targeted the ATF5 3'-UTR in glioma cells. Functional studied suggested that miR-141-3p overexpression inhibited proliferation and promoted apoptosis of glioma cells (U87MG and U251). Xenograft experiments proved the inhibition of miR-141-3p on glioma growth in vivo. Moreover, exogenous ATF5 without 3'-UTR restored the cell proliferation inhibition triggered by miR-141-3p. Taken together, we put forward that miR-141-3p is a new upstream target towards ATF5. It can serve as a crucial tumor suppressor in regulating the ATF5-regulated growth of malignant glioma. Copyright © 2017 Elsevier Inc. All rights reserved.

Management of venous thromboembolism in patients with glioma.

PubMed

Al Megren, Mosaad; De Wit, Carine; Al Qahtani, Mohammad; Le Gal, Grégoire; Carrier, Marc

2017-08-01

Venous thromboembolism (VTE) is a common complication among patients with glioma. However, data on the safety of therapeutic doses of anticoagulation is scarce in this patient population. The purpose of this study is to evaluate the risk of intracranial hemorrhage (ICH) in glioma patients receiving therapeutic anticoagulation for VTE treatment. We conducted a case-control study including glioma patients with and without acute VTE from Jan 2010 to March 2015. Controls were matched based on age, gender and tumor grade. 569 patients with glioma were identified, 76 (13.3%) developed acute VTE. Of the 70 patients treated with full dose anticoagulant therapy, 14 (20%) patients had a major bleeding including 11 (15.7%) ICH. The odds ratio for ICH in patients with glioma and VTE who were treated with anticoagulation compared to the control group was 7.5 (95% CI, 1.6-34.9) p=0.01. Overall survival was similar for VTE and control group (36 vs. 42months, p=0.93). Therapeutic anticoagulation is associated with a 7-fold increase risk of ICH in glioma patients. Data emerging from this study support the need for high quality studies to evaluate the risk of ICH in patients with glioma and VTE. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cigarette smoking, alcohol intake, and risk of glioma in the NIH-AARP Diet and Health Study.

PubMed

Braganza, M Z; Rajaraman, P; Park, Y; Inskip, P D; Freedman, N D; Hollenbeck, A R; de González, A Berrington; Kitahara, C M

2014-01-07

Although cigarette smoking and alcohol drinking increase the risk of several cancers and certain components of cigarette smoke and alcohol can penetrate the blood-brain barrier, it remains unclear whether these exposures influence the risk of glioma. We examined the associations between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a prospective study of 477,095 US men and women ages 50-71 years at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using models with age as the time metric and adjusted for sex, race/ethnicity, education, and marital status. During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with first primary glioma. Among men, current, heavier smoking was associated with a reduced risk of glioma compared with never smoking, but this was based on only nine cases. No associations were observed between smoking behaviours and glioma risk in women. Greater alcohol consumption was associated with a decreased risk of glioma, particularly among men (>2 drinks per day vs <1 drink per week: HR=0.67, 95% CI=0.51-0.90). Smoking and alcohol drinking do not appear to increase the risk of glioma.

Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

PubMed Central

Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

2015-01-01

Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p < 0.05). The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated. PMID:26788112

Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics.

PubMed

Chertok, Beata; David, Allan E; Huang, Yongzhuo; Yang, Victor C

2007-10-08

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma- versus contralateral brain-relevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting.

Single-wall carbon nanohorns (SWNHs) inhibited proliferation of human glioma cells and promoted its apoptosis

NASA Astrophysics Data System (ADS)

Li, Yunjun; Zhang, Jinqian; Zhao, Ming; Shi, Zujin; Chen, Xin; He, Xihui; Han, Nanyin; Xu, Ruxiang

2013-08-01

Although single-wall carbon nanohorns (SWNHs) have been demonstrated to accumulate to cytotoxic levels within organs of various animal models and cell types, they have been exploited for cancer therapies. The role of SWNHs in human glioma cell lines was unclear. To address this question, the research about direct role of SWNHs on the growth, proliferation, and apoptosis of human glioma cell lines (U87, U251, and U373) had been performed. Our results indicate that particle size of SWNHs in water is between 342 and 712 nm, the films of SEM show that SWNHs on PS surface are individual particles. SWNHs significantly delayed mitotic entry of human glioma cell lines cells, and inhibited its proliferation in a time- and dose-dependent manner. SWNHs induced a significant increase in G1 phase and inhibition of S phase followed the gradually increasing concentrations. SWNHs in human glioma cell lines cells significantly induced apoptosis followed by their gradually increasing concentrations. The TEM images showed that individual spherical SWNHs particles smaller than 100 nm in diameters were localized inside lysosomes of human glioma cell lines. SWNHs inhibited mitotic entry, growth, and proliferation of human glioma cell lines, and promoted its apoptosis. SWNHs may be a novel opportunity or method for the research on treatment of human glioma.

The Ubiquitin Ligase COP1 Promotes Glioma Cell Proliferation by Preferentially Downregulating Tumor Suppressor p53.

PubMed

Zou, Shenshan; Zhu, Yufu; Wang, Bin; Qian, Fengyuan; Zhang, Xiang; Wang, Lei; Fu, Chunling; Bao, Hanmo; Xie, Manyi; Gao, Shangfeng; Yu, Rutong; Shi, Hengliang

2017-09-01

Human glioma causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying glioma progression are still largely unknown. COP1 (constitutively photomorphogenic 1), an E3 ubiquitin ligase, is important in cell survival, development, cell growth, and cancer biology by regulating different substrates. As is well known, both tumor suppressor p53 and oncogenic protein c-JUN could be ubiquitinated and degraded by ubiquitin ligase COP1, which may be the reason that COP1 serves as an oncogene or a tumor suppressor in different cancer types. Up to now, the possible role of COP1 in human glioma is still unclear. In the present study, we found that the expression of COP1 was upregulated in human glioma tissues. The role of COP1 in glioma cell proliferation was investigated using COP1 loss- and gain-of-function. The results showed that downregulation of COP1 by short hairpin RNA (shRNA) inhibited glioma cell proliferation, while overexpression of COP1 significantly promoted it. Furthermore, we demonstrated that COP1 only interacted with and regulated p53, but not c-JUN. Taken together, these results indicate that COP1 may play a role in promoting glioma cell proliferation by interacting with and downregulating tumor suppressor p53 rather than oncogenic protein c-JUN.

Glioma epidemiology in the central Tunisian population: 1993-2012.

PubMed

Trabelsi, Saoussen; Brahim, Dorra H'mida-Ben; Ladib, Mohamed; Mama, Nadia; Harrabi, Imed; Tlili, Kalthoum; Yacoubi, Mohamed Tahar; Krifa, Hedi; Hmissa, Sihem; Saad, Ali; Mokni, Moncef

2014-01-01

Glioma is a heterogeneous central nervous system (CNS) tumor group that encompasses different histological subtypes with high variability in prognosis. The lesions account for almost 80% of primary malignant brain tumors. The aim of this study is to extend our understanding of the glioma epidemiology in the central Tunisian region. We analyzed 393 gliomas recorded in cancer registry of central Tunisia from 1993 to 2012. Crude incidence rates (CR) and world age-standardized rates (ASR) were estimated using annual population data size and age structure. Statistic correlations were established using Chi-square and Kaplan-Meier test. Tunisian glioma patients were identified with a mean age at diagnosis of 48 years and 1.5 sex ratio (male/female). During the 19 years period of study the highest incidence value was observed in male group between 1998 and 2002 (CR: 0.28, ASR: 0.3). Incidence results underline increasing high grade glioma occurring in the adulthood in the last period (2007-2012). Median survival was 27 months, with 1-, 2- and 5-year survival rates of 42%, 30% and 26%, respectively. Survival was greater in patients with younger age, lower tumor grade, infratentrial tumor location and undergoing a palliative treatment. This central Tunisia gliomas registry study provides important information that could improve glioma management and healthcare practice.

Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma.

PubMed

Gravendeel, Lonneke A M; Kloosterhof, Nanne K; Bralten, Linda B C; van Marion, Ronald; Dubbink, Hendrikus Jan; Dinjens, Winand; Bleeker, Fonnet E; Hoogenraad, Casper C; Michiels, Erna; Kros, Johan M; van den Bent, Martin; Smitt, Peter A E Sillevis; French, Pim J

2010-03-01

Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes. (c) 2010 Wiley-Liss, Inc.

Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes.

PubMed

Auvergne, Romane M; Sim, Fraser J; Wang, Su; Chandler-Militello, Devin; Burch, Jaclyn; Al Fanek, Yazan; Davis, Danielle; Benraiss, Abdellatif; Walter, Kevin; Achanta, Pragathi; Johnson, Mahlon; Quinones-Hinojosa, Alfredo; Natesan, Sridaran; Ford, Heide L; Goldman, Steven A

2013-06-27

Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II-IV. Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, which included the transcription factor SIX1 and its principal cofactors, EYA1 and DACH2. Small hairpin RNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs with those of normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood and more specifically targeted. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Aberrant rhythmic expression of cryptochrome2 regulates the radiosensitivity of rat gliomas.

PubMed

Fan, Wang; Caiyan, Li; Ling, Zhu; Jiayun, Zhao

2017-09-29

In this study, we investigated the role of the clock regulatory protein cryptochrome 2 (Cry2) in determining the radiosensitivity of C6 glioma cells in a rat model. We observed that Cry2 mRNA and protein levels showed aberrant rhythmic periodicity of 8 h in glioma tissues, compared to 24 h in normal brain tissue. Cry2 mRNA and protein levels did not respond to irradiation in normal tissues, but both were increased at the ZT4 (low Cry2) and ZT8 (high Cry2) time points in gliomas. Immunohistochemical staining of PCNA and TUNEL assays demonstrated that high Cry2 expression in glioma tissues was associated with increased cell proliferation and decreased apoptosis. Western blot analysis showed that glioma cell fate was independent of p53, but was probably dependent on p73, which was more highly expressed at ZT4 (low Cry2) than at ZT8 (high Cry2). Levels of both p53 and p73 were unaffected by irradiation in normal brain tissues. These findings suggest aberrant rhythmic expression of Cry2 influence on radiosensitivity in rat gliomas.

Ion channel gene expression predicts survival in glioma patients

PubMed Central

Wang, Rong; Gurguis, Christopher I.; Gu, Wanjun; Ko, Eun A; Lim, Inja; Bang, Hyoweon; Zhou, Tong; Ko, Jae-Hong

2015-01-01

Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients. PMID:26235283

Differential sensitivity of Glioma stem cells to Aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics.

PubMed

Mannino, Mariella; Gomez-Roman, Natividad; Hochegger, Helfrid; Chalmers, Anthony J

2014-07-01

Glioma stem-cell-like cells are considered to be responsible for treatment resistance and tumour recurrence following chemo-radiation in glioblastoma patients, but specific targets by which to kill the cancer stem cell population remain elusive. A characteristic feature of stem cells is their ability to undergo both symmetric and asymmetric cell divisions. In this study we have analysed specific features of glioma stem cell mitosis. We found that glioma stem cells appear to be highly prone to undergo aberrant cell division and polyploidization. Moreover, we discovered a pronounced change in the dynamic of mitotic centrosome maturation in these cells. Accordingly, glioma stem cell survival appeared to be strongly dependent on Aurora A activity. Unlike differentiated cells, glioma stem cells responded to moderate Aurora A inhibition with spindle defects, polyploidization and a dramatic increase in cellular senescence, and were selectively sensitive to Aurora A and Plk1 inhibitor treatment. Our study proposes inhibition of centrosomal kinases as a novel strategy to selectively target glioma stem cells. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Cationizable lipid micelles as vehicles for intraarterial glioma treatment.

PubMed

Nguyen, Juliane; Cooke, Johann R N; Ellis, Jason A; Deci, Michael; Emala, Charles W; Bruce, Jeffrey N; Bigio, Irving J; Straubinger, Robert M; Joshi, Shailendra

2016-05-01

The relative abundance of anionic lipids on the surface of endothelia and on glioma cells suggests a workable strategy for selective drug delivery by utilizing cationic nanoparticles. Furthermore, the extracellular pH of gliomas is relatively acidic suggesting that tumor selectivity could be further enhanced if nanoparticles can be designed to cationize in such an environment. With these motivating hypotheses the objective of this study was to determine whether nanoparticulate (20 nm) micelles could be designed to improve their deposition within gliomas in an animal model. To test this, we performed intra-arterial injection of micelles labeled with an optically quantifiable dye. We observed significantly greater deposition (end-tissue concentration) of cationizable micelles as compared to non-ionizable micelles in the ipsilateral hemisphere of normal brains. More importantly, we noted enhanced deposition of cationizable as compared to non-ionizable micelles in glioma tissue as judged by semiquantitative fluorescence analysis. Micelles were generally able to penetrate to the core of the gliomas tested. Thus we conclude that cationizable micelles may be constructed as vehicles for facilitating glioma-selective delivery of compounds after intraarterial injection.

Serum immunoreactivity of cancer/testis antigen OY-TES-1 and its tissues expression in glioma

PubMed Central

Li, Xisheng; Yan, Jun; Fan, Rong; Luo, Bin; Zhang, Qingmei; Lin, Yongda; Zhou, Sufang; Luo, Guorong; Xie, Xiaoxun; Xiao, Shaowen

2017-01-01

OY-TES-1 is a member of the cancer/testis antigen family that is expressed in healthy testis tissue and certain types of cancerous tissue. The present study aimed to analyze the expression pattern of OY-TES-1 and serum anti-OY-TES-1 antibody concentration in patients with glioma. OY-TES-1 mRNA was detected in 28/36 (78%) of glioma cases using conventional reverse transcription polymerase chain reaction (RT-PCR) analysis. RT-quantitative-PCR revealed that OY-TES-1 was expressed at a higher level in glioma tissues compared with normal adult tissues (with the exception of testis tissue). Anti-OY-TES-1 antibodies were present in the serum of 5/36 (14%) of patients with glioma, but absent in all the serum samples from 107 healthy donors. Immunohistochemical analysis demonstrated that OY-TES-1 protein was expressed in all glioma tissues from patients with anti-OY-TES-1 antibody seropositivity. These results suggest that OY-TES-1 is a novel candidate for glioma immunotherapy. PMID:28529561

The expression and significance of HIF-1alpha and GLUT-3 in glioma.

PubMed

Liu, Yang; Li, Yun-ming; Tian, Rui-feng; Liu, Wei-ping; Fei, Zhou; Long, Qian-fa; Wang, Xiao-an; Zhang, Xiang

2009-12-22

HIF-1alpha plays an indispensable role in tumor formation and histogenesis. Target genes involved in glucose transport are acutely transactivated by HIF-1alpha. GLUT-3 protein is the rate-limiting factor related to glucose transport, which is classified as brain-type glucose transporter. This study was the initial one aiming to probe into the co-expression and clinical significance of HIF-1alpha and GLUT-3 in glioma. One hundred and twenty cases of glioma tissues and ten human normal cerebral tissues decompressed in glioma excision were examined using immunohistochemistry and Western blot. The expression of HIF-1alpha and GLUT-3 increased gradually with the increase of pathological grade of glioma, respectively. There was significant difference in the expression of HIF-1alpha and GLUT-3 in every two groups, respectively. There was a positive correlation between HIF-1alpha and GLUT-3. In conclusion, the expression of HIF-1alpha and GLUT-3 in glioma was correlated significantly with tumors' pathological grade, which can be taken as a pair of useful markers for predicting the biological behavior of glioma.

Adiposity at different periods of life and risk of adult glioma in a cohort of postmenopausal women.

PubMed

Kabat, Geoffrey C; Rohan, Thomas E

2018-06-01

Little is known about risk factors for adult glioma. Adiposity has received some attention as a possible risk factor. We examined the association of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR), measured at enrollment, as well as self-reported weight earlier in life, with risk of glioma in a large cohort of postmenopausal women. Over 18 years of follow-up, 217 glioma cases were ascertained, including 164 glioblastomas. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. There was a modest, non-significant trend toward increasing risk of glioma and glioblastoma with increasing measured BMI and WHR. No trend was seen for WC. Self-reported BMI earlier in life showed no association with risk. Our weak findings regarding the association of adiposity measures with risk of glioma are in agreement the results of several large cohort studies. In view of the available evidence, adiposity is unlikely to represent an important risk factor for glioma. Copyright © 2018 Elsevier Ltd. All rights reserved.

[A Rare Case of Cerebellar Hemangioblastoma Causing Taste Disorder].

PubMed

Nakashiro, Hiroko; Kawashima, Masatou; Yoshioka, Fumitaka; Nakahara, Yukiko; Takase, Yukinori; Ogata, Atsushi; Shimokawa, Shoko; Masuoka, Jun; Abe, Tatsuya; Matsushima, Toshio

2017-03-01

Taste(gustation)is one of the five senses, and comprises the types: sweet, bitter, salty, sour, and umami. Taste disorders, such as dysgeusia and parageusia, are classified into 2 types: those with peripheral origin and those with central origin. The peripheral origin-type taste disorder is caused by zinc deficiency, mouth dryness, a side effect of radiotherapy or complication of systemic diseases such as, diabetes, hepatopathy, and nephropathy. The central origin-type taste disorder is reported to be caused due to demyelinating disease, pontine hemorrhage, pontine infarction, and thalamic infarction; it is very rarely caused by a brain tumor. We surgically treated a 69-year-old man with cerebellar hemangioblastoma who had developed taste disorder. The tumor compressed the solitary nucleus, which includes the taste tract in the central nervous system. On removal of the tumor, the taste disorder gradually improved.

Proton spectroscopy in the narcoleptic syndrome. Is there evidence of a brainstem lesion?

PubMed

Ellis, C M; Simmons, A; Lemmens, G; Williams, S C; Parkes, J D

1998-02-01

There is controversy regarding the relationship of structural or biochemical brainstem lesions to "idiopathic" narcolepsy. Most cases of the narcoleptic syndrome are considered to be idiopathic because no structural lesion is detectable, although some cases of secondary narcolepsy are known to be associated with no structural brainstem lesions. Using proton spectroscopy, we determined levels of ventral pontine metabolite pools in 12 normal subjects and 12 subjects with idiopathic narcolepsy. REM sleep is generated in ventral pontine areas. Proton spectroscopy was used to study levels of N-acetyl aspartate (NAA) as a marker of cell mass, creatine and phosphocreatine (Cr + PCr), and choline (Cho). The intensity of the peaks, as determined by the area under the peak (AUP), was measured. The AUP correlates with the quantity of chemical present. In this study, the ratios of NAA to Cr + PCr were similar in normal subjects and in narcoleptic subjects with idiopathic narcolepsy. No differences in measured metabolic ratio were observed in subjects who slept during the scan procedure compared with those who remained awake. Subjects with "symptomatic" narcolepsy accompanied by an obvious structural brain lesion were not studied. Proton spectroscopy of the brain initiates a new kind of neurochemistry, allowing the noninvasive study of metabolic pools in the living human brain without the use of any kind of tracer or radioactive molecule. In this study, there was no evidence of cell loss in the ventral pontine areas of subjects with the narcoleptic syndrome.

Childhood Brain Stem Glioma Treatment (PDQ®)—Patient Version

Cancer.gov

Childhood brain stem glioma treatment options can include surgery, radiation therapy, chemotherapy, cerebral spinal fluid diversion, observation, and targeted therapy. Learn more about newly diagnosed and recurrent childhood brain stem glioma in this expert-reviewed summary.

A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2

ClinicalTrials.gov

2018-04-09

Malignant Glioma of Brain; Astrocytoma; Malignant Astrocytoma; Oligodendroglioma; Anaplastic Oligodendroglioma of Brain (Diagnosis); Mixed Oligo-Astrocytoma; Ependymoma; Ganglioglioma; Pylocytic/Pylomyxoid Astrocytoma; Brain Tumor; Glioma; Brain Cancer; Glioblastoma; Glioblastoma Multiforme

Brain tumor modeling: glioma growth and interaction with chemotherapy

NASA Astrophysics Data System (ADS)

Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

2011-10-01

In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

FoxM1 Promotes Glioma Cells Progression by Up-Regulating Anxa1 Expression

PubMed Central

Cheng, Shi-Xiang; Tu, Yue; Zhang, Sai

2013-01-01

Forkhead box M1 (FoxM1) is a member of the forkhead transcription factor family and is overexpression in malignant gliomas. However, the molecular mechanisms by which FoxM1lead to glioma carcinogenesis and progression are still not well known. In the present study, we show that Anxa1 was overexpression in gliomas and predicted the poor outcome. Furthermore, Anxa1 closely related to the FoxM1 expression and was a direct transcriptional target of FoxM1. Overexpression of FoxM1 up-regulated Anxa1 expression, whereas suppression of FoxM1 expression down-regulated Anxa1 expression in glioma cells. Finally, FoxM1 enhanced the proliferation, migration, and angiogenesis in Anxa1-dependent manner both in vitro and in vivo. Our findings provide both clinical and mechanistic evidences that FoxM1 contributes to glioma development by directly up-regulating Anxa1 expression. PMID:23991102

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

PubMed

Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

A mathematical model describes the malignant transformation of low grade gliomas: Prognostic implications.

PubMed

Bogdańska, Magdalena U; Bodnar, Marek; Piotrowska, Monika J; Murek, Michael; Schucht, Philippe; Beck, Jürgen; Martínez-González, Alicia; Pérez-García, Víctor M

2017-01-01

Gliomas are the most frequent type of primary brain tumours. Low grade gliomas (LGGs, WHO grade II gliomas) may grow very slowly for the long periods of time, however they inevitably cause death due to the phenomenon known as the malignant transformation. This refers to the transition of LGGs to more aggressive forms of high grade gliomas (HGGs, WHO grade III and IV gliomas). In this paper we propose a mathematical model describing the spatio-temporal transition of LGGs into HGGs. Our modelling approach is based on two cellular populations with transitions between them being driven by the tumour microenvironment transformation occurring when the tumour cell density grows beyond a critical level. We show that the proposed model describes real patient data well. We discuss the relationship between patient prognosis and model parameters. We approximate tumour radius and velocity before malignant transformation as well as estimate the onset of this process.

Combating immunosuppression in glioma

PubMed Central

Vega, Eleanor A; Graner, Michael W; Sampson, John H

2012-01-01

Despite maximal therapy, malignant gliomas have a very poor prognosis. Patients with glioma express significant immune defects, including CD4 lymphopenia, increased fractions of regulatory T cells in peripheral blood and shifts in cytokine profiles from Th1 to Th2. Recent studies have focused on ways to combat immunosuppression in patients with glioma as well as in animal models for glioma. We concentrate on two specific ways to combat immunosuppression: inhibition of TGF-β signaling and modulation of regulatory T cells. TGF-β signaling can be interrupted by antisense oligonucleotide technology, TGF-β receptor I kinase inhibitors, soluble TGF-β receptors and antibodies against TGF-β. Regulatory T cells have been targeted with antibodies against T-cell markers, such as CD25, CTLA-4 and GITR. In addition, vaccination against Foxp3 has been explored. The results of these studies have been encouraging; combating immunosuppression may be one key to improving prognosis in malignant glioma. PMID:18518768

Involvement of nitric oxide synthase in matrix metalloproteinase-9- and/or urokinase plasminogen activator receptor-mediated glioma cell migration

PubMed Central

2013-01-01

Background Src tyrosine kinase activates inducible nitric oxide synthase (iNOS) and, in turn, nitric oxide production as a means to transduce cell migration. Src tyrosine kinase plays a key proximal role to control α9β1 signaling. Our recent studies have clearly demonstrated the role of α9β1 integrin in matrix metalloproteinase-9 (MMP-9) and/or urokinase plasminogen activator receptor (uPAR)-mediated glioma cell migration. In the present study, we evaluated the involvement of α9β1 integrin-iNOS pathway in MMP-9- and/or uPAR-mediated glioma cell migration. Methods MMP-9 and uPAR shRNAs and overexpressing plasmids were used to downregulate and upregulate these molecules, respectively in U251 glioma cells and 5310 glioma xenograft cells. The effect of treatments on migration and invasion potential of these glioma cells were assessed by spheroid migration, wound healing, and Matrigel invasion assays. In order to attain the other objectives we also performed immunocytochemical, immunohistochemical, RT-PCR, Western blot and fluorescence-activated cell sorting (FACS) analysis. Results Immunohistochemical analysis revealed the prominent association of iNOS with glioblastoma multiforme (GBM). Immunofluorescence analysis showed prominent expression of iNOS in glioma cells. MMP-9 and/or uPAR knockdown by respective shRNAs reduced iNOS expression in these glioma cells. RT-PCR analysis revealed elevated iNOS mRNA expression in either MMP-9 or uPAR overexpressed glioma cells. The migration potential of MMP-9- and/or uPAR-overexpressed U251 glioma cells was significantly inhibited after treatment with L-NAME, an inhibitor of iNOS. Similarly, a significant inhibition of the invasion potential of the control or MMP-9/uPAR-overexpressed glioma cells was noticed after L-NAME treatment. A prominent reduction of iNOS expression was observed in the tumor regions of nude mice brains, which were injected with 5310 glioma cells, after MMP-9 and/or uPAR knockdown. Protein expressions of cSrc, phosphoSrc and p130Cas were reduced with simultaneous knockdown of both MMP-9 and uPAR. Conclusions Taken together, our results from the present and earlier studies clearly demonstrate that α9β1 integrin-mediated cell migration utilizes the iNOS pathway, and inhibition of the migratory potential of glioma cells by simultaneous knockdown of MMP-9 and uPAR could be attributed to the reduced α9β1 integrin and iNOS levels. PMID:24325546

Osthole exhibits anti-cancer property in rat glioma cells through inhibiting PI3K/Akt and MAPK signaling pathways.

PubMed

Ding, Daofang; Wei, Songpu; Song, Yi; Li, Linghui; Du, Guoqing; Zhan, Hongsheng; Cao, Yuelong

2013-01-01

The purpose of this study was to investigate how Osthole affects glioma cell proliferation, apoptosis, invasion and migration. Rat glioma cells were treated with different concentrations of Osthole (0 µM, 25 µM, 50 µM, and 100 µM). Cell proliferation was assessed by measuring PCNA expression and CCK8 assay at different time points. Apoptosis was evaluated by measuring the expression of pro-apoptotic protein including Bax, Bcl2, PARP, and cleaved Caspase3, and of anti-apoptotic protein Survivin. Cell migration and invasion were assessed using different methods. Signaling pathways such as PI3K/Akt and MAPK, which are involved in the development of glioma cells, were also investigated in this study. Treatment with Osthole markedly inhibits glioma cell proliferation, as assessed by western blot with the PCNA antibody. Osthole also induces cell apoptosis by upregulating the expression of pro-apoptotic proteins, and by reducing the expression of anti-apoptotic factors. Moreover, C6 cell migration and invasion were efficiently inhibited in groups treated with Osthole, compared to the control group. Additionally, inhibition of PI3K/Akt and MAPK signaling pathway was also observed in C6 cells treated with Osthole. Our findings showed an anti-cancer effect of Osthole on glioma cells, including the proliferation inhibition, apoptosis induction, and migration/invasion inhibition. Further investigation in C6 glioma cells implicated the role of Osthole in essential pathways controlling glioma cell progression. Taken together, our data suggested that Osthole may have a potential application in glioma therapy. © 2014 S. Karger AG, Basel.

Non-optic glioma in adults and children with neurofibromatosis 1.

PubMed

Sellmer, Laura; Farschtschi, Said; Marangoni, Marco; Heran, Manraj K S; Birch, Patricia; Wenzel, Ralph; Friedman, Jan M; Mautner, Victor-Felix

2017-02-15

Non-optic gliomas occur in 5% of children with NF1, but little is known about these tumours in adults. We aimed to investigate progression, spontaneous regression and the natural history of non-optic gliomas in adults and compare these findings to the results found in children. One thousand seven hundred twenty-two brain MRI scans of 562 unselected individuals with NF1 were collected at the NF outpatient department of the University Hospital Hamburg-Eppendorf between 2003 and 2015. The number of scans per patient ranged from one to 12; patients were followed for a median of 3.7 years. We identified 24 patients (4.3%) with non-optic gliomas. Median age at first scan with glioma was 21.2 years, much higher than in previous publications. Only seven of the 24 non-optic glioma patients were symptomatic. Five of 24 patients had multiple non-optic gliomas. Four individuals developed a new tumour, and 4 cases showed progression. The risk of new tumour development was 0.19% (95% confidence interval 0.06% to 0.52%) per patient year of follow-up for patients over 10 years. The rate of progressing non-optic gliomas per patient year of follow-up in the first 5 years after tumour diagnosis was 4.7% (95% confidence interval 1.5% to 12%). Non-optic gliomas are twice as common in an unselected cohort of NF1 patients as previously reported. This is likely due to increased frequency of diagnosis of asymptomatic tumours when routine MRIs are performed and a higher prevalence in older individuals.

Detection of ATRX and IDH1-R132H immunohistochemistry in the progression of 211 paired gliomas

PubMed Central

Li, Qingbin; Wang, Zhiliang; Li, Guanzhang; Wang, Guangzhi; Yang, Pei; Li, Jianlong; Han, Bo; Jiang, Chuanlu; Sun, Ying; Jiang, Tao

2016-01-01

Recurrence and progression to higher grade lesions are key biological events and characteristic behaviors in the evolution process of glioma. A small residual population of cells always escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence or progression. IDH mutation (isocitrate dehydrogenase) and ATRX (alpha-thalassemia/mental retardation, X-linked) loss/mutation occur in association and may represent early genetic alterations in the development of gliomas. However, their prognostic value in the evolution of gliomas still needs further investigation. Two hundreds and eleven serial sampling of gliomas were included in our study. We used immunohistochemistry (IHC) to detect IDH1-R132H mutation and ATRX status and showed that the IDH1-R132H and (or) ATRX status could be necessary to provide the basic molecular information for the “integrated diagnosis” of gliomas. We illustrated an evaluation formula for the evolution of gliomas by IDH1-R132H combined with ATRX immunohistochemistry and identified the association of IDH1-R132H/ATRX loss accompanied by longer progression time interval of patients with gliomas. Furthermore, we observed that most recurrences had a consistent IDH1 and ATRX status with their matched primary tumors and demonstrated the progressive pattern of grade II astrocytoma/oligodendroglial tumors and anaplastic oligoastrocytoma with or without IDH1-R132H. Identification of IDH1-R132H and ATRX loss status in the primary-recurrent gliomas may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation. PMID:26918938

Coffee, tea, caffeine intake and risk of adult glioma in 3 prospective cohort studies

PubMed Central

Holick, Crystal N.; Smith, Scott G.; Giovannucci, Edward; Michaud, Dominique S.

2009-01-01

Current data suggest that caffeinated beverages may be associated with lower risk of glioma. Caffeine has different effects on the brain, some which could play a role in brain carcinogenesis, and coffee has been consistently associated with reduced risk of liver cancer, thus suggesting a potential anticarcinogenic effect. A total of 335 incident cases of gliomas (men = 133, women = 202) were available from three independent cohort studies. Dietary intake was assessed by food-frequency questionnaires obtained at baseline and during follow-up. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between consumption of coffee, tea, carbonated beverages, caffeine, and glioma risk adjusting for age and total caloric intake. Estimates from each cohort were pooled using a random-effects model. Consumption of five or more cups of coffee and tea a day compared to no consumption was associated with a decrease risk of glioma (RR = 0.60; 95% CI: 0.41–0.87; p-trend = 0.04). Inverse, although weaker, associations were also observed between coffee, caffeinated coffee, tea, carbonated beverages and glioma risk. No association was observed between decaffeinated coffee and glioma risk. Among men, a statistically significant inverse association was observed between caffeine consumption and risk of glioma (RR = 0.46; 95% CI: 0.26–0.81; p-trend = 0.03); the association was weaker among women. Our findings suggest that consumption of caffeinated beverages, including coffee and tea, may reduce the risk of adult glioma, but further research is warranted to confirm these findings in other populations. PMID:20056621

MicroRNA-1231 exerts a tumor suppressor role through regulating the EGFR/PI3K/AKT axis in glioma.

PubMed

Zhang, Jiale; Zhang, Jie; Qiu, Wenjin; Zhang, Jian; Li, Yangyang; Kong, Enjun; Lu, Ailin; Xu, Jia; Lu, Xiaoming

2018-05-17

MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of glioma. However, the underlying molecular mechanisms are still unclear. We performed microarray analysis to evaluate miRNA expression levels in 158 glioma tissue samples, and examined miR-1231 levels in glioma samples and healthy brain tissues using qRT-PCR. In vitro analyses were performed using miR-1231 mimics, inhibitors, and siRNA targeting EGFR. We used flow cytometry, CCK-8 assays, and colony formation assays to examine glioma proliferation and cell cycle analysis. A dual luciferase reporter assay was performed to examine miR-1231 regulation of EGFR, and the effect of upregulated miR-1231 was investigated in a subcutaneous GBM model. We found that miR-1231 expression was decreased in human glioma tissues and negatively correlated with EGFR levels. Moreover, the downregulation of miR-1231 negatively correlated with the clinical stage of human glioma patients. miR-1231 overexpression dramatically downregulated glioma cell proliferation, and suppressed tumor growth in a nude mouse model. Bioinformatics prediction and a luciferase assay confirmed EGFR as a direct target of miR-1231. EGFR overexpression abrogated the suppressive effect of miR-1231 on the PI3K/AKT pathway and G1 arrest. Taken together, these results demonstrated that EGFR is a direct target of miR-1231. Our findings suggest that the miR-1231/EGFR axis may be a helpful future diagnostic target for malignant glioma.

Sirt2 suppresses glioma cell growth through targeting NF-κB–miR-21 axis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ya’nan; Dai, Dongwei; Lu, Qiong

Highlights: •Sirt2 expression is down-regulated in human glioma tissues and cell lines. •Sirt2 regresses glioma cell growth and colony formation via inducing apoptosis. •miR-21 is essential for the functions of Sirt2 in glioma cells. •Sirt2 deacetylates p65 to decrease miR-21 expression. -- Abstract: Sirtuins are NAD{sup +}-dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We foundmore » that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up-regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-κB–miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy.« less

DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis.

PubMed

Yin, Jinlong; Park, Gunwoo; Lee, Jeong Eun; Choi, Eun Young; Park, Ju Young; Kim, Tae-Hoon; Park, Nayun; Jin, Xiong; Jung, Ji-Eun; Shin, Daye; Hong, Jun Hee; Kim, Hyunggee; Yoo, Heon; Lee, Seung-Hoon; Kim, Youn-Jae; Park, Jong Bae; Kim, Jong Heon

2015-09-01

Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Atorvastatin Promotes Cytotoxicity and Reduces Migration and Proliferation of Human A172 Glioma Cells.

PubMed

Oliveira, Karen A; Dal-Cim, Tharine; Lopes, Flávia G; Ludka, Fabiana K; Nedel, Cláudia B; Tasca, Carla I

2018-02-01

Malignant gliomas have resistance mechanisms to chemotherapy that enable tumor invasiveness and aggressiveness. Alternative therapies in cancer treatment, as statins, have been suggested to decrease proliferation, inhibit cell migration, and induce cell death. The aim of this study was to evaluate the effect of atorvastatin (ATOR) on cell viability, migration, proliferation, apoptosis, and autophagy in A172 human glioma cells. Temozolomide (TMZ), a chemotherapic used to glioma treatment, was tested as a comparison to cytotoxic effects on gliomas. Cell viability was also assessed in primary culture of cortical astrocytes. ATOR treatment (0.1 to 20 μM) did not alter astrocytic viability. However, in glioma cells, ATOR showed cytotoxic effect at 10 and 20 μM concentrations. TMZ (500 μM) reduced cell viability similarly to ATOR, and drug association did not show additive effect on cell viability. ATOR, TMZ, and their association decreased cell migration. ATOR also decreased glioma cell proliferation. ATOR increased apoptosis, and TMZ association showed a potentiation effect, enhancing it. ATOR and TMZ treatment increased acidic vesicular organelle (AVO) presence in A172 cells, an indicative of autophagy. ATOR effect of reducing A172 cell viability did not alter glutamate transport and glutamine synthetase activity, but it was partially prevented through antagonism of ionotropic and metabotropic glutamate receptors. Our data shows a cytotoxic effect of ATOR on glioma cells, whereas no toxicity was observed to astrocytes. ATOR showed similar cytotoxic effect as TMZ to glioma cells, and it may be a safer drug, regarding side effect induction, than chemotherapic agents.

Interaction of allergy history and antibodies to specific Varicella zoster virus proteins on glioma risk

PubMed Central

Lee, Seung-Tae; Bracci, Paige; Zhou, Mi; Rice, Terri; Wiencke, John; Wrensch, Margaret; Wiemels, Joseph

2014-01-01

Glioma is the most common cancer of the central nervous system but with few confirmed risk factors. Glioma has been inversely associated with chicken pox, shingles, and seroreactivity to varicella virus (VZV), as well as to allergies and allergy-associated IgE. The role of antibody reactivity against individual VZV antigens has not been assessed. Ten VZV-related proteins, selected for high immunogenicity or known function, were synthesized and used as targets for antibody measurements in the sera of 143 glioma cases and 131 healthy controls selected from the San Francisco Bay Area Adult Glioma Study. Glioma cases exhibited significantly reduced seroreactivity compared to controls for six antigens, including proteins IE63 (OR = 0.26, 95%CI:0.12-0.58, comparing lowest quartile to highest), and the VZV-unique protein ORF2p (OR = 0.44, 95%CI:0.21-0.96, lowest quartile to highest). When stratifying the study population into those with low and high self-reported allergy history, VZV protein seroreactivity was only associated inversely with glioma among individuals self-reporting more than two allergies. The data provide insight into both allergy and VZV effects on glioma: strong anti-VZV reactions in highly allergic individuals is associated with reduced occurrence of glioma. This result suggests a role for specificity in the anti-VZV immunity in brain tumor suppression for both individual VZV antigens and in the fine-tuning of the immune response by allergy. Anti-VZV reactions may also be a biomarker of effective CNS immunosurveillance due to the tropism of the virus. PMID:24127236

Identifying novel glioma associated pathways based on systems biology level meta-analysis.

PubMed

Hu, Yangfan; Li, Jinquan; Yan, Wenying; Chen, Jiajia; Li, Yin; Hu, Guang; Shen, Bairong

2013-01-01

With recent advances in microarray technology, including genomics, proteomics, and metabolomics, it brings a great challenge for integrating this "-omics" data to analysis complex disease. Glioma is an extremely aggressive and lethal form of brain tumor, and thus the study of the molecule mechanism underlying glioma remains very important. To date, most studies focus on detecting the differentially expressed genes in glioma. However, the meta-analysis for pathway analysis based on multiple microarray datasets has not been systematically pursued. In this study, we therefore developed a systems biology based approach by integrating three types of omics data to identify common pathways in glioma. Firstly, the meta-analysis has been performed to study the overlapping of signatures at different levels based on the microarray gene expression data of glioma. Among these gene expression datasets, 12 pathways were found in GeneGO database that shared by four stages. Then, microRNA expression profiles and ChIP-seq data were integrated for the further pathway enrichment analysis. As a result, we suggest 5 of these pathways could be served as putative pathways in glioma. Among them, the pathway of TGF-beta-dependent induction of EMT via SMAD is of particular importance. Our results demonstrate that the meta-analysis based on systems biology level provide a more useful approach to study the molecule mechanism of complex disease. The integration of different types of omics data, including gene expression microarrays, microRNA and ChIP-seq data, suggest some common pathways correlated with glioma. These findings will offer useful potential candidates for targeted therapeutic intervention of glioma.

Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas.

PubMed

Filley, Anna; Henriquez, Mario; Bhowmik, Tanmoy; Tewari, Brij Nath; Rao, Xi; Wan, Jun; Miller, Margaret A; Liu, Yunlong; Bentley, R Timothy; Dey, Mahua

2018-05-01

Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies.

Joint associations between genetic variants and reproductive factors in glioma risk among women.

PubMed

Wang, Sophia S; Hartge, Patricia; Yeager, Meredith; Carreón, Tania; Ruder, Avima M; Linet, Martha; Inskip, Peter D; Black, Amanda; Hsing, Ann W; Alavanja, Michael; Beane-Freeman, Laura; Safaiean, Mahboobeh; Chanock, Stephen J; Rajaraman, Preetha

2011-10-15

In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9.

PubMed

Katakowski, Mark; Charteris, Nicholas; Chopp, Michael; Khain, Evgeniy

2016-12-01

The phenotypic axis of invasion and proliferation in malignant glioma cells is a well-documented phenomenon. Invasive glioma cells exhibit a decreased proliferation rate and a resistance to apoptosis, and invasive tumor cells dispersed in brain subsequently revert to proliferation and contribute to secondary tumor formation. One miRNA can affect dozens of mRNAs, and some miRNAs are potent oncogenes. Multiple miRNAs are implicated in glioma malignancy, and several of which have been identified to regulate tumor cell motility and division. Using rat 9 L gliosarcoma and human U87 glioblastoma cell lines, we investigated miRNAs associated with the switch between glioma cell invasion and proliferation. Using micro-dissection of 9 L glioma tumor xenografts in rat brain, we identified disparate expression of miR-9 between cells within the periphery of the primary tumor, and those comprising tumor islets within the invasive zone. Modifying miR-9 expression in in vitro assays, we report that miR-9 controls the axis of glioma cell invasion/proliferation, and that its contribution to invasion or proliferation is biphasic and dependent upon local tumor cell density. In addition, immunohistochemistry revealed elevated hypoxia inducible factor 1 alpha (HIF-1α) in the invasive zone as compared to the primary tumor periphery. We also found that hypoxia promotes miR-9 expression in glioma cells. Based upon these findings, we propose a hypothesis for the contribution of miR-9 to the dynamics glioma invasion and satellite tumor formation in brain adjacent to tumor.

Detection of ATRX and IDH1-R132H immunohistochemistry in the progression of 211 paired gliomas.

PubMed

Cai, Jinquan; Zhu, Ping; Zhang, Chuanbao; Li, Qingbin; Wang, Zhiliang; Li, Guanzhang; Wang, Guangzhi; Yang, Pei; Li, Jianlong; Han, Bo; Jiang, Chuanlu; Sun, Ying; Jiang, Tao

2016-03-29

Recurrence and progression to higher grade lesions are key biological events and characteristic behaviors in the evolution process of glioma. A small residual population of cells always escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence or progression. IDH mutation (isocitrate dehydrogenase) and ATRX (alpha-thalassemia/mental retardation, X-linked) loss/mutation occur in association and may represent early genetic alterations in the development of gliomas. However, their prognostic value in the evolution of gliomas still needs further investigation.Two hundreds and eleven serial sampling of gliomas were included in our study. We used immunohistochemistry (IHC) to detect IDH1-R132H mutation and ATRX status and showed that the IDH1-R132H and (or) ATRX status could be necessary to provide the basic molecular information for the "integrated diagnosis" of gliomas. We illustrated an evaluation formula for the evolution of gliomas by IDH1-R132H combined with ATRX immunohistochemistry and identified the association of IDH1-R132H/ATRX loss accompanied by longer progression time interval of patients with gliomas. Furthermore, we observed that most recurrences had a consistent IDH1 and ATRX status with their matched primary tumors and demonstrated the progressive pattern of grade II astrocytoma/oligodendroglial tumors and anaplastic oligoastrocytoma with or without IDH1-R132H. Identification of IDH1-R132H and ATRX loss status in the primary-recurrent gliomas may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation.

Expression of complement membrane regulators membrane cofactor protein (CD46), decay accelerating factor (CD55), and protectin (CD59) in human malignant gliomas.

PubMed Central

Mäenpää, A.; Junnikkala, S.; Hakulinen, J.; Timonen, T.; Meri, S.

1996-01-01

Gliomas are malignant brain tumors, which, despite recent progress in surgical and radiological treatment, still have a poor prognosis. Since gliomas apparently resist immunological clearance mechanisms, we became interested in examining bow gliomas resist killing by the human complement system. The resistance of human cells to complement-mediated damage is, in large part, mediated by specific inhibitors of complement:membrane cofactor protein (CD46), decay-accelerating factor (CD55), and protectin (CD59). In the present study we examined the expression of complement regulators in 14 human glioma tumors and in 7 glioma cell lines (U251, U87, HS683, U373, U138, U118, and H2). Protectin was found to be strongly expressed by all glioma tumors and cell lines. Northern blotting analysis demonstrated the typical pattern of four to five protectin mRNAs in the glioma cells. Except for blood vessels, the expression of decay-accelerating factor was weak or absent in the tumors in situ, whereas in the cell lines its expression varied, ranging from negative to intermediate. Membrane cofactor protein was moderately expressed by all the cell lines but only weakly in the tumors. Cell-killing experiments demonstrated that the glioma cell lines were exceptionally resistant to C-mediated lysis. Five of the seven cell lines (U373, HS683, U118, U138, and H2) resisted complement lysis under conditions where most other cell lines were sensitive to killing. Neutralization experiments using specific monoclonal antibodies indicated that protectin was functionally the most important complement regulator in the glioma cells. The killing of the U87 and U251 cells could be significantly increased by a blocking anti-protectin monoclonal antibody, whereas for the other cell lines only moderate or no response was observed. The H2 cell line resisted killing by all antibodies and by complement. These results show that protectin is the most important complement regulator on human glioma cells. The exceptional complement resistance of some glioma cell lines suggests that they may utilize other, hitherto less well characterized, mechanisms to resist complement killing. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 Figure 7 PMID:8644856

A report on radiation-induced gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salvati, M.; Artico, M.; Caruso, R.

1991-01-15

Radiation-induced gliomas are uncommon, with only 73 cases on record to date. The disease that most frequently occasioned radiation therapy has been acute lymphoblastic leukemia (ALL). Three more cases are added here, two after irradiation for ALL and one after irradiation for tinea capitis. In a review of the relevant literature, the authors stress the possibility that the ALL-glioma and the retinoblastoma-glioma links point to syndromes in their own right that may occur without radiation therapy.56 references.

Distinction of brain tissue, low grade and high grade glioma with time-resolved fluorescence spectroscopy

PubMed Central

Yong, William H.; Butte, Pramod V.; Pikul, Brian K.; Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Black, Keith L.; Marcu, Laura

2010-01-01

Neuropathology frozen section diagnoses are difficult in part because of the small tissue samples and the paucity of adjunctive rapid intraoperative stains. This study aims to explore the use of time-resolved laser-induced fluorescence spectroscopy as a rapid adjunctive tool for the diagnosis of glioma specimens and for distinction of glioma from normal tissues intraoperatively. Ten low grade gliomas, 15 high grade gliomas without necrosis, 6 high grade gliomas with necrosis and/or radiation effect, and 14 histologically uninvolved “normal” brain specimens are spectroscopicaly analyzed and contrasted. Tissue autofluorescence was induced with a pulsed Nitrogen laser (337 nm, 1.2 ns) and the transient intensity decay profiles were recorded in the 370-500 nm spectral range with a fast digitized (0.2 ns time resolution). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site were used for tissue characterization. A linear discriminant analysis diagnostic algorithm was used for tissue classification. Both low and high grade gliomas can be distinguished from histologically uninvolved cerebral cortex and white matter with high accuracy (above 90%). In addition, the presence or absence of treatment effect and/or necrosis can be identified in high grade gliomas. Taking advantage of tissue autofluorescence, this technique facilitates a direct and rapid investigation of surgically obtained tissue. PMID:16368511

Cellular phones, cordless phones, and the risks of glioma and meningioma (Interphone Study Group, Germany).

PubMed

Schüz, Joachim; Böhler, Eva; Berg, Gabriele; Schlehofer, Brigitte; Hettinger, Iris; Schlaefer, Klaus; Wahrendorf, Jürgen; Kunna-Grass, Katharina; Blettner, Maria

2006-03-15

The widespread use of cellular telephones has generated concern about possible adverse health effects, particularly brain tumors. In this population-based case-control study carried out in three regions of Germany, all incident cases of glioma and meningioma among patients aged 30-69 years were ascertained during 2000-2003. Controls matched on age, gender, and region were randomly drawn from population registries. In total, 366 glioma cases, 381 meningioma cases, and 1,494 controls were interviewed. Overall use of a cellular phone was not associated with brain tumor risk; the respective odds ratios were 0.98 (95% confidence interval (CI): 0.74, 1.29) for glioma and 0.84 (95% CI: 0.62, 1.13) for meningioma. Among persons who had used cellular phones for 10 or more years, increased risk was found for glioma (odds ratio = 2.20, 95% CI: 0.94, 5.11) but not for meningioma (odds ratio = 1.09, 95% CI: 0.35, 3.37). No excess of temporal glioma (p = 0.41) or meningioma (p = 0.43) was observed in cellular phone users as compared with nonusers. Cordless phone use was not related to either glioma risk or meningioma risk. In conclusion, no overall increased risk of glioma or meningioma was observed among these cellular phone users; however, for long-term cellular phone users, results need to be confirmed before firm conclusions can be drawn.

Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma

PubMed Central

Kim, Yongbo; Che, Lihua; Kim, Jeong Beom; Chang, Gyeong Eon; Cheong, Eunji; Kang, Seok-Gu; Ha, Yoon

2017-01-01

Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule–induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs. PMID:29161257

Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas.

PubMed

Wang, Huamin; Wang, Hua; Zhang, Wei; Huang, Helen J; Liao, Warren S L; Fuller, Gregory N

2004-08-01

Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal growth factor receptor (EGFR) gene contribute to the progression of gliomas. As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis. We examined the activation status of Akt, NFkappaB, and Stat3 in 259 diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated their association with glioma grade. We observed significant positive correlations between the activation status of Akt and NFkappaB and glioma grade. In contrast, only focal immunoreactivity for phospho-Stat3 was observed in < 9% of high-grade gliomas. In addition, we observed a significant correlation between the activation of Akt and NFkappaB. Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFkappaB-binding activity. Thus, our results demonstrate that constitutive activation of Akt and NFkappaB, but not Stat3, contributes significantly to the progression of diffuse gliomas, and activation of Akt may lead to NFkappaB activation in high-grade gliomas.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique].

PubMed

Figarella-Branger, Dominique; Labrousse, François; Mohktari, Karima

2012-10-01

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas. Copyright © 2012. Published by Elsevier Masson SAS.

Methylation-mediated miR-155-FAM133A axis contributes to the attenuated invasion and migration of IDH mutant gliomas.

PubMed

Huang, Guo-Hao; Du, Lei; Li, Ningning; Zhang, Ying; Xiang, Yan; Tang, Jun-Hai; Xia, Shuli; Zhang, Eric Erquan; Lv, Sheng-Qing

2018-06-06

Gliomas with isocitrate dehydrogenases genes mutation (IDH MT ) were found to be less aggressive than their wildtype (IDH WT ) counterparts. However, the mechanism remains unclear. The current study aims to investigate the role of silenced oncogenic microRNAs in IDH MT gliomas, which were largely ignored and may contribute to the less aggressive behavior of IDH MT gliomas. Microarrays, bioinformatics analysis of the data from TCGA and qPCR analysis of samples from our experimental cohort (LGG: IDH WT =10, IDH MT =31; GBM: IDH WT =34, IDH MT =9) were performed. The results show that miR-155 was consistently down-regulated in IDH MT gliomas. Establishment of IDH1 R132H overexpressing glioma cell line and bisulfite sequencing PCR suggested that miR-155 down-regulation was associated with IDH1 R132H mutation induced promoter CpG islands methylation. The cancer testis antigen FAM133A is a direct downstream target of miR-155 and is a negative regulator of glioma invasion and migration possibly by regulating matrix metallopeptidase 14 (MMP14). Together, we found that methylation-regulated miR-155-FAM133A axis may contribute to the attenuated invasion and migration of IDH MT gliomas by targeting MMP14. Copyright © 2018. Published by Elsevier B.V.

Hu antigen R (HuR) multimerization contributes to glioma disease progression.

PubMed

Filippova, Natalia; Yang, Xiuhua; Ananthan, Subramaniam; Sorochinsky, Anastasia; Hackney, James R; Gentry, Zachery; Bae, Sejong; King, Peter; Nabors, L Burt

2017-10-13

Among primary brain cancers, gliomas are the most deadly and most refractory to current treatment modalities. Previous reports overwhelmingly support the role of the RNA-binding protein Hu antigen R (HuR) as a positive regulator of glioma disease progression. HuR expression is consistently elevated in tumor tissues, and a cytoplasmic localization appears essential for HuR-dependent oncogenic transformation. Here, we report HuR aggregation (multimerization) in glioma and the analysis of this tumor-specific HuR protein multimerization in clinical brain tumor samples. Using a split luciferase assay, a bioluminescence resonance energy transfer technique, and site-directed mutagenesis, we examined the domains involved in HuR multimerization. Results obtained with the combination of the split HuR luciferase assay with the bioluminescence resonance energy transfer technique suggested that multiple (at least three) HuR molecules come together during HuR multimerization in glioma cells. Using these data, we developed a model of HuR multimerization in glioma cells. We also demonstrate that exposing glioma cells to the HuR inhibitor tanshinone group compound 15,16-dihydrotanshinone-I or to the newly identified compound 5 disrupts HuR multimerization modules and reduces tumor cell survival and proliferation. In summary, our findings provide new insights into HuR multimerization in glioma and highlight possible pharmacological approaches for targeting HuR domains involved in cancer cell-specific multimerization.

Synergism between PKCδ regulators hypericin and rottlerin enhances apoptosis in U87 MG glioma cells after light stimulation.

PubMed

Misuth, Matus; Horvath, Denis; Miskovsky, Pavol; Huntosova, Veronika

2017-06-01

Gliomas belong to the most infiltrative types of tumors. Photodynamic therapy (PDT) can be applied to regulate glioma cell proliferation. The inhibitors of PKCs (Protein Kinase C) are very promising drugs that can mediate glioma cells apoptosis in PDT. Hypericin is one of PKCs regulators, and thanks to its physicochemical properties it can be used in PDT. Rottlerin is also considered to be the PKCδ inhibitor. Its implementation in PDT may significantly influence glioma cells response to PDT. The viability of U87 MG glioma cells in the presence of rottlerin and hypericin was assessed by MTT assay and flow cytometry in the absence and presence of light. The flow cytometric data were analyzed through Shannon entropy. The oxidative stress and immunocytochemistry of PKCδ and phosphorylated Bcl-2 (the regulators of apoptosis) were observed using fluorescence microscopy. A pretreatment of glioma cells with rottlerin before hypericin induced PDT led to significant increase in apoptosis accompanied by the decrease of intracellular oxidative stress and increase of phosphorylated Bcl-2 in the cytoplasm of U87 MG cells. In conclusion, we assume that the synergism between rottlerin and hypericin leads firstly to activation of rescue mechanisms in the glioma cells, but finally this cooperation triggers apoptosis rather than necrosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Older age at the completion of linear growth is associated with an increased risk of adult glioma.

PubMed

Little, Rebecca B; Nabors, L Burt; Olson, Jeffrey J; Thompson, Zachary J; Rozmeski, Carrie M; LaRocca, Renato V; Forsyth, Peter A; Thompson, Reid C; Oster, Robert A; Chowdhary, Sajeel A; Egan, Kathleen M

2017-07-01

To examine the association of age when adult height was attained with glioma risk. We analyzed data from a US-based case-control study of glioma risk factors. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated between age at attainment of adult height and glioma risk. Multivariate models were adjusted for age, race, sex, education, and state of residence. We examined associations overall, and according to glioma grade, sex, and final adult height. The study set included n = 951 controls and n = 776 cases, with a median age of 56 (18-92); the majority was male (53.8%) and identified as Caucasian. Older age at height completion was associated with an increased risk of glioma. A significant positive trend was observed both for glioblastoma (OR 1.10; 95% CI 1.04-1.17 per 1-year increase in age) and lower grade non-glioblastoma subtypes combined (OR 1.18; 95% CI 1.10-1.28 per year increase in age). The association was observed in men and women, and in all categories of final adult height. We observed for the first time a positive association between glioma risk and a prolonged adolescent growth phase. Our results suggest a role for factors governing the timing and intensity of growth in adolescence as risk-determining exposures in adult glioma.

Long term reshaping of language, sensory, and motor maps after glioma resection: a new parameter to integrate in the surgical strategy

PubMed Central

Duffau, H; Denvil, D; Capelle, L

2002-01-01

Objectives: To describe cortical reorganisation and the effects of glioma infiltration on local brain function in three patients who underwent two operations 12–24 months apart. Methods: Three patients who had no neurological deficit underwent two operations for low grade glioma, located in functionally important brain regions. During each operation, local brain function was characterised by electrical mapping and awake craniotomy. Results: Language or sensorimotor areas had been invaded by the tumour at the time of the first operation, leading to incomplete glioma removal in all cases. Because of a tumour recurrence, the patients were reoperated on between 12 and 24 months later. Functional reorganisation of the language, sensory, and motor maps was detected by electrical stimulation of the brain, and this allowed total glioma removal without neurological sequelae. Conclusions: These findings show that surgical resection of a glioma can lead to functional reorganisation in the peritumorous and infiltrated brain. It may be that this reorganisation is directly or indirectly caused by the surgical procedure. If this hypothesis is confirmed by other studies, the use of such brain plasticity potential could be used when planning surgical options in some patients with low grade glioma. Such a strategy could extend the limits of tumour resection in gliomas involving eloquent brain areas without causing permanent morbidity. PMID:11909913

Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas.

PubMed

Yu, Jinhua; Shi, Zhifeng; Ji, Chunhong; Lian, Yuxi; Wang, Yuanyuan; Chen, Liang; Mao, Ying

2017-10-01

Anatomical location of gliomas has been considered as a factor implicating the contributions of a specific precursor cells during the tumor growth. Isocitrate dehydrogenase 1 (IDH1) is a pathognomonic biomarker with a significant impact on the development of gliomas and remarkable prognostic effect. The correlation between anatomical location of tumor and IDH1 states for low-grade gliomas was analyzed quantitatively in this study. Ninety-two patients diagnosed of low-grade glioma pathologically were recruited in this study, including 65 patients with IDH1-mutated glioma and 27 patients with wide-type IDH1. A convolutional neural network was designed to segment the tumor from three-dimensional magnetic resonance imaging images. Voxel-based lesion symptom mapping was then employed to study the tumor location distribution differences between gliomas with mutated and wild-type IDH1. In order to characterize the location differences quantitatively, the Automated Anatomical Labeling Atlas was used to partition the standard brain atlas into 116 anatomical volumes of interests (AVOIs). The percentages of tumors with different IDH1 states in 116 AVOIs were calculated and compared. Support vector machine and AdaBoost algorithms were used to estimate the IDH1 status based on the 116 location features of each patient. Experimental results proved that the quantitative tumor location measurement could be a very important group of imaging features in biomarker estimation based on radiomics analysis of glioma.

Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images.

PubMed

Inano, Rika; Oishi, Naoya; Kunieda, Takeharu; Arakawa, Yoshiki; Kikuchi, Takayuki; Fukuyama, Hidenao; Miyamoto, Susumu

2016-07-26

Preoperative glioma grading is important for therapeutic strategies and influences prognosis. Intratumoral heterogeneity can cause an underestimation of grading because of the sampling error in biopsies. We developed a voxel-based unsupervised clustering method with multiple magnetic resonance imaging (MRI)-derived features using a self-organizing map followed by K-means. This method produced novel magnetic resonance-based clustered images (MRcIs) that enabled the visualization of glioma grades in 36 patients. The 12-class MRcIs revealed the highest classification performance for the prediction of glioma grading (area under the receiver operating characteristic curve = 0.928; 95% confidential interval = 0.920-0.936). Furthermore, we also created 12-class MRcIs in four new patients using the previous data from the 36 patients as training data and obtained tissue sections of the classes 11 and 12, which were significantly higher in high-grade gliomas (HGGs), and those of classes 4, 5 and 9, which were not significantly different between HGGs and low-grade gliomas (LGGs), according to a MRcI-based navigational system. The tissues of classes 11 and 12 showed features of malignant glioma, whereas those of classes 4, 5 and 9 showed LGGs without anaplastic features. These results suggest that the proposed voxel-based clustering method provides new insights into preoperative regional glioma grading.

MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations.

PubMed

Cui, Daming; Sajan, Pandey; Shi, Jinlong; Shen, Yiwen; Wang, Ke; Deng, Xianyu; Zhou, Lin; Hu, Pingping; Gao, Liang

2017-04-11

High-grade gliomas are severe tumors with poor prognosis. An R132H mutation in the isocitrate dehydrogenase (IDH1) gene prolongs the life of glioma patients. In this study, we investigated which genes are differentially regulated in IDH1 wild type (IDH1WT) or IDH1 R132H mutation (IDH1R132H) glioblastoma cells. Growth arrest and DNA-damage-inducible protein (GADD45A) was downregulated and microRNA 148a (miR-148a) was upregulated in in IDH1R132H human glioblastomas tissues. The relationship between GADD45A and miR-148a is unknown. In vitro experiments showed that GADD45A negatively regulates IDH1R132H glioma cell proliferation, migration, and invasion, and neurosphere formation in IDH1R132H glioblastoma stem cells (GSC). In addition, a human orthotopic xenograft mouse model showed that GADD45A reduced tumorigenesis in vivo. Our findings demonstrated that miR-148a promotes glioma cell invasion and tumorigenesis by downregulating GADD45A. Our findings provide novel insights into how GADD45A is downregulated by miR-148a in IDH1R132H glioma and may help to identify therapeutic targets for the effective treatment of high-grade glioma.

[Expression of isocitrate dehydrogenase 1 gene R132H and its diagnostic application in glioma].

PubMed

PIAO, Yue-shan; LU, De-hong; ZHANG, Xiao-juan; TANG, Guo-cai; YANG, Hong

2011-03-01

To investigate the immunohistochemical expression of isocitrate dehydrogenase 1 gene (IDH1) R132H in glioma and its diagnostic utility. Immunohistochemical study of IDH1R132H expression was performed on formalin-fixed paraffin-embedded tissue samples of 75 gliomas, including 33 cases of grade II, 20 cases of grade III and 22 cases of grade IV tumors. Six cases of pilocytic astrocytoma and 12 cases of gliosis were used as controls. Nineteen in 33 cases of grade II (57.6%), 8 in 20 cases of grade III (40.0%), 6 in 22 cases of grade IV (27.3%) showed positive cytoplasmic staining of IDH1R132H. Scattered invasive glioma cells at the tumor periphery also expressed IDH1R132H. Gliomas involving the frontal lobe showed more strong IDH1R132H staining. In contrast, none of the pilocytic astrocytomas and gliosis showed IDH1R132H staining. Moreover, the rate of p53 immunopositivities were 42.4% (14/33) in grade II, 65.0% (13/20) in grade III and 77.3% (17/22) in grade IV gliomas. There were no statistic correlations between expression of IDH1R132H and p53. IDH1R132H tends to express preferentially in low-grade gliomas, and it thus may serve as a valuable marker in distinguishing low grade gliomas from gliosis.

MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations

PubMed Central

Shi, Jinlong; Shen, Yiwen; Wang, Ke; Deng, Xianyu; Zhou, Lin; Hu, Pingping; Gao, Liang

2017-01-01

High-grade gliomas are severe tumors with poor prognosis. An R132H mutation in the isocitrate dehydrogenase (IDH1) gene prolongs the life of glioma patients. In this study, we investigated which genes are differentially regulated in IDH1 wild type (IDH1WT) or IDH1 R132H mutation (IDH1R132H) glioblastoma cells. Growth arrest and DNA-damage-inducible protein (GADD45A) was downregulated and microRNA 148a (miR-148a) was upregulated in in IDH1R132H human glioblastomas tissues. The relationship between GADD45A and miR-148a is unknown. In vitro experiments showed that GADD45A negatively regulates IDH1R132H glioma cell proliferation, migration, and invasion, and neurosphere formation in IDH1R132H glioblastoma stem cells (GSC). In addition, a human orthotopic xenograft mouse model showed that GADD45A reduced tumorigenesis in vivo. Our findings demonstrated that miR-148a promotes glioma cell invasion and tumorigenesis by downregulating GADD45A. Our findings provide novel insights into how GADD45A is downregulated by miR-148a in IDH1R132H glioma and may help to identify therapeutic targets for the effective treatment of high-grade glioma. PMID:28445981

Red and processed meat consumption and risk of glioma in adults: A systematic review and meta-analysis of observational studies

PubMed Central

Saneei, Parvane; Willett, Walter; Esmaillzadeh, Ahmad

2015-01-01

Background: These findings from several observational studies, investigated the association between red meat consumption and gliomas, were inconsistent. We conducted a systematic review and meta-analysis of observational studies to summarize available date on the relation between meat intake and risk of glioma. Materials and Methods: A systematic literature search of relevant reports published until May 2014 of the PubMed/Medline, ISI Web of Knowledge, Excerpta Medica database, Ovid database, Google Scholar, and Scopus databases was conducted. From 723 articles yielded in the preliminary literature search, data from eighteen publications (14 case-control, three cohort, and one nested case-control study) on unprocessed red meat, processed meat, and/or total red meat consumption in relation to glioma in adults were included in the analysis. Quality assessment of studies was performed. Random effects model was used to conduct the meta-analysis. Results: We found a positive significant association between unprocessed red meat intake and risk of glioma (relative risk [RR] = 1.30; 95% confidence interval [CI]: 1.08-1.58) after excluding three studies with uncertain type of brain cancer. This analysis included only one cohort study which revealed no relation between unprocessed red meat intake and glioma (RR = 1.75; 95% CI: 0.35-8.77). Consumption of processed meats was not related to increased risk of glioma in population-based case-control studies (RR = 1.26; 95% CI: 1.05-1.51) and reduced risk in hospital-based case-controls (RR = 0.79; 95% CI: 0.65-0.97). No significant association was seen between processed red meat intake and risk of glioma in cohort studies (RR: 1.08; 95% CI: 0.84-1.37). Total red meat consumption was not associated with risk of adult glioma in case-control or cohort studies. Conclusion: In this meta-analysis of 18 observational studies, we found a modest positive association between unprocessed red meat intake and risk of gliomas based almost entirely on case-control studies. Processed red meat was overall not associated with risk of gliomas in case-control or cohort studies. PMID:26600837

Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment

PubMed Central

Karthikeyan, Aparna; Gupta, Neelima; Tang, Carol; Mallilankaraman, Karthik; Silambarasan, Maskomani; Shi, Meng; Lu, Lei; Ang, Beng Ti; Ling, Eng-Ang; Dheen, S. Thameem

2018-01-01

Glioma tumors constitute a significant portion of microglial cells, which are known to support tumor progression. The present study demonstrates that transforming growth factor-β (TGFβ) signaling pathway in microglia in a glioma environment is involved in tumor progression and pathogenesis. It has been shown that the TGFβ level is elevated in higher grades of gliomas and its signaling pathway regulates tumor progression through phosphorylation of SMAD2 and SMAD3, which form a complex with SMAD4 to regulate target gene transcription. In an in vitro cell line-based model increased protein levels of pSMAD2/3, total SMAD2/3 and SMAD4 were observed in murine BV2 microglia cultured in glioma conditioned medium (GCM), indicative of the activated TGFβ signaling pathway in microglia associated with glioma environment. Immunofluorescence labeling further revealed the expression of SMAD4 in microglial and non-microglial cells of human glioblastomas tissue in vivo. Functional analysis through shRNA-mediated stable knockdown of SMAD4 in microglia revealed the downregulation of the expression of matrix metalloproteinase 9 (MMP9), which has been shown to be involved in tumor progression and cell migration. Further, knockdown of SMAD4 in microglia decreased the migration of microglial cells towards GCM, indicating that SMAD4 promotes microglial migration in glioma environment. In addition, SMAD4 has been shown to be post-transcriptionally regulated by microRNA-146a, which was downregulated in microglia treated with GCM. Overexpression of miR-146a resulted in decreased expression of SMAD4 together with tumor supportive gene MMP9 in microglia, and subsequently suppressed microglial migration towards GCM, possibly through regulation of SMAD4. On the other hand, the cell viability assay revealed decreased viability of glioma cells when they were treated with conditioned medium derived from SMAD4 knockdown microglia or miR-146a overexpressed microglia as compared to glioma cells treated with the medium from control microglial cells. Taken together, the present study suggests that microglial SMAD4 which is epigenetically regulated by miR-146a promotes microglial migration in gliomas and glioma cell viability.

Gliomas: Application of Cumulative Histogram Analysis of Normalized Cerebral Blood Volume on 3 T MRI to Tumor Grading

PubMed Central

Kim, Hyungjin; Choi, Seung Hong; Kim, Ji-Hoon; Ryoo, Inseon; Kim, Soo Chin; Yeom, Jeong A.; Shin, Hwaseon; Jung, Seung Chai; Lee, A. Leum; Yun, Tae Jin; Park, Chul-Kee; Sohn, Chul-Ho; Park, Sung-Hye

2013-01-01

Background Glioma grading assumes significant importance in that low- and high-grade gliomas display different prognoses and are treated with dissimilar therapeutic strategies. The objective of our study was to retrospectively assess the usefulness of a cumulative normalized cerebral blood volume (nCBV) histogram for glioma grading based on 3 T MRI. Methods From February 2010 to April 2012, 63 patients with astrocytic tumors underwent 3 T MRI with dynamic susceptibility contrast perfusion-weighted imaging. Regions of interest containing the entire tumor volume were drawn on every section of the co-registered relative CBV (rCBV) maps and T2-weighted images. The percentile values from the cumulative nCBV histograms and the other histogram parameters were correlated with tumor grades. Cochran’s Q test and the McNemar test were used to compare the diagnostic accuracies of the histogram parameters after the receiver operating characteristic curve analysis. Using the parameter offering the highest diagnostic accuracy, a validation process was performed with an independent test set of nine patients. Results The 99th percentile of the cumulative nCBV histogram (nCBV C99), mean and peak height differed significantly between low- and high-grade gliomas (P = <0.001, 0.014 and <0.001, respectively) and between grade III and IV gliomas (P = <0.001, 0.001 and <0.001, respectively). The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000). Validation using the two cutoff values of nCBV C99 achieved a diagnostic accuracy of 66.7% (6/9) for the separation of all three glioma grades. Conclusion Cumulative histogram analysis of nCBV using 3 T MRI can be a useful method for preoperative glioma grading. The nCBV C99 value is helpful in distinguishing high- from low-grade gliomas and grade IV from III gliomas. PMID:23704910

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future.

PubMed

Chen, Ricky; Cohen, Adam L; Colman, Howard

2016-08-01

High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

A long noncoding RNA UCA1 promotes proliferation and predicts poor prognosis in glioma.

PubMed

Zhao, W; Sun, C; Cui, Z

2017-06-01

Acting as a proto-oncogene, long noncoding RNAs (lncRNAs) urothelial carcinoembryonic antigen 1 (UCA1) plays a key role in the occurrence and development of several human tumors. However, the expression and biological functions of UCA1 in glioma are less known. This study discussed the expression of UCA1 in glioma and its effect on the proliferation and cell cycle of glioma cells. LncRNA UCA1 expressions in 64 glioma samples (Grade I-II in 22 cases and Grade III-IV in 42 cases, according to WHO criteria) and 10 normal brain samples were detected using real-time fluorescence quantitative PCR. On this basis, the correlations of UCA1 to clinicopathological characteristics and prognosis of glioma were assessed. Then, using qPCR, the lncRNA UCA1 expressions in glioma cell lines and astrocytes were detected. UCA1-overexpressing glioma cell lines U87 and U251 were further detected after siRNA transfection of these two cell lines, and the impact on cell proliferation and cell cycle was assessed with CCK-8 (cell counting kit-8) assay and flow cytometry method (FCM), respectively. The expression of cyclin D1, a cell cycle-related protein, was detected using Western Blot. LncRNA UCA1 expression in the glioma samples was obviously higher as compared with the normal brain samples (P < 0.001), and the expression was correlated significantly with grading of the tumors (P < 0.05). However, lncRNA UCA1 expression was not correlated with age, gender, tumor size and KPS score (P > 0.05). After interference of UCA1 expression by siRNA transfection, the proliferation of both U251 and SHG-44 cells was inhibited (P < 0.05), with more cells arrested in G0/G1 (P < 0.05). Moreover, cyclin D1 expression was also downregulated considerably. LncRNA UCA1 can promote the proliferation and cell cycle progression of glioma cells by upregulating cyclin D1 transcription. So UCA1 may serve as an independent prognostic indicator and a novel therapeutic target for glioma.

Proton Beam Radiation Therapy in Treating Patients With Low Grade Gliomas

ClinicalTrials.gov

2015-12-14

Adult Brain Tumor; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Melanocytic Lesion; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma; Adult Pineocytoma; Recurrent Adult Brain Tumor

Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma

ClinicalTrials.gov

2017-10-11

Brain Stem Glioma; Cerebral Astrocytoma; Childhood Cerebellar Anaplastic Astrocytoma; Childhood Cerebral Anaplastic Astrocytoma; Childhood Spinal Cord Neoplasm; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebral Astrocytoma

3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects.

PubMed

El Sayed, S M; El-Magd, R M Abou; Shishido, Y; Chung, S P; Diem, T H; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

2012-02-01

Oxidative stress-energy depletion therapy using oxidative stress induced by D-amino acid oxidase (DAO) and energy depletion induced by 3-bromopyruvate (3BP) was reported recently (El Sayed et al., Cancer Gene Ther., 19, 1-18, 2012). Even in the presence of oxygen, cancer cells oxidize glucose preferentially to produce lactate (Warburg effect) which seems vital for cancer microenvironment and progression. 3BP is a closely related structure to lactate and pyruvate and may antagonize their effects as a novel mechanism of its action. Pyruvate exerted a potent H(2)O(2) scavenging effect to exogenous H(2)O(2), while lactate had no scavenging effect. 3BP induced H(2)O(2) production. Pyruvate protected against H(2)O(2)-induced C6 glioma cell death, 3BP-induced C6 glioma cell death but not against DAO/D-serine-induced cell death, while lactate had no protecting effect. Lactate and pyruvate protected against 3BP-induced C6 glioma cell death and energy depletion which were overcome with higher doses of 3BP. Lactate and pyruvate enhanced migratory power of C6 glioma which was blocked by 3BP. Pyruvate and lactate did not protect against C6 glioma cell death induced by other glycolytic inhibitors e.g. citrate (inhibitor of phosphofructokinase) and sodium fluoride (inhibitor of enolase). Serial doses of 3BP were synergistic with citrate in decreasing viability of C6 glioma cells and spheroids. Glycolysis subjected to double inhibition using 3BP with citrate depleted ATP, clonogenic power and migratory power of C6 glioma cells. 3BP induced a caspase-dependent cell death in C6 glioma. 3BP was powerful in decreasing viability of human glioblastoma multiforme cells (U373MG) and C6 glioma in a dose- and time-dependent manner.

Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators

PubMed Central

Lo, Hui-Wen; Cao, Xinyu; Zhu, Hu; Ali-Osman, Francis

2009-01-01

Purpose The goals of this study are to elucidate the relationship of the oncogenic transcription factor signal transducer and activator of transcription 3(STAT3) with glioma aggressiveness and to understand the role of high STAT3 activity in the resistance of malignant gliomas and medulloblastomas to chemotherapy. Experimental Design Immunohistochemical staining and biochemical methods were used to examine the extent of STAT3 activation and EGFR expression in primary specimens and cell lines, respectively. Cellular response to drug treatments was determined using cell cytotoxicity and clonogenic growth assays. Results We found STAT3 to be constitutively activated in 60% of primary high-grade/malignant gliomas and the extent of activation correlated positively with glioma grade. High levels of activated/phosphorylated STAT3 were also present in cultured human malignant glioma and medulloblastoma cells. Three STAT3-activating kinases, Janus-activated kinase 2 (JAK2), EGFR, and EGFRvIII, contributed to STAT3 activation. An inhibitor toJAK2/STAT3, JSI-124, significantly reduced expression of STAT3 target genes, suppressed cancer cell growth, and induced apoptosis. Furthermore, we found that STAT3 constitutive activation coexisted with EGFR expression in 27.2% of primary high-grade/malignant gliomas and such coexpression correlated positively with glioma grade. Combination of an anti-EGFR agent Iressa and a JAK2/STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII. JSI-124 also sensitized malignant glioma and medulloblastoma cells to temozolomide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and cisplatin in which a synergism existed between JSI-124 and cisplatin. Conclusion STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents. PMID:18829483

Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Si-Jian; Wu, Yue-Bing; Cai, Shang

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitromore » proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma. - Highlights: • Tspn8 is over-expressed in multiple clinical malignant glioma tissues. • Tspn8 expression is correlated with the grade of malignant gliomas. • Tspn8 knockdown suppresses U251MG/U87MG proliferation and in vitro migration. • Tspn8 knockdown significantly increases TMZ sensitivity in U251MG/U87MG cells. • Tspn8 forms a complex with FAK, required for FAK activation.« less

Interactions between glioma and pregnancy: insight from a 52-case multicenter series.

PubMed

Peeters, Sophie; Pagès, Mélanie; Gauchotte, Guillaume; Miquel, Catherine; Cartalat-Carel, Stéphanie; Guillamo, Jean-Sébastien; Capelle, Laurent; Delattre, Jean-Yves; Beauchesne, Patrick; Debouverie, Marc; Fontaine, Denys; Jouanneau, Emmanuel; Stecken, Jean; Menei, Philippe; De Witte, Olivier; Colin, Philippe; Frappaz, Didier; Lesimple, Thierry; Bauchet, Luc; Lopes, Manuel; Bozec, Laurence; Moyal, Elisabeth; Deroulers, Christophe; Varlet, Pascale; Zanello, Marc; Chretien, Fabrice; Oppenheim, Catherine; Duffau, Hugues; Taillandier, Luc; Pallud, Johan

2018-01-01

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Upregulation of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 Promotes Radioresistance of Glioma by Repressing Semaphorin 5A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Rong; Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian; Yao, Qiwei

Purpose: Although increasing evidence has shown that long noncoding RNAs play an important regulatory role in carcinogenesis and tumor progression, little is known about the role of small nucleolar RNA host gene 18 (SNHG18) in cancer. The goal of this study was to investigate the expression of SNHG18 and its clinical significance in glioma. Methods and Materials: Differences in the lncRNA expression profile between M059K and M059J cells were assessed by lncRNA expression microarray analysis. The expression and localization of SNHG18 in glioma cells or tissues was evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH),more » respectively. the clinical associations of SNHG18 in glioma was evaluated by qRT-PCR, ISH and immunohistochemistry. The role of SNHG18 in glioma radiosensitivity was evaluated by colony formation assays, immunofluorescence, Western blot and tumor growth inhibition study. Results: The present study investigated the clinical associations of SNHG18 and its role in glioma. Our results showed that the expression of SNHG18 was remarkably upregulated in clinical glioma tissues compared with normal brain tissues. SNHG18 expression was associated with the clinical tumor grade and correlated negatively with isocitrate dehydrogenase 1 mutation. In addition, knockdown of SNHG18 with short hairpin RNA suppressed the radioresistance of glioma cells, and transgenic expression of SNHG18 had the opposite effect. Furthermore, xenograft tumors grown from cells with SNHG18 deletion were more radiosensitive than tumors grown from control cells. Further studies revealed that SNHG18 promotes radioresistance by inhibiting semaphorin 5A and that inhibition of semaphorin 5A expression abrogated the radiosensitizing effect caused by SNHG18 deletion. Conclusions: Our findings provide new insights into the role of SNHG18 in glioma and suggest its potential as a target for glioma therapy.« less

Long non-coding RNA SNHG6 promotes glioma tumorigenesis by sponging miR-101-3p.

PubMed

Meng, Qiang; Yang, Bao-Ying; Liu, Bei; Yang, Ji-Xue; Sun, Yang

2018-05-01

Glioma is the most common primary brain tumor. The small nucleolar RNA host gene (SNHG) SNHG6 is a potential oncogene in the development of several types of cancers. In this study, we investigated the functional role of long non-coding RNA (lncRNA) SNHG6 in the malignancy of glioma in cell lines and transplanted nude mice. We found that the expression of lncRNA SNHG6 was higher in glioma tissues and cells than in normal brain tissues and cells. The expression of lncRNA SNHG6 was positively correlated with the malignancy and poor prognosis of glioma patients. microRNA (miR)-101-3p expression was decreased in glioma tissues and cells and was negatively correlated with the malignancy and poor prognosis of glioma patients. In glioma tissues, the expression of lncRNA SNHG6 was negatively correlated with the expression of miR-101-3p. SNHG6 contained a binding site of miR-101-3p. Knockdown of SNHG6 expression resulted in a significant increase of miR-101-3p expression. miR-101-3p mimic markedly decreased the luciferase activity of SNHG6. Knockdown of SNHG6 inhibited glioma cell proliferation, migration, and epithelial-mesenchymal transition (EMT), and increased apoptosis. miR-101-3p mimic enhanced knockdown of SNHG6-induced inhibition of cell proliferation, migration, and EMT, and an increase of apoptosis. Anti-miR-101-3p reversed the the effects of si-SNHG6 on cell malignancy. Knockdown of SNHG6 remarkably reduced the increase of tumor volumes in xenograft mouse models. In tumor tissues, knockdown of SNHG6 increased the expression of miR-101-3p and reduced EMT biomarker expression. Our study provides novel insights into the functions of lncRNA SNHG6/miR-101-3p axis in the tumorigenesis of glioma.

Body mass index, physical activity, and risk of adult meningioma and glioma: A meta-analysis.

PubMed

Niedermaier, Tobias; Behrens, Gundula; Schmid, Daniela; Schlecht, Inga; Fischer, Beate; Leitzmann, Michael F

2015-10-13

Whether adiposity and lack of physical activity affect the risk for developing meningioma and glioma is poorly understood. Our objective was to characterize these associations in detail. We conducted a systematic review and meta-analysis of adiposity and physical activity in relation to meningioma and glioma using cohort and case-control studies published through February 2015. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified 12 eligible studies of body mass index (BMI) and 6 studies of physical activity, comprising up to 2,982 meningioma cases and 3,057 glioma cases. Using normal weight as the reference group, overweight (summary relative risk [RR] = 1.21, 95% confidence interval [CI] = 1.01-1.43) and obesity (RR = 1.54, 95% CI = 1.32-1.79) were associated with increased risk of meningioma. In contrast, overweight (RR = 1.06, 95% CI = 0.94-1.20) and obesity (RR = 1.11, 95% CI = 0.98-1.27) were unrelated to glioma. Similarly, dose-response meta-analyses revealed a statistically significant positive association of BMI with meningioma, but not glioma. High vs low physical activity levels showed a modest inverse relation to meningioma (RR = 0.73, 95% CI = 0.61-0.88) and a weak inverse association with glioma (RR = 0.86, 95% CI = 0.76-0.97). Relations persisted when the data were restricted to prospective studies, except for the association between physical activity and glioma, which was rendered statistically nonsignificant (RR = 0.91, 95% CI = 0.77-1.07). Adiposity is related to enhanced risk for meningioma but is unassociated with risk for glioma. Based on a limited body of evidence, physical activity is related to decreased risk of meningioma but shows little association with risk of glioma. © 2015 American Academy of Neurology.

Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients

PubMed Central

Kanamori, Masayuki; Higa, Tsuyoshi; Sonoda, Yukihiko; Murakami, Shohei; Dodo, Mina; Kitamura, Hiroshi; Taguchi, Keiko; Shibata, Tatsuhiro; Watanabe, Mika; Suzuki, Hiroyoshi; Shibahara, Ichiyo; Saito, Ryuta; Yamashita, Yoji; Kumabe, Toshihiro; Yamamoto, Masayuki; Motohashi, Hozumi; Tominaga, Teiji

2015-01-01

Background Nuclear factor erythroid 2–related factor 2 (NRF2) plays pivotal roles in cytoprotection. We aimed at clarifying the contribution of the NRF2 pathway to malignant glioma pathology. Methods NRF2 target gene expression and its association with prognosis were examined in 95 anaplastic gliomas with or without isocitrate dehydrogenase (IDH) 1/2 gene mutations and 52 glioblastomas. To explore mechanisms for the altered activity of the NRF2 pathway, we examined somatic mutations and expressions of the NRF2 gene and those encoding NRF2 regulators, Kelch-like ECH-associated protein 1 (KEAP1) and p62/SQSTSM. To clarify the functional interaction between IDH1 mutations and the NRF2 pathway, we introduced a mutant IDH1 to T98 glioblastoma-derived cells and examined the NRF2 activity in these cells. Results NRF2 target genes were elevated in 13.7% and 32.7% of anaplastic gliomas and glioblastomas, respectively. Upregulation of NRF2 target genes correlated with poor prognosis in anaplastic gliomas but not in glioblastomas. Neither somatic mutations of NRF2/KEAP1 nor dysregulated expression of KEAP1/p62 explained the increased expression of NRF2 target genes. In most cases of anaplastic glioma with mutated IDH1/2, NRF2 and its target genes were downregulated. This was reproducible in IDH1 R132H–expressing T98 cells. In minor cases of IDH1/2-mutant anaplastic gliomas with increased expression of NRF2 target genes, the clinical outcomes were significantly poor. Conclusions The NRF2 activity is increased in a significant proportion of malignant gliomas in general but decreased in the majority of IDH1/2-mutant anaplastic gliomas. It is plausible that the NRF2 pathway plays an important role in tumor progression of anaplastic gliomas with IDH1/2 mutations. PMID:25304134

The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells.

PubMed

Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Nam, Do-Hyun; Kim, Hyunggee

2010-11-01

A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.

Noninvasive amide proton transfer magnetic resonance imaging in evaluating the grading and cellularity of gliomas.

PubMed

Bai, Yan; Lin, Yusong; Zhang, Wei; Kong, Lingfei; Wang, Lifu; Zuo, Panli; Vallines, Ignacio; Schmitt, Benjamin; Tian, Jie; Song, Xiaolei; Zhou, Jinyuan; Wang, Meiyun

2017-01-24

Using noninvasive magnetic resonance imaging techniques to accurately evaluate the grading and cellularity of gliomas is beneficial for improving the patient outcomes. Amide proton transfer imaging is a noninvasive molecular magnetic resonance imaging technique based on chemical exchange saturation transfer mechanism that detects endogenous mobile proteins and peptides in biological tissues. Between August 2012 and November 2015, a total number of 44 patients with pathologically proven gliomas were included in this study. We compared the capability of amide proton transfer magnetic resonance imaging with that of noninvasive diffusion-weighted imaging and noninvasive 3-dimensional pseudo-continuous arterial spin imaging in evaluating the grading and cellularity of gliomas. Our results reveal that amide proton transfer magnetic resonance imaging is a superior imaging technique to diffusion-weighted imaging and 3-dimensional pseudo-continuous arterial spin imaging in the grading of gliomas. In addition, our results showed that the Ki-67 index correlated better with the amide proton transfer-weighted signal intensity than with the apparent diffusion coefficient value or the cerebral blood flow value in the gliomas. Amide proton transfer magnetic resonance imaging is a promising method for predicting the grading and cellularity of gliomas.

CPEB1 modulates differentiation of glioma stem cells via downregulation of HES1 and SIRT1 expression

PubMed Central

Lee, Jeong Eun; Park, Ju Young; Kim, Tae-Hoon; Kim, Youn-Jae; Lee, Seung-Hoon; Yoo, Heon; Kim, Jong Heon; Park, Jong Bae

2014-01-01

Glioma stemness has been recognized as the most important reason for glioma relapse and drug resistance. Differentiation of glioma stem cells (GSCs) has been implicated as a novel approach to target recurrent glioma. However, the detailed molecular mechanism involved in the differentiation of GSCs has not yet been elucidated. This study identified CPEB1 as the key modulator that induces the differentiation of GSCs at the post-transcriptional level. Gain and loss of function experiments showed that CPEB1 expression reduced sphere formation ability and the expression of stemness markers such as Nestin and Notch. To elucidate the detailed molecular mechanism underlying the action of CPEB1, we investigated the interacting ribonome of the CPEB1 complex using a Ribonomics approach. CPEB1 specifically suppressed the translation of HES1 and SIRT1 by interacting with a cytoplasmic polyadenylation element. The expression profile of CPEB1 negatively correlated with overall survival in glioma patients. Overexpression of CPEB1 decreased the number of GSCs in an orthotopically implanted glioma animal model. These results suggest that CPEB1-mediated translational control is essential for the differentiation of GSCs and provides novel therapeutic concepts for differentiation therapy. PMID:25216517

Plexin-B2 promotes invasive growth of malignant glioma

PubMed Central

Pingle, Sandeep C.; Kesari, Santosh; Wang, Huaien; Yong, Raymund L.; Zou, Hongyan; Friedel, Roland H.

2015-01-01

Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma. PMID:25762646

WWC3 Inhibits Glioma Cell Proliferation Through Suppressing the Wnt/β-Catenin Signaling Pathway.

PubMed

Wang, Yanni; Jiang, Man; Yao, Yongshan; Cai, Zhengwei

2018-01-01

The scaffolding protein WW and C2 domain-containing protein 3 (WWC3) belonging to the WWC protein family plays important roles in regulating cell proliferation, cell migration, and synaptic signaling. The critical role of WWC3 in tumorigenesis has emerged recently; however, the expression and function of WWC3 in glioma remain largely unknown. Here, we found that WWC3 was significantly downregulated in glioma tissues and cell lines. Overexpression of WWC3 inhibited the glioma cell proliferation, migration, and invasion. Depletion of WWC3 promoted the proliferation of glioma cells. Mechanistically, we found that overexpression of WWC3 suppressed the activity of β-catenin, the signaling that tightly associates with cell proliferation and growth. Depletion of WWC3 enhanced the activity of β-catenin/Wnt signaling. Further investigation demonstrated that WWC3 interacted with T cell factor 4 (TCF4), an identified associated binding partner of β-catenin. The interaction between WWC3 and TCF4 might inhibit the transcriptional activation of β-catenin. Our results provide novel insights into the aberrant expression and molecular mechanism of WWC3 in glioma, which indicated WWC3 as a potential target for clinical intervention in glioma.

MiR-592 functions as a tumor suppressor in glioma by targeting IGFBP2.

PubMed

Peng, Tao; Zhou, Lixiang; Qi, Hui; Wang, Guangming; Luan, Yongxin; Zuo, Ling

2017-07-01

A growing body of evidence suggests that microRNA-592 is involved in tumor initiation and development in several types of human cancers. However, the biological functions and molecular mechanism of microRNA-592 in glioma remain unclear. In this study, we explored the potential role of microRNA-592 in glioma as well as the possible molecular mechanisms. Our results proved that microRNA-592 expression was significantly downregulated in glioma tissues and cell lines (p < 0.01). Functional assays revealed that overexpression of microRNA-592 dramatically reduced the cell proliferation, migration, and invasion and induced cell arrest at G1/G0 phase in vitro. Mechanistic investigations defined insulin-like growth factor binding protein 2 as a direct and functional downstream target of microRNA-592, which was involved in the microRNA-592-mediated tumor-suppressive effects in glioma cells. Moreover, the in vivo study showed that microRNA-592 overexpression produced the smaller tumor volume and weight in nude mice. In summary, these results elucidated the function of microRNA-592 in glioma progression and suggested a promising application of it in glioma treatment.

Extent of Resection in Glioma-A Review of the Cutting Edge.

PubMed

D'Amico, Randy S; Englander, Zachary K; Canoll, Peter; Bruce, Jeffrey N

2017-07-01

Modern glioma surgery has evolved from the principal belief that safe, maximal tumor resection improves symptom management, quality of life, progression-free survival, and overall survival in both low-grade and high-grade glioma. However, in the absence of level I data, the overwhelming support for this idea is derived largely from retrospective series. As a result, the influence of increasing extent of resection and reducing tumor burden on the efficacy of postoperative chemotherapy and radiotherapy, and survival, remains inadequately defined. This situation is particularly true because gliomas represent a widely heterogeneous group of tumors with varying behaviors and prognoses rooted in their complex molecular profile. The neurosurgical community has made a large effort to define the clinical benefits of maximizing tumor resection, with particular attention paid to the ever-evolving understanding of glioma molecular heterogeneity. Important new technologies have been developed concurrently to mitigate neurologic risks related to the pursuit of maximizing extent of resection. These advances reflect the modern goal of glioma surgery to find the optimal balance between tumor removal and neurologic compromise. We review the current literature supporting safe, maximal resection for gliomas. Copyright © 2017 Elsevier Inc. All rights reserved.

HP1α is highly expressed in glioma cells and facilitates cell proliferation and survival.

PubMed

Lai, Xianliang; Deng, Zhifeng; Guo, Hua; Zhu, Xingen; Tu, Wei

2017-08-19

Epigenetic alteration plays critical roles in gliomagenesis by regulating gene expression through modifications of Histones and DNA. Trimethylation of H3K9, an essential repressed transcription mark, and one of its methyltransferase, SUV39H1, are implicated in glioma pathogenesis and progression. We find that the protein level of HP1α, a reader of H3K9me3 is elevated in cultured glioma cell lines and glioma tissues. H3K9me3 is also upregulated. Depletion of HP1α and SUV39H1 weakens glioma cell proliferation capacity and results in apoptosis of cells. Furthermore, we find that HP1α and H3K9me3 are enriched in the FAS and PUMA promoters, which suggests that upregulated HP1α and H3K9me3 contribute to cell survival by suppressing apoptotic activators. These data suggests that up-regulated HP1α and H3K9me3 in glioma cells are functionally associated with glioma pathogenesis and progression and may serve as novel biomarkers for diagnostic and therapeutic targeting of brain tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

PubMed Central

Kaneko, Sadahiro

2016-01-01

Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

A super gene expression system enhances the anti-glioma effects of adenovirus-mediated REIC/Dkk-3 gene therapy

NASA Astrophysics Data System (ADS)

Oka, Tetsuo; Kurozumi, Kazuhiko; Shimazu, Yosuke; Ichikawa, Tomotsugu; Ishida, Joji; Otani, Yoshihiro; Shimizu, Toshihiko; Tomita, Yusuke; Sakaguchi, Masakiyo; Watanabe, Masami; Nasu, Yasutomo; Kumon, Hiromi; Date, Isao

2016-09-01

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87ΔEGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.

Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆

PubMed Central

Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

2013-01-01

Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma

PubMed Central

Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-01-01

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion. PMID:28212546

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma.

PubMed

Xiong, Ye; Liu, Liyun; Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-04-11

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

[The expression of IDH1 (R132H) is positively correlated with cell proliferation and angiogenesis in glioma samples].

PubMed

Shi, Jiankuan; Zhao, Yuanlin; Yuan, Yuan; Wang, Chao; Xie, Zhonglin; Gao, Xing; Xiao, Liming; Ye, Jing

2016-03-01

To explore the correlations of the expression of mutant isocitrate dehydrogenase (IDH1) (R132H) protein with angiogenesis and cell proliferation in glioma. We performed polymerase chain reaction-based IDH gene mutation screening in 385 glioma samples, and the subcellular localization and expression levels of IDH1 (R132H) was examined by immunohistochemistry (IHC). Ki-67 labeling index was introduced to determine the proliferation of glioma cells, and the microvessel density was measured through CD34 staining. Statistical analyses were performed to show the correlations of IDH1 mutation with cell proliferation and microvessel density. The mutant rates of IDH1 were about 50%-60% in grade II-III gliomas and secondary glioblastomas, which were significantly higher than those in pilocytic astrocytoma (grade I) and primary glioblastoma (grade IV). Moreover, the level of IDH1 (R132H) protein was positively correlated with Ki-67 labeling index and microvessel density. IDH mutation was common in grade II-III glioma and secondary glioblastoma, and the mutant IDH1 (R132H) might play a critical role in the cell proliferation and angiogenesis of glioma.

NUMB does not impair growth and differentiation status of experimental gliomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Euskirchen, Philipp, E-mail: philipp.euskirchen@charite.de; Laboratory for Gene Therapy and Molecular Imaging, Max-Planck-Institute for Neurological Research, Cologne; Skaftnesmo, Kai-Ove

2011-12-10

The cell fate determinant NUMB orchestrates asymmetric cell division in flies and mammals and has lately been suggested to have a tumor suppressor function in breast and lung cancer. Here, we studied NUMB in the context of malignant gliomas. We used ectopic expression of NUMB in order to inhibit proliferation and induce differentiation in glioma cells by alteration of Notch, Hedgehog and p53 signaling. We found that NUMB is consistently expressed in glioma biopsies with predominance of NUMB2/4 isoforms as determined by isoform-specific real-time PCR and Western blotting. Upon lentiviral overexpression, in vitro proliferation rate and the grade of differentiationmore » as assessed by morphology and expression of neural and glial markers remained unchanged. Orthotopic xenografts of NUMB-transduced human U87 glioma cells could be established in nude rats without impairing engraftment or causing significant changes in morphology based on magnetic resonance imaging (MRI). The previously reported alteration of Hedgehog and p53 signaling by NUMB could not be recapitulated in glioma cells. We thus show that in experimental gliomas, NUMB overexpression most likely does not exert a tumor suppressor function such as seen in epithelial cancers.« less

Armodafinil in Reducing Cancer-Related Fatigue in Patients With High Grade Glioma | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies armodafinil to see how well it works in reducing cancer-related fatigue in patients with high grade glioma. Armodafinil may help relieve fatigue in patients with high grade glioma. |

Prenatal Diagnosis of Nasal Glioma Associated with Metopic Craniosynostosis: Case Report and Review of the Literature

PubMed Central

Boyer, Andrew C; Krishnan, Anant; Goncalves, Luis F; Williams, Lindsay; Chaiyasate, Kongkrit

2015-01-01

Nasal gliomas (nasal glial heterotopia) are rare benign congenital frontonasal lesions occurring in approximately 1: 20.000 – 40,000 live births. The diagnosis is rarely reported prenatally. Nasal gliomas are typically isolated lesions, with syndromic association being exceedingly rare. Metopic craniosynostosis can occur as an isolated abnormality or in association with multiple syndromes. This case is the first reported case of nasal glioma in association with craniosynostosis in the published literature. PMID:26622922

Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets

PubMed Central

Miranda-Gonçalves, Vera; Honavar, Mrinalini; Pinheiro, Céline; Martinho, Olga; Pires, Manuel M.; Pinheiro, Célia; Cordeiro, Michelle; Bebiano, Gil; Costa, Paulo; Palmeirim, Isabel; Reis, Rui M.; Baltazar, Fátima

2013-01-01

Background Gliomas exhibit high glycolytic rates, and monocarboxylate transporters (MCTs) play a major role in the maintenance of the glycolytic metabolism through the proton-linked transmembrane transport of lactate. However, their role in gliomas is poorly studied. Thus, we aimed to characterize the expression of MCT1, MCT4, and their chaperone CD147 and to assess the therapeutic impact of MCT inhibition in gliomas. Methods MCTs and CD147 expressions were characterized by immunohistochemistry in nonneoplastic brain and glioma samples. The effect of CHC (MCT inhibitor) and MCT1 silencing was assessed in in vitro and in vivo glioblastoma models. Results MCT1, MCT4, and CD147 were overexpressed in the plasma membrane of glioblastomas, compared with diffuse astrocytomas and nonneoplastic brain. CHC decreased glycolytic metabolism, migration, and invasion and induced cell death in U251 cells (more glycolytic) but only affected proliferation in SW1088 (more oxidative). The effectiveness of CHC in glioma cells appears to be dependent on MCT membrane expression. MCT1 downregulation showed similar effects on different glioma cells, supporting CHC as an MCT1 inhibitor. There was a synergistic effect when combining CHC with temozolomide treatment in U251 cells. In the CAM in vivo model, CHC decreased the size of tumors and the number of blood vessels formed. Conclusions This is the most comprehensive study reporting the expression of MCTs and CD147 in gliomas. The MCT1 inhibitor CHC exhibited anti-tumoral and anti-angiogenic activity in gliomas and, of importance, enhanced the effect of temozolomide. Thus, our results suggest that development of therapeutic approaches targeting MCT1 may be a promising strategy in glioblastoma treatment. PMID:23258846

Repeated assessment of orthotopic glioma pO2 by multi-site EPR oximetry: A technique with the potential to guide therapeutic optimization by repeated measurements of oxygen

PubMed Central

Khan, Nadeem; Mupparaju, Sriram; Hou, Huagang; Williams, Benjamin B.; Swartz, Harold

2011-01-01

Tumor hypoxia plays a vital role in therapeutic resistance. Consequently, measurements of tumor pO2 could be used to optimize the outcome of oxygen-dependent therapies, such as, chemoradiation. However, the potential optimizations are restricted by the lack of methods to repeatedly and quantitatively assess tumor pO2 during therapies, particularly in gliomas. We describe the procedures for repeated measurements of orthotopic glioma pO2 by multi-site electron paramagnetic resonance (EPR) oximetry. This oximetry approach provides simultaneous measurements of pO2 at more than one site in the glioma and contralateral cerebral tissue. The pO2 of intracerebral 9L, C6, F98 and U251 tumors, as well as contralateral brain, were measured repeatedly for five consecutive days. The 9L glioma was well oxygenated with pO2 of 27 - 36 mm Hg, while C6, F98 and U251 glioma were hypoxic with pO2 of 7 - 12 mm Hg. The potential of multi-site EPR oximetry to assess temporal changes in tissue pO2 was investigated in rats breathing 100% O2. A significant increase in F98 tumor and contralateral brain pO2 was observed on day 1 and day 2, however, glioma oxygenation declined on subsequent days. In conclusion, EPR oximetry provides the capability to repeatedly assess temporal changes in orthotopic glioma pO2. This information could be used to test and optimize the methods being developed to modulate tumor hypoxia. Furthermore, EPR oximetry could be potentially used to enhance the outcome of chemoradiation by scheduling treatments at times of increase in glioma pO2. PMID:22079559

The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas.

PubMed

Guo, Jun; Yao, Chengjun; Chen, Hong; Zhuang, Dongxiao; Tang, Weijun; Ren, Guang; Wang, Yin; Wu, Jinsong; Huang, Fengping; Zhou, Liangfu

2012-08-01

The marginal delineation of gliomas cannot be defined by conventional imaging due to their infiltrative growth pattern. Here we investigate the relationship between changes in glioma metabolism by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and histopathological findings in order to determine an optimal threshold value of choline/N-acetyl-aspartate (Cho/NAA) that can be used to define the extent of glioma spread. Eighteen patients with different grades of glioma were examined using (1)H-MRSI. Needle biopsies were performed under the guidance of neuronavigation prior to craniotomy. Intraoperative magnetic resonance imaging (MRI) was performed to evaluate the accuracy of sampling. Haematoxylin and eosin, and immunohistochemical staining with IDH1, MIB-1, p53, CD34 and glial fibrillary acidic protein (GFAP) antibodies were performed on all samples. Logistic regression analysis was used to determine the relationship between Cho/NAA and MIB-1, p53, CD34, and the degree of tumour infiltration. The clinical threshold ratio distinguishing tumour tissue in high-grade (grades III and IV) glioma (HGG) and low-grade (grade II) glioma (LGG) was calculated. In HGG, higher Cho/NAA ratios were associated with a greater probability of higher MIB-1 counts, stronger CD34 expression, and tumour infiltration. Ratio threshold values of 0.5, 1.0, 1.5 and 2.0 appeared to predict the specimens containing the tumour with respective probabilities of 0.38, 0.60, 0.79, 0.90 in HGG and 0.16, 0.39, 0.67, 0.87 in LGG. HGG and LGG exhibit different spectroscopic patterns. Using (1)H-MRSI to guide the extent of resection has the potential to improve the clinical outcome of glioma surgery.

Re-evaluating TTF-1 immunohistochemistry in diffuse gliomas: Expression is clone-dependent and associated with tumor location.

PubMed

Pratt, Drew; Afsar, Nina; Allgauer, Michael; Fetsch, Patricia; Palisoc, Maryknoll; Pittaluga, Stefania; Quezado, Martha

TTF-1 is widely used as a marker in routine surgical pathology in the work-up of malignancy. Aberrant expression of TTF-1 in extrapulmonary and extrathyroidal malignancies is a frequently reported phenomenon. In addition to the recently characterized pituicyte-derived tumors of the sella, immunoreactivity has been reported in diffuse gliomas with the SPT24 clone. Here, we sought to evaluate TTF-1 expression with three commercially available clones in a large series of gliomas. Expression was compared across the newly defined diagnostic entities in the 2016 WHO Classification of CNS Tumors. Using tissue microarrays (TMA), 212 diffuse gliomas (WHO grades II - IV) were systematically evaluated with TTF-1 immunohistochemistry using three clones: SPT24, 8G7G3/1, and SP141, and results correlated with clinicopathologic features. 14 high-grade diffuse gliomas demonstrated nuclear staining with the SP141 and SPT24 clones. Two tumors showed weak positivity with the 8G7G3/1 clone. All tumors were high grade by histology (WHO grades III and IV). 86% (12/14) of TTF-1-positive gliomas involved the frontal lobes at diagnosis. No relationship with IDH R132H, ATRX, p53, H3K27M, or EGFR immunohistochemistry was identified. TTF-1 expression in gliomas was not independently prognostic of overall survival. TTF-1 expression in diffuse gliomas is a rare but potentially misleading occurrence. In our cohort, staining occurred with both the SPT24 and SP141 clones at equal intensity and frequency. Clustering of TTF-1-positive tumors in the frontal lobe(s) suggests lineage-specific expression. Due to clone-specific expression in diffuse gliomas, caution must be exercised in the work-up of intracranial tumors with TTF-1.
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Antiangiogenic drugs synergize with a membrane macrophage colony-stimulating factor-based tumor vaccine to therapeutically treat rats with an established malignant intracranial glioma.

PubMed

Jeffes, Edward W B; Zhang, Jian Gang; Hoa, Neil; Petkar, Animesh; Delgado, Christina; Chong, Samuel; Obenaus, Andre; Sanchez, Ramon; Khalaghizadeh, Sakineh; Khomenko, Tetyana; Knight, Brandon A; Alipanah, Reza; Nguyen, Tuong-Vi; Shah, Chirag; Vohra, Seema; Zhuang, Jing-Li; Liu, Jessie; Wepsic, H Terry; Jadus, Martin R

2005-03-01

Combining a T9/9L glioma vaccine, expressing the membrane form of M-CSF, with a systemic antiangiogenic drug-based therapy theoretically targeted toward growth factor receptors within the tumor's vasculature successfully treated >90% of the rats bearing 7-day-old intracranial T9/9L gliomas. The antiangiogenic drugs included (Z)-3-[4-(dimethylamino)benzylidenyl]indolin-2-one (a platelet-derived growth factor receptor beta and a fibroblast growth factor receptor 1 kinase inhibitor) and oxindole (a vascular endothelial growth factor receptor 2 kinase inhibitor). A total of 20-40% of the animals treated with the antiangiogenic drugs alone survived, while all nontreated controls and tumor vaccine-treated rats died within 40 days. In vitro, these drugs inhibited endothelial cells from proliferating in response to the angiogenic factors produced by T9/9L glioma cells and prevented endothelial cell tubulogenesis. FITC-labeled tomato lectin staining demonstrated fewer and constricted blood vessels within the intracranial tumor after drug therapy. Magnetic resonance imaging demonstrated that the intracranial T9 glioma grew much slower in the presence of these antiangiogenic drugs. These drugs did not affect in vitro glioma cell growth nor T cell mitogenesis. Histological analysis revealed that the tumor destruction occurred at the margins of the tumor, where there was a heavy lymphocytic infiltrate. Real-time PCR showed more IL-2-specific mRNA was present within the gliomas in the vaccinated rats treated with the drugs. Animals that rejected the established T9/9L glioma by the combination therapy proved immune against an intracranial rechallenge by T9/9L glioma, but showed no resistance to an unrelated MADB106 breast cancer.

Induction of anti-glioma NK cell response following multiple low-dose intracerebral CpG therapy

PubMed Central

Alizadeh, Darya; Zhang, Leying; Brown, Christine E.; Farrukh, Omar; Jensen, Michael C.; Badie, Behnam

2010-01-01

Purpose Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG-ODN) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. These studies, however, have used high doses of CpG-ODN which can induce toxicity in a clinical setting. The goal of this study was to evaluate the anti-tumor efficacy of multiple low-dose intratumoral CpG- ODN in a glioma model. Experimental Design Mice bearing four-day old intracranial GL261 gliomas received a single or multiple (two or four) intratumoral injections of CpG-ODN (3 μg) every 4 days. Tumor growth was measured by bioluminescent imaging, brain histology, and animal survival. Flow cytometry and cytotoxicity assays were used to assess anti-glioma immune response. Results Two and four intracranial injections of low-dose CpG-ODN, but not a single injection, eradicated gliomas in 70% of mice. Moreover, surviving animals exhibited durable tumor free remission (> 3 months), and were protected from intracranial rechallenge with GL21 gliomas, demonstrating the capacity for long-term anti-tumor immunity. Although most inflammatory cells appeared to increase, activated NK cells (i.e. NK+CD107a+) were more frequent than CD8+CD107a+ in the brains of rechallenged CpG-ODN-treated animals and demonstrated a stronger in vitro cytotoxicity against GL261 target cells. Leukocyte depletion studies confirmed that NK cells played an important role in the initial CpG-ODN anti-tumor response, but both CD8 and NK cells were equally important in long-term immunity against gliomas. Conclusions These findings suggest that multiple low-dose intratumoral injections of CpG-ODN can eradicate intracranial gliomas possibly through mechanisms involving NK mediated effector function. PMID:20570924

Induction of anti-glioma natural killer cell response following multiple low-dose intracerebral CpG therapy.

PubMed

Alizadeh, Darya; Zhang, Leying; Brown, Christine E; Farrukh, Omar; Jensen, Michael C; Badie, Behnam

2010-07-01

Stimulation of toll-like receptor-9 by CpG oligodeoxynucleotides (CpG-ODN) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. These studies, however, have used high doses of CpG-ODN, which can induce toxicity in a clinical setting. The goal of this study was to evaluate the antitumor efficacy of multiple low-dose intratumoral CpG-ODN in a glioma model. Mice bearing 4-day-old intracranial GL261 gliomas received a single or multiple (two or four) intratumoral injections of CpG-ODN (3 microg) every 4 days. Tumor growth was measured by bioluminescent imaging, brain histology, and animal survival. Flow cytometry and cytotoxicity assays were used to assess anti-glioma immune response. Two and four intracranial injections of low-dose CpG-ODN, but not a single injection, eradicated gliomas in 70% of mice. Moreover, surviving animals exhibited durable tumor-free remission (> 3 months) and were protected from intracranial rechallenge with GL261 gliomas, showing the capacity for long-term antitumor immunity. Although most inflammatory cells seemed to increase, activated natural killer (NK) cells (i.e., NK(+)CD107a(+)) were more frequent than CD8(+)CD107a(+) in the brains of rechallenged CpG-ODN-treated animals and showed a stronger in vitro cytotoxicity against GL261 target cells. Leukocyte depletion studies confirmed that NK cells played an important role in the initial CpG-ODN antitumor response, but both CD8 and NK cells were equally important in long-term immunity against gliomas. These findings suggest that multiple low-dose intratumoral injections of CpG-ODN can eradicate intracranial gliomas possibly through mechanisms involving NK-mediated effector function.

Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas

PubMed Central

Mohapatra, Gayatry; Engler, David A.; Starbuck, Kristen D.; Kim, James C.; Bernay, Derek C.; Scangas, George A.; Rousseau, Audrey; Batchelor, Tracy T.; Betensky, Rebecca A.; Louis, David N.

2010-01-01

Molecular genetic analysis of cancer is rapidly evolving as a result of improvement in genomic technologies and the growing applicability of such analyses to clinical oncology. Array based comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA), particularly in solid tumors, and has been applied to the study of malignant gliomas. In the clinical setting, however, gliomas are often sampled by small biopsies and thus formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis, especially for rare types of gliomas. Moreover, the biological basis for the marked intratumoral heterogeneity in gliomas is most readily addressed in FFPE material. Therefore, for gliomas, the ability to use DNA from FFPE tissue is essential for both clinical and research applications. In this study, we have constructed a custom bacterial artificial chromosome (BAC) array and show excellent sensitivity and specificity for detecting CNAs in a panel of paired frozen and FFPE glioma samples. Our study demonstrates a high concordance rate between CNAs detected in FFPE compared to frozen DNA. We have also developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. This labeling technique was applied to a panel of biphasic anaplastic oligoastrocytomas (AOA) to identify genetic changes unique to each component. Together, results from these studies suggest that BAC and oligonucleotide aCGH are sensitive tools for detecting CNAs in FFPE DNA, and can enable genome-wide analysis of rare, small and/or histologically heterogeneous gliomas. PMID:21080181

Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells

PubMed Central

Kosaka, Akemi; Ohkuri, Takayuki

2014-01-01

Malignant gliomas are heavily infiltrated by immature myeloid cells that mediate immuno-suppression. Agonistic CD40 monoclonal antibody (mAb) has been shown to activate myeloid cells and promote antitumor immunity. Our previous study has also demonstrated blockade of cyclooxygenase-2 (COX-2) reduces immunosuppressive myeloid cells, thereby suppressing glioma development in mice. We therefore hypothesized that a combinatory strategy to modulate myeloid cells via two distinct pathways, i.e., CD40/CD40L stimulation and COX-2 blockade, would enhance anti-glioma immunity. We used three different mouse glioma models to evaluate therapeutic effects and underlying mechanisms of a combination regimen with an agonist CD40 mAb and the COX-2 inhibitor celecoxib. Treatment of glioma-bearing mice with the combination therapy significantly prolonged survival compared with either anti-CD40 mAb or celecoxib alone. The combination regimen promoted maturation of CD11b+ cells in both spleen and brain, and enhanced Cxcl10 while suppressing Arg1 in CD11b+Gr-1+ cells in the brain. Anti-glioma activity of the combination regimen was T-cell dependent because depletion of CD4+ and CD8+ cells in vivo abrogated the anti-glioma effects. Furthermore, the combination therapy significantly increased the frequency of CD8+ T-cells, enhanced IFN-γ-production and reduced CD4+CD25+Foxp3+ T regulatory cells in the brain, and induced tumor-antigen-specific T-cell responses in lymph nodes. Our findings suggest that the combination therapy of anti-CD40 mAb with celecoxib enhances anti-glioma activities via promotion of type-1 immunity both in myeloid cells and T-cells. PMID:24878890

Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models

PubMed Central

Shoji, Takuhiro; Saito, Ryuta; Chonan, Masashi; Shibahara, Ichiyo; Sato, Aya; Kanamori, Masayuki; Sonoda, Yukihiko; Kondo, Toru; Ishii, Naoto; Tominaga, Teiji

2016-01-01

Background Glioblastoma is one of the most malignant brain tumors in adults and has a dismal prognosis. In a previous report, we reported that CD40, a TNF-R-related cell surface receptor, and its ligand CD40L were associated with glioma outcomes. Here we attempted to activate CD40 signaling in the tumor and determine if it exerted therapeutic efficacy. Methods CD40 expression was examined in 3 mouse glioma cell lines (GL261, NSCL61, and bRiTs-G3) and 5 human glioma cell lines (U87, U251, U373, T98, and A172). NSCL61 and bRiTs-G3, as glioma stem cells, also expressed the glioma stem cell markers MELK and CD44. In vitro, we demonstrated direct antitumor effects of an anti-CD40 agonistic monoclonal antibody (FGK45) against the cell lines. The efficacy of FGK45 was examined by local convection-enhanced delivery of the monoclonal antibody against each glioma model. Results CD40 was expressed in all mouse and human cell lines tested and was found at the cell membrane of each of the 3 mouse cell lines. FGK45 administration induced significant, direct antitumor effects in vitro. The local delivery of FGK45 significantly prolonged survival compared with controls in the NSCL61 and bRiTs-G3 models, but the effect was not significant in the GL261 model. Increases in apoptosis and CD4+ and CD8+ T cell infiltration were observed in the bRiTs-G3 model after FGK45 treatment. Conclusions Local delivery of FGK45 significantly prolonged survival in glioma stem cell models. Thus, local delivery of this monoclonal antibody is promising for immunotherapy against gliomas. PMID:26917236