WorldWideScience

Sample records for brain reveals glioma

  1. The progress of radiosensitive genes of human brain glioma

    International Nuclear Information System (INIS)

    Wang Xi; Liu Qiang

    2008-01-01

    Human gliomas are one of the most aggressive tumors in brain which grow infiltrativly. Surgery is the mainstay of treatment. But as the tumor could not be entirely cut off, it is easy to relapse. Radiotherapy plays an important role for patients with gliomas after surgery. The efficacy of radiotherapy is associated with radio sensitivity of human gliomas. This paper makes a summary of current situation and progress for radiosensitive genes of human brain gliomas. (authors)

  2. UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma.

    Science.gov (United States)

    Zhang, Bo; Zhang, Yujie; Liao, Ziwei; Jiang, Ting; Zhao, Jingjing; Tuo, Yanyan; She, Xiaojian; Shen, Shun; Chen, Jun; Zhang, Qizhi; Jiang, Xinguo; Hu, Yu; Pang, Zhiqing

    2015-01-01

    Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.

  3. Known glioma risk loci are associated with glioma with a family history of brain tumours

    DEFF Research Database (Denmark)

    Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika

    2013-01-01

    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...... 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...

  4. Childhood Brain Stem Glioma Treatment

    Science.gov (United States)

    ... The tentorium separates the supratentorium from the infratentorium (right panel). The skull and meninges protect the brain and spinal cord (left panel). Brain tumors are the second most common ...

  5. Childhood Brain Stem Glioma Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Childhood brain stem glioma can be a benign (not cancer) or malignant (cancer) condition where abnormal cells form in the tissues of the brain stem. Get information about the symptoms, diagnosis, prognosis, and treatment of newly diagnosed and recurrent childhood brain stem glioma in this expert-reviewed summary.

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

    Science.gov (United States)

    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 EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p EPF levels was shorter than in patients with low expression (p EPF was significantly shorter than patients with only nuclear E2-EPF (p 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.

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

    Science.gov (United States)

    2018-06-18

    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

  8. DELETION AND 5'CPG ISLAND METHYLATION OF p15 GENE IN BRAIN GLIOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the abnormality of p15 gene in brain glioma and the correlation of it with occurrence or malignant progression of brain glioma. Methods: Deletion and 5'CPG island methylation of p15 gene were detected by the methods of PCR and PCR-based methylation in 56 cases of brain glioma. Results: Out of 43 cases of high grade glioma, 14 cases were found to have homozygous deletion of p15E1, while none of the 13 cases of low grade glioma was found to have deletion of p15E1 (P<0.05). Methylation of 5'CPG Island of p15 gene was found only in four cases of glioma. Conclusion: Abnormality of p15 gene may involved in the occurrence and malignant progression of brain glioma. Homozygous deletion of gene is the major mechanism of inactivation for p15 gene in brain glioma.

  9. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  10. Childhood Brain Stem Glioma Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Childhood brain stem glioma presents as a diffuse intrinsic pontine glioma (DIPG; a fast-growing tumor that is difficult to treat and has a poor prognosis) or a focal glioma (grows more slowly, is easier to treat, and has a better prognosis). Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed summary.

  11. Malignant gliomas of the brain managed by radiotherapy after surgery

    Energy Technology Data Exchange (ETDEWEB)

    Fichardt, T.; Sandison, A.G. (Pretoria Univ. (South Africa). Dept. of Radiotherapy)

    The article reviews the literature and gives an account of the authors' experience during a 20-year period (1960-1980) of the value of radiotherapy after surgery in the management of 76 patients suffering from brain gliomas classified into 3 grades according to the degree of anaplasia present in the histological sections, viz. grades II, III and IV. Radiotherapy was not given to grade I malignant gliomas as they are treated by surgery only. The period is divided into 2 subperiods. The first is from 1960-1972 when part-brain, high-dose irradiation following surgery was used on 33 patients in various age groups. The second period covers whole-brain, low-dose irradiation following surgery and was used on 43 patients in various age groups.

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

    Science.gov (United States)

    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

  13. Signal intensity in T2' magnetic resonance imaging is related to brain glioma grade

    International Nuclear Information System (INIS)

    Saitta, Laura; Castellan, Lucio; Heese, Oliver; Westphal, Manfred; Foerster, Ann-Freya; Siemonsen, Susanne; Fiehler, Jens; Goebell, Einar; Matschke, Jakob

    2011-01-01

    T2' values reflect the presence of deoxyhaemoglobin related to high local oxygen extraction. We assessed the feasibility of T2' imaging to display regions with high metabolic activity in brain gliomas. MRI was performed in 25 patients (12 female; median age 46 years; range 2-69) with brain gliomas with additional T2 and T2* sequences. T2' maps were derived from T2 and T2*. Dynamic susceptibility weighted contrast (DSC) perfusion was performed in 12/25 patients. Images were visually assessed by two readers and five ROIs were evaluated for each patient. Pearson correlation, Mann-Whitney and Kruskal-Wallis tests were applied for statistical analysis. Three patients were not further evaluated because of artefacts. Mean values of high-grade (III-IV) gliomas showed significantly lower T2' values than low-grade (II) gliomas (p < 0.001). An inverse relationship was observed between rCBV and sqr (T2') (r = -0.463, p < 0.001). No correlation was observed between T2' and rCBV for grade II tumours (r = 0.038; p = 0.875). High-grade tumours revealed lower T2' values, presumably because of higher oxygen consumption in proliferating tissue. Our results indicate that T2' imaging can be used as an alternative to DSC perfusion in the detection of subtle deviations in tumour metabolism. (orig.)

  14. Resection of deep-seated brain glioma by microsurgery assisted with neuronavigation

    International Nuclear Information System (INIS)

    Feng Ming; Zhou Youxin; Sun Chunming; Zhang Shiming

    2009-01-01

    Objective: To investigate the clinical value of neuronavigator assisted microsurgery for deep-seated brain glioma. Methods: The electromagnetic neuronavigation system had been applied for microsurgery of deep-seated brain glioma in fifteen cases. Results: Ten from 15 patients were totally removed, 2 were subtotally removed and 3 were partial removed.All patients had no new neurological deficit. Conclusion: The neuronavigator assisted microsurgery for deep-seated brain glioma is of characters including accurate location, minimal invasiveness, and can enhance the rate of total resection and decrease the operative complications in the patients with deep-seated brain glioma. (authors)

  15. Wavelet-domain de-noising of OCT images of human brain malignant glioma

    Science.gov (United States)

    Dolganova, I. N.; Aleksandrova, P. V.; Beshplav, S.-I. T.; Chernomyrdin, N. V.; Dubyanskaya, E. N.; Goryaynov, S. A.; Kurlov, V. N.; Reshetov, I. V.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

    2018-04-01

    We have proposed a wavelet-domain de-noising technique for imaging of human brain malignant glioma by optical coherence tomography (OCT). It implies OCT image decomposition using the direct fast wavelet transform, thresholding of the obtained wavelet spectrum and further inverse fast wavelet transform for image reconstruction. By selecting both wavelet basis and thresholding procedure, we have found an optimal wavelet filter, which application improves differentiation of the considered brain tissue classes - i.e. malignant glioma and normal/intact tissue. Namely, it allows reducing the scattering noise in the OCT images and retaining signal decrement for each tissue class. Therefore, the observed results reveals the wavelet-domain de-noising as a prospective tool for improved characterization of biological tissue using the OCT.

  16. Uptake of iodine-123-α-methyl tyrosine by gliomas and non-neoplastic brain lesions

    International Nuclear Information System (INIS)

    Kuwert, T.; Morgenroth, C.; Woesler, B.; Matheja, P.; Palkovic, S.; Vollet, B.; Samnick, S.; Maasjosthusmann, U.; Lerch, H.; Gildehaus, F.J.; Wassmann, H.; Schober, O.

    1996-01-01

    Using single-photon emission tomography (SPET), the radiopharmaceutical L-3-iodine-123-α-methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating higc-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours. (orig.)

  17. Postoperative radiotherapy for low grade glioma of the brain

    International Nuclear Information System (INIS)

    Chun, Ha Chung; Lee, Myung Za

    2000-01-01

    To evaluate the effectiveness and tolerance of postoperative external beam radiotherapy for patients with low grade glioma of the brain and define the optimal radiotherapeutic regimen. Between June, 1985 and May, 1998, 72 patients with low grade gliomas were treated with postoperative radiotherapy immediately following surgery. Median age was 37 years with range of 11 to 76 years. Forty one patients were male and 31 patients were female with male to female ratio of 1.3:1. Of those patients, 15 underwent biopsy alone and remaining 57 did subtotal resection. The distribution of the patients according to histologic type was as follows: astrocytomas-42 patients (58%), mixed oligodendrogliomas-19 patients (27%), oligodendrogliomas-11 patients (15%). Two patients were treated with whole brain irradiation followed by cone down boost and remaining 70 patients were treated with localized field with appropriate margin. All of the patients were treated with conventional once a day fractionation. Most of patients received total tumor dose of 5000-5500 cGy. The overall 5 and 7 year survival rates for entire group of 72 patients were 61% and 50%. Corresponding disease free survival rates for entire patients were 53% and 45%, respectively. The 5 and 7 year overall survival rates for astrocytomas, mixed oligodendrogliomas, and oligodendrogliomas were 48% and 45%, 76% and 56%, and 80% and 52%, respectively. Patients who underwent subtotal resection showed better survival rates than those who did biopsy alone. The overall 5 year survival rates for subtotal resection patients and biopsy alone patients were 67% and 43%, respectively. Forty six patients who were 40 years or younger survived better than 26 patients who were 41 years or older (overall survival rate at 5 years, 69% vs 45%). Although one patient was not able to complete the treatment because of neurological deterioration, there was no significant treatment related acute toxicities. Postoperative radiotherapy was safe and

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

    Science.gov (United States)

    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.

  19. Diffuse brain calcification after radiation therapy in infantile cerebral malignant glioma

    International Nuclear Information System (INIS)

    Hondo, Hiroaki; Tanaka, Ryuichi; Yamada, Nobuhisa; Takeda, Norio

    1987-01-01

    We reported a case of infantile cerebral malignant glioma, which showed extensive intracranial calcification following radiation therapy, and reviewed the literature. A 4-month-old female infant was admitted to our hospital because of vomiting, enlargement of the head and convulsive seizures. Computerized tomography (CT) scans demonstrated a heterogeneously contrast-enhanced mass in the right temporo-parieto-occipital region and marked obstructive hydrocephalus. Subsequent to ventriculo-peritoneal shunt, biopsy was performed. The surgical specimen revealed anaplastic glioma. She then underwent whole brain irradiation with 1800 rads before subtotal removal and 3000 rads postoperatively. Calcification was first identified in the right frontal region and left basal ganglia 2.5 months after radiation therapy. At the age of 14 months, CT scans demonstrated extensive intracranial calcification in the cerebral hemispheres, basal ganglias, thalami, pons and cerebellum. A biopsy specimen of the frontal lobe revealed calcospherites of various sizes within and beside the walls of small vessels, but no tumor cells were observed. Cranial radiation therapy is a standard modality for treatment of children with neoplasm in the central nervous system. Since, however this therapy possibly causes long-term complications on the developing brain, it is important to plan radiation therapy for the brain tumor carefully. (author)

  20. Expression and relevant research of MGMT and XRCC1 gene in differentgrades of brain glioma and normal brain tissues

    Institute of Scientific and Technical Information of China (English)

    Ya-Fei Zhang

    2015-01-01

    Objective: To explore and analyze expression and relevant research of MGMT and XRCC1 gene in different grades of brain glioma and normal brain tissues. Methods: 52 cases of patients with brain glioma treated in our hospital from December 2013 to December 2014, and 50 cases of normal brain-tissue patients with intracranial hypertension were selected, and proceeding test to the surgical resection of brain tissue of the above patients to determine its MGMT and XRCC1 protein content, sequentially to record the expression of MGMT and XRCC1 of both groups. Grading of tumors to brain glioma after operation was carried out, and the expression of MGMT and XRCC1 gene in brain tissues of different patients was analyzed and compared;finally the contingency tables of X2 test was used to analyze the correlation of XRCC1and MGMT. Results:Positive rate of MGMT expression in normal brain tissue was 2%,while positive rate of MGMT expression in brain glioma was 46.2%,which was obviously higher than that in normal brain tissues (χ2=26.85, P0.05), which had no statistical significance. There were 12 cases of patients whose MGMT protein expression was positive and XRCC1 protein expression was positive; there were 18 cases of patients whose MGMT protein expression was negative and XRCC1 protein expression was negative. Contingency tables of X2 test was used to analyze the correlation of XRCC1 and MGMT, which indicated that the expression of XRCCI and MGMT in brain glioma had no correlation (r=0.9%, P=0.353), relevancy of both was r=0.9%. Conclusions: Positive rate of the expression of MGMT and XRCC1 in brain glioma was obviously higher than that in normal brain tissues, but the distribution of different grades of brain glioma had no obvious difference, and MGMT and XRCC1 expression had no obvious correlation, which needed further research.

  1. The influence of low-grade glioma on resting state oscillatory brain activity: a magnetoencephalography study

    NARCIS (Netherlands)

    Bosma, I.; Stam, C.; Douw, L.; Bartolomei, F.; Heimans, J.; Dijk, van B.; Postma, T.; Klein, M.; Reijneveld, J.

    2008-01-01

    Purpose: In the present MEG-study, power spectral analysis of oscillatory brain activity was used to compare resting state brain activity in both low-grade glioma (LGG) patients and healthy controls. We hypothesized that LGG patients show local as well as diffuse slowing of resting state brain

  2. The influence of low-grade glioma on resting state oscillatory brain activity: a magnetoencephalography study

    NARCIS (Netherlands)

    Bosma, I.; Stam, C. J.; Douw, L.; Bartolomei, F.; Heimans, J. J.; van Dijk, B. W.; Postma, T. J.; Klein, M.; Reijneveld, J. C.

    2008-01-01

    In the present MEG-study, power spectral analysis of oscillatory brain activity was used to compare resting state brain activity in both low-grade glioma (LGG) patients and healthy controls. We hypothesized that LGG patients show local as well as diffuse slowing of resting state brain activity

  3. Establishment of SHG-44 human glioma model in brain of wistar rat with stereotactic technique

    International Nuclear Information System (INIS)

    Hong Xinyu; Luo Yi'nan; Fu Shuanglin; Wang Zhanfeng; Bie Li; Cui Jiale

    2004-01-01

    Objective: To establish solid intracerebral human glioma model in Wistar rat with xenograft methods. Methods: The SHG-44 cells were injected into brain right caudate nucleus of previous immuno-inhibitory Wistar rats with stereotactic technique. The MRI scans were performed at 1 week and 2 weeks later after implantation. After 2 weeks the rats were killed and pathological examination and immunohistologic stain for human GFAP were used. Results: The MRI scan after 1 week of implantation showed the glioma was growing, pathological histochemical examination demonstrated the tumor was glioma. Human GFAP stain was positive. The growth rate of glioma model was about 60%. Conclusion: Solid intracerebral human glioma model in previous immuno-inhibitory Wistar rat is successfully established

  4. "Unusual brain stone": heavily calcified primary neoplasm with some features suggestive of angiocentric glioma.

    Science.gov (United States)

    Sajjad, Jahangir; Kaliaperumal, Chandrasekaran; Bermingham, Niamh; Marks, Charles; Keohane, Catherine

    2015-11-01

    This 40-year-old man presented with a 5-month history of progressive right-sided headache associated with visual blurring. He also had a history of epilepsy but had been seizure free with medication for the past 10 years. An initial CT scan of his brain performed 16 years previously had revealed a small area of calcification in the right parietal region. In the current presentation, he had a left-sided homonymous hemianopia but no other neurological deficits. A CT scan of his brain showed a much larger calcified, partly cystic lesion in the right parietal region. Because he was symptomatic, the lesion was excised and the cyst was drained. Histological examination of the excised tissue showed an unusual primary tumor that was difficult to classify but had some features of angiocentric glioma. The heavy calcification, mixed-density cell population, and regions with features of angiocentric glioma were most unusual. The patient remained asymptomatic 5 years after surgery, and follow-up scans did not show recurrence.

  5. Effect of dexmedetomidine combined with propofol on brain tissue damage in brain glioma resection

    Institute of Scientific and Technical Information of China (English)

    2017-01-01

    Objective:To study the effect of dexmedetomidine combined with propofol on brain tissue damage in brain glioma resection.Methods: A total of 74 patients who received brain glioma resection in our hospital between May 2014 and December 2016 were selected and randomly divided into Dex group and control group who received dexmedetomidine intervention and saline intervention before induction respectively. Serum brain tissue damage marker, PI3K/AKT/iNOS and oxidation reaction molecule contents as well as cerebral oxygen metabolism index levels were determined before anesthesia (T0), at dura mater incision (T1), immediately after recovery (T2) and 24 h after operation (T3).Results: Serum NSE, S100B, MBP, GFAP, PI3K, AKT, iNOS and MDA contents as well as AVDO2 and CERO2 levels of both groups at T2 and T3 were significantly higher than those at T0 and T1 while serum SOD and CAT contents as well as SjvO2levels were significantly lower than those at T0 and T1, and serum NSE, S100B, MBP, GFAP, PI3K, AKT, iNOS and MDA contents as well as AVDO2 and CERO2 levels of Dex group at T2 and T3 were significantly lower than those of control group while serum SOD and CAT contents as well as SjvO2 levels were significantly higher than those of control group.Conclusions: Dexmedetomidine combined with propofol can reduce the brain tissue damage in brain glioma resection.

  6. Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

    International Nuclear Information System (INIS)

    Ostrom, Quinn T.; McCulloh, Christopher; Chen, Yanwen; Devine, Karen; Wolinsky, Yingli

    2012-01-01

    Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases.

  7. Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ostrom, Quinn T. [Department of Anthropology, Case Western Reserve University, Cleveland, OH (United States); McCulloh, Christopher [Case Western Reserve University School of Medicine, Cleveland, OH (United States); Chen, Yanwen; Devine, Karen; Wolinsky, Yingli, E-mail: qto@case.edu [Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH (United States)

    2012-02-28

    Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases.

  8. Family history of cancer in benign brain tumor subtypes versus gliomas

    Directory of Open Access Journals (Sweden)

    Quinn eOstrom

    2012-02-01

    Full Text Available Purpose: Family history is associated with gliomas, but this association has not ben established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study (OBTS. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%, 78 meningioma (65%, 49 pituitary adenoma (73.1% and 152 glioma patients (58.2%. The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs and 95% confidence intervals (95% CI. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusions: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases.

  9. [A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma].

    Science.gov (United States)

    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 (pAK, 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.

  10. Studies on the reliability of high-field intra-operative MRI in brain glioma resection

    Directory of Open Access Journals (Sweden)

    Zhi-jun SONG

    2011-07-01

    Full Text Available Objective To evaluate the reliability of high-field intra-operative magnetic resonance imaging(iMRI in detecting the residual tumors during glioma resection.Method One hundred and thirty-one cases of brain glioma(69 males and 62 females,aged from 7 to 79 years with mean of 39.6 years hospitalized from Nov.2009 to Aug.2010 were involved in present study.All the patients were evaluated using magnetic resonance imaging(MRI before the operation.The tumors were resected under conventional navigation microscope,and the high-field iMRI was used for all the patients when the operators considered the tumor was satisfactorily resected,while the residual tumor was difficult to detect under the microscope,but resected after being revealed by high-field iMRI.Histopathological examination was performed.The patients without residual tumors recieved high-field MRI scan at day 4 or 5 after operation to evaluate the accuracy of high-field iMRI during operation.Results High quality intra-operative images were obtained by using high-field iMRI.Twenty-eight cases were excluded because their residual tumors were not resected due to their location too close to functional area.Combined with the results of intra-operative histopathological examination and post-operative MRI at the early recovery stage,the sensitivity of high-field iMRI in residual tumor diagnosis was 98.0%(49/50,the specificity was 94.3%(50/53,and the accuracy was 96.1%(99/103.Conclusion High-quality intra-operative imaging could be acquired by high-field iMRI,which maybe used as a safe and reliable method in detecting the residual tumors during glioma resection.

  11. Comparative expression analysis reveals lineage relationships between human and murine gliomas and a dominance of glial signatures during tumor propagation in vitro.

    Science.gov (United States)

    Henriquez, Nico V; Forshew, Tim; Tatevossian, Ruth; Ellis, Matthew; Richard-Loendt, Angela; Rogers, Hazel; Jacques, Thomas S; Reitboeck, Pablo Garcia; Pearce, Kerra; Sheer, Denise; Grundy, Richard G; Brandner, Sebastian

    2013-09-15

    Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/rhabdoid tumor (AT/RT), a rare childhood tumor. ©2013 AACR.

  12. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

    Directory of Open Access Journals (Sweden)

    Sharma Kamal

    2008-12-01

    Full Text Available Abstract Background Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.

  13. Cortical and Subcortical Structural Plasticity Associated with the Glioma Volumes in Patients with Cerebral Gliomas Revealed by Surface-Based Morphometry

    Directory of Open Access Journals (Sweden)

    Jinping Xu

    2017-06-01

    Full Text Available Postlesional plasticity has been identified in patients with cerebral gliomas by inducing a large functional reshaping of brain networks. Although numerous non-invasive functional neuroimaging methods have extensively investigated the mechanisms of this functional redistribution in patients with cerebral gliomas, little effort has been made to investigate the structural plasticity of cortical and subcortical structures associated with the glioma volume. In this study, we aimed to investigate whether the contralateral cortical and subcortical structures are able to actively reorganize by themselves in these patients. The compensation mechanism following contralateral cortical and subcortical structural plasticity is considered. We adopted the surface-based morphometry to investigate the difference of cortical and subcortical gray matter (GM volumes in a cohort of 14 healthy controls and 13 patients with left-hemisphere cerebral gliomas [including 1 patients with World Health Organization (WHO I, 8 WHO II, and 4 WHO III]. The glioma volume ranges from 5.1633 to 208.165 cm2. Compared to healthy controls, we found significantly increased GM volume of the right cuneus and the left thalamus, as well as a trend toward enlargement in the right globus pallidus in patients with cerebral gliomas. Moreover, the GM volumes of these regions were positively correlated with the glioma volumes of the patients. These results provide evidence of cortical and subcortical enlargement, suggesting the usefulness of surface-based morphometry to investigate the structural plasticity. Moreover, the structural plasticity might be acted as the compensation mechanism to better fulfill its functions in patients with cerebral gliomas as the gliomas get larger.

  14. The role of p97 in iron metabolism in human brain glioma cells

    International Nuclear Information System (INIS)

    Xia Chunlin; Chen Guiwen; Qian Zhongming

    2000-01-01

    Objective: To investigate the role of p97 (melanotransferrin) in iron uptake in human brain glioma cells . Methods: Human brain glioma cell lines, GBM and BT325 were incubated in the medium containing 59 Fe-Citrate. The cells were treated with phosphatidylinositol-phospholipase C (PI-PLC) and pronase. The iron uptake of the cells was expressed as relative iron uptake level according to the cpm measured by the gamma scintillation counter. Results: 59 Fe uptake of the cells was significantly declined with the certain concentration of PI-PCL. 59 Fe uptake of the cells treated with pronase tended to coincide with that of the cells treated without pronase in the increasing concentration of PI-PLC. Conclusion: p97 expresses a high level and plays an important role in iron uptake in human brain glioma cells

  15. Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis.

    Science.gov (United States)

    Annibali, Daniela; Whitfield, Jonathan R; Favuzzi, Emilia; Jauset, Toni; Serrano, Erika; Cuartas, Isabel; Redondo-Campos, Sara; Folch, Gerard; Gonzàlez-Juncà, Alba; Sodir, Nicole M; Massó-Vallés, Daniel; Beaulieu, Marie-Eve; Swigart, Lamorna B; Mc Gee, Margaret M; Somma, Maria Patrizia; Nasi, Sergio; Seoane, Joan; Evan, Gerard I; Soucek, Laura

    2014-08-18

    Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

  16. Concurrent thermochemoradiotherapy for brain high-grade glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ryabova, A. I., E-mail: ranigor@mail.ru; Novikov, V. A.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Choinzonov, E. L. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Siberian State Medical University, Tomsk, 634050 (Russian Federation); Gribova, O. V. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation); Baranova, A. V. [National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

    2016-08-02

    Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

  17. 测定脑胶质瘤患者神经肽、神经降压素的含量变化及意义%Clinical Significance and Detection of Neuro- Peptide and Neurotensin in Patients with Brain Glioma

    Institute of Scientific and Technical Information of China (English)

    尹秋霞; 司永兵; 齐法莲

    2001-01-01

    Objective To investigate the change of neuropeptide Y(NPY)and neurotensin(NT)in pqtients with brain glioma.Method The concentration of NPY and NT in and around brain glioma tissue and plasma were detected with inequilibrant radio- imunology method.Result NPY concentrqtion in brain glioma tissue was obviously higher than that in tissue around the tumor(P<0.01).The Concentration of NT in brain glioma tissue was obviously higher that in tissue around the glioma(P<0.01).Conclusion Detection of NPY and NTin brain glion aprovides basis for further study on brain glioma and explainning dlinical and imaginal symiptom of brain glioma.

  18. Predictive value of brain SPECT with 99 technetium - MIBI for differentiation of histologic grade brain gliomas

    International Nuclear Information System (INIS)

    León Castellón, Roberto; Martín Escuela, Juan Miguel; López Díaz, Ing. Adlin; Salva Camaño, Silvia; Gómez Viera, DrC. Nelson; San Pedro, Aley Palau; Castro Jiménez, Mayté

    2016-01-01

    Diagnosis and treatment of primary tumors of the nervous system remain difficult and are a challenge to be addressed in a multidisciplinary way. In order to determine the usefulness of brain SPECT 99 Tc MIBI to differentiate histologic grade brain gliomas - Frequently brain tumors - they were studied 68 patients with this technique. A dynamic study first step in AP and lateral view was performed, and a SPECT at 20 minutes post-administration and at 2 hours late views. the post-surgical histological study of injuries was used as control. several imaging parameters such as the absolute activity of 99m Tc-MIBI were calculated both early and late phase, cortex contralateral tumor rates; pituitary tumor; choroid plexus tumor and Reason Late / Early phase tumor index / contralateral cortex tumor volume functional phase, the volume concentration of MIBI activity in the tumor and the retention rate of the radiopharmaceutical. Of the 68 patients studied, 11 were high-grade tumors and 57 low grade. The cortex contralateral tumor in late stage index showed a negative satisfactory sensitivity of 98.6% and specificity 77.1%, positive predictive value (PPV) of 48.2% and (NPV) of 99.8%. The reason late stage / early in the index tumor / contralateral cortex showed values ​​in turn 96.3%, 98.7%, 98.8% and 98.8% sensitivity, specificity, PPV and NPV respectively. The retention rate showed a 99% sensitivity, 89% specificity and PPV, NPV of 95% and 99% respectively. Conclusion: The combination cortex contralateral tumor rate in late stage, the reason late stage / early stage tumor index / contralateral cortex and the retention rate of the radiopharmaceutical are the most useful parameters to predict histologic grade of brain gliomas. (author)

  19. Altered intraoperative cerebrovascular reactivity in brain areas of high-grade glioma recurrence.

    Science.gov (United States)

    Fierstra, Jorn; van Niftrik, Bas; Piccirelli, Marco; Burkhardt, Jan Karl; Pangalu, Athina; Kocian, Roman; Valavanis, Antonios; Weller, Michael; Regli, Luca; Bozinov, Oliver

    2016-07-01

    Current MRI sequences are limited in identifying brain areas at risk for high grade glioma recurrence. We employed intraoperative 3-Tesla functional MRI to assess cerebrovascular reactivity (CVR) after high-grade glioma resection and analyzed regional CVR responses in areas of tumor recurrence on clinical follow-up imaging. Five subjects with high-grade glioma that underwent an intraoperative Blood Oxygen-Level Dependent (BOLD) MRI CVR examination and had a clinical follow-up of at least 18months were selected from a prospective database. For this study, location of tumor recurrence was spatially matched to the intraoperative imaging to assess CVR response in that particular area. CVR is defined as the percent BOLD signal change during repeated cycles of apnea. Of the 5 subjects (mean age 44, 2 females), 4 were diagnosed with a WHO grade III and 1 subject with a WHO grade IV glioma. Three subjects exhibited a tumor recurrence on clinical follow-up MRI (mean: 15months). BOLD CVR measured in the spatially matched area of tumor recurrence was on average 94% increased (range-32% to 183%) as compared to contralateral hemisphere CVR response, 1.50±0.81 versus 1.03±0.46 respectively (p=0.31). For this first analysis in a small cohort, we found altered intraoperative CVR in brain areas exhibiting high grade glioma recurrence on clinical follow-up imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

    Directory of Open Access Journals (Sweden)

    Mónica Díaz-Coránguez

    Full Text Available Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

  1. Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

    Science.gov (United States)

    Díaz-Coránguez, Mónica; Segovia, José; López-Ornelas, Adolfo; Puerta-Guardo, Henry; Ludert, Juan; Chávez, Bibiana; Meraz-Cruz, Noemi; González-Mariscal, Lorenza

    2013-01-01

    Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB) was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs) cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM) from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

  2. Similarities and differences in neuroplasticity mechanisms between brain gliomas and nonlesional epilepsy.

    Science.gov (United States)

    Bourdillon, Pierre; Apra, Caroline; Guénot, Marc; Duffau, Hugues

    2017-12-01

    To analyze the conceptual and practical implications of a hodotopic approach in neurosurgery, and to compare the similarities and the differences in neuroplasticity mechanisms between low-grade gliomas and nonlesional epilepsy. We review the recent data about the hodotopic organization of the brain connectome, alongside the organization of epileptic networks, and analyze how these two structures interact, suggesting therapeutic prospects. Then we focus on the mechanisms of neuroplasticity involved in glioma natural course and after glioma surgery. Comparing these mechanisms with those in action in an epileptic brain highlights their differences, but more importantly, gives an original perspective to the consequences of surgery on an epileptic brain and what could be expected after pathologic white matter removal. The organization of the brain connectome and the neuroplasticity is the same in all humans, but different pathologic mechanisms are involved, and specific therapeutic approaches have been developed in epilepsy and glioma surgery. We demonstrate that the "connectome" point of view can enrich epilepsy care. We also underscore how theoretical and practical tools commonly used in epilepsy investigations, such as invasive electroencephalography, can be of great help in awake surgery in general. Putting together advances in understanding of connectomics and neuroplasticity, leads to significant conceptual improvements in epilepsy surgery. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  3. Dosimetric comparison of three-dimensional conformal and intensity modulated radiotherapy in brain glioma

    International Nuclear Information System (INIS)

    Lu Jie; Zhang Guifang; Bai Tong; Yin Yong; Fan Tingyong; Wu Chaoxia

    2009-01-01

    Objective: To investigate the dosimetry advantages of intensity modulated radiotherapy (IMRT)of brain glioma compared with that of three-dimensional conformal radiotherapy (SD CRT). Methods: Ten patients with brain glioma were enrolled in this study. Three-dimensional conf0rmal and intensity modulated radiotherapy plans were performed for each patient. The dose distributions of target volume and normal tissues, conformal index (CI) and heterogeneous index (HI) were analyzed using the dose-volume histogram (DVH). The prescription dose was 60 Gy in 30 fractions. Results: IMRT plans decrease the maximum dose and volume of brainstem, mean dose of affected side parotid and maximum dose of spinal-cord. The CI for PTV of IMRT was superior to that of SD CRT, the HI for PTV has no statistical significance of the two model plans. Conclusions: IMRT plans can obviously decrease the dose and volume of brainstem. IMRT is a potential method in the treatment of brain glioma, and dose escalation was possible in patients with brain glioma. (authors)

  4. Sixth nerve palsy - Window to a dreaded brain tumor in children (pontine glioma

    Directory of Open Access Journals (Sweden)

    Sujit Das

    2017-01-01

    Full Text Available Pontine glioma is a rare tumor and exclusively occurs in children. It originates from the glial (connective/supporting cells of the brain. In children, they are the leading cause of deaths from brain tumors. The usual age of presentation is later half of first decade. Most of the children die within 18 months of diagnosis. It mostly affects 6th and 7th cranial nerves along with hearing defect.

  5. Detection of radiation brain injury of malignant glioma by 1H-MRS

    International Nuclear Information System (INIS)

    Zhang Mao; Jin Haiguo; Sun Shuquan; Bu Mingwei; Su Qingxiu; Liu Guigang; Sun Baosheng

    2011-01-01

    Objective: Using proton magnetic resonance spectroscopy ( 1 H-MRS) method, to evaluate the difference of radiation brain injury between volumetric modulated arc therapy (VMAT) and three-dimensional conformal radiation therapy (3DCRT) in patients with postoperative glioma after radiation therapy. Methods: 24 patients with malignant glioma (WHOII-IV grade glioma) confirmed with clinical surgery were selected, among them 12 patients were treated with VMAT technique, and another 12 patients with 3DCRT technique, all received DT60-66GY/30-33F dose prescriptions. 1 H-MRS examination was performed to analyze the change of metabolites in the brain tissues of region of interest (ROI) before and after radiotherapy,and the ratios of NAA/ Cr, Cho / Cr, NAA / Cho were computed. Results: The dose distribution of VMAT group was superior to 3DCRT group, the NAA/Cr in two groups after radiation were decreased compared with before radiation, there was a statistically difference in NAA/Cr after radiation between two groups (P<0.01). The Cho / Cr and NAA / Cho in two groups were increased compared with before radiation;after radiation, only NAA/Cho had a statistical difference between two groups (P<0.01). Conclusion: VMAT technique is superior to 3DCTR to reduce radiation brain injury in patients with postoperative glioma. (authors)

  6. Emerging role of functional brain MRI in low-grade glioma surgery

    DEFF Research Database (Denmark)

    Friismose, Ancuta; Traise, Peter; Markovic, Ljubo

    Learning objectives 1. To describe the use of functional MRI (fMRI) in cranial surgery planning for patients with low-grade gliomas (LGG). 2. To show the increasing importance of fMRI in the clinical setting. Background LGG include brain tumors classified by the World Health Organization as grade I...... be used to map eloquent cortex areas, thus minimizing postoperative deficits and improving surgical performance. Findings and procedure details Patients diagnosed with low-grade gliomas located in eloquent brain areas undergo fMRI prior to surgery. The exams are performed on a 3T MR system (Achieva TX....... Language comprehension and visual tasks can be added to visualize Wernicke’s area or the visual cortex. Diffusion tensor imaging (DTI) is used to map nerve tract course relative to the tumour. Conclusion FMRI has proven its clinical utility in locating eloquent brain areas with relation to tumor site...

  7. Characterization of the gamma-aminobutyric acid receptor system in human brain gliomas

    International Nuclear Information System (INIS)

    Frattola, L.; Ferrarese, C.; Canal, N.; Gaini, S.M.; Galluso, R.; Piolti, R.; Trabucchi, M.

    1985-01-01

    The properties of [ 3 H]-gamma-aminobutyric acid [( 3 H]GABA) binding were studied in biopsied specimens from normal human brain and from 18 cases of human brain gliomas, made up of 6 astrocytomas, 6 glioblastomas, 3 oligodendrogliomas, and 3 medulloblastomas. In fresh membranes obtained from normal gray and white matter one population of Na+-dependent GABA receptors was observed, while in the frozen Triton X-100-treated membranes two distinct populations of Na+-independent binding sites were detected. Specific GABA binding sites in brain gliomas were shown only in frozen Triton X-100-treated membranes. As in normal tissue, these receptors are Na+-independent and bind [ 3 H]GABA with two distinct affinity components. The biochemical profiles of [ 3 H]GABA binding to membranes obtained from different tumors of glial origin are quite similar and cannot be related to the degree of malignancy of the neoplasia

  8. Capillary electrophoresis - Mass spectrometry metabolomics analysis revealed enrichment of hypotaurine in rat glioma tissues.

    Science.gov (United States)

    Gao, Peng; Ji, Min; Fang, Xueyan; Liu, Yingyang; Yu, Zhigang; Cao, Yunfeng; Sun, Aijun; Zhao, Liang; Zhang, Yong

    2017-11-15

    Glioma is one of the most lethal brain malignancies with unknown etiologies. Many metabolomics analysis aiming at diverse kinds of samples had been performed. Due to the varied adopted analytical platforms, the reported disease-related metabolites were not consistent across different studies. Comparable metabolomics results are more likely to be acquired by analyzing the same sample types with identical analytical platform. For tumor researches, tissue samples metabolomics analysis own the unique advantage that it can gain more direct insight into disease-specific pathological molecules. In this light, a previous reported capillary electrophoresis - mass spectrometry human tissues metabolomics analysis method was employed to profile the metabolome of rat C6 cell implantation gliomas and the corresponding precancerous tissues. It was found that 9 metabolites increased in the glioma tissues. Of them, hypotaurine was the only metabolite that enriched in the malignant tissues as what had been reported in the relevant human tissues metabolomics analysis. Furthermore, hypotaurine was also proved to inhibit α-ketoglutarate-dependent dioxygenases (2-KDDs) through immunocytochemistry staining and in vitro enzymatic activity assays by using C6 cell cultures. This study reinforced the previous conclusion that hypotaurine acted as a competitive inhibitor of 2-KDDs and proved the value of metabolomics in oncology studies. Copyright © 2017. Published by Elsevier Inc.

  9. External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Sminia, Peter, E-mail: p.sminia@vumc.nl [Department of Radiation Oncology, Radiobiology Section, VU University Medical Center, De Boelelaan 1117, P.O. Box 7057, Amsterdam (Netherlands); Mayer, Ramona [EBG MedAustron GmbH., Viktor Kaplan-Strasse 2, A-2700, Wiener Neustadt (Austria)

    2012-04-05

    Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis), to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2{sub cumulative}). Analysis shows that the EQD2{sub cumulative} increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT) to LINAC-based stereotactic radiosurgery (SRS). The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2{sub cumulative} around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials.

  10. External Beam Radiotherapy of Recurrent Glioma: Radiation Tolerance of the Human Brain

    Directory of Open Access Journals (Sweden)

    Peter Sminia

    2012-04-01

    Full Text Available Malignant gliomas relapse in close proximity to the resection site, which is the postoperatively irradiated volume. Studies on re-irradiation of glioma were examined regarding radiation-induced late adverse effects (i.e., brain tissue necrosis, to obtain information on the tolerance dose and treatment volume of normal human brain tissue. The studies were analyzed using the linear-quadratic model to express the re-irradiation tolerance in cumulative equivalent total doses when applied in 2 Gy fractions (EQD2cumulative. Analysis shows that the EQD2cumulative increases from conventional re-irradiation series to fractionated stereotactic radiotherapy (FSRT to LINAC-based stereotactic radiosurgery (SRS. The mean time interval between primary radiotherapy and the re-irradiation course was shortened from 30 months for conventional re-irradiation to 17 and 10 months for FSRT and SRS, respectively. Following conventional re-irradiation, radiation-induced normal brain tissue necrosis occurred beyond an EQD2cumulative around 100 Gy. With increasing conformality of therapy, the smaller the treatment volume is, the higher the radiation dose that can be tolerated. Despite the dose escalation, no increase in late normal tissue toxicity was reported. On basis of our analysis, the use of particle therapy in the treatment of recurrent gliomas, because of the optimized physical dose distribution in the tumour and surrounding healthy brain tissue, should be considered for future clinical trials.

  11. Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu-Ming; Shiau, Cheng-Ying; Wong, Tai-Tong; Wang, Ling-Wei; Wu, Le-Jung; Chi, Kwan-Hwa; Chen, Kuang Y.; Yen, Sang-Hue [Veterans General Hospital-Taipei, Taipei, Taiwan (China)

    1998-08-01

    A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n=7), radiotherapy alone (n=10) and radiotherapy with adjuvant chemotherapy (n=5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P=0.017 and 0.036). A trend of better outcome with radiation dose >6600 cGy and the hyperfractionation scheme was also noted in our study (P=0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P=0.0355). Survival was not significantly affected by age, gender or method of diagnosis. Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival. (author)

  12. Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas

    International Nuclear Information System (INIS)

    Liu, Yu-Ming; Shiau, Cheng-Ying; Wong, Tai-Tong; Wang, Ling-Wei; Wu, Le-Jung; Chi, Kwan-Hwa; Chen, Kuang Y.; Yen, Sang-Hue

    1998-01-01

    A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n=7), radiotherapy alone (n=10) and radiotherapy with adjuvant chemotherapy (n=5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P=0.017 and 0.036). A trend of better outcome with radiation dose >6600 cGy and the hyperfractionation scheme was also noted in our study (P=0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P=0.0355). Survival was not significantly affected by age, gender or method of diagnosis. Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival. (author)

  13. Demethoxycurcumin Retards Cell Growth and Induces Apoptosis in Human Brain Malignant Glioma GBM 8401 Cells

    Directory of Open Access Journals (Sweden)

    Tzuu-Yuan Huang

    2012-01-01

    Full Text Available Demethoxycurcumin (DMC; a curcumin-related demethoxy compound has been recently shown to display antioxidant and antitumor activities. It has also produced a potent chemopreventive action against cancer. In the present study, the antiproliferation (using the MTT assay, DMC was found to have cytotoxic activities against GBM 8401 cell with IC50 values at 22.71 μM and induced apoptosis effects of DMC have been investigated in human brain malignant glioma GBM 8401 cells. We have studied the mitochondrial membrane potential (MMP, DNA fragmentation, caspase activation, and NF-κB transcriptional factor activity. By these approaches, our results indicated that DMC has produced an inhibition of cell proliferation as well as the activation of apoptosis in GBM 8401 cells. Both effects were observed to increase in proportion with the dosage of DMC treatment, and the apoptosis was induced by DMC in human brain malignant glioma GBM 8401 cells via mitochondria- and caspase-dependent pathways.

  14. Validation of DWI pre-processing procedures for reliable differentiation between human brain gliomas.

    Science.gov (United States)

    Vellmer, Sebastian; Tonoyan, Aram S; Suter, Dieter; Pronin, Igor N; Maximov, Ivan I

    2018-02-01

    Diffusion magnetic resonance imaging (dMRI) is a powerful tool in clinical applications, in particular, in oncology screening. dMRI demonstrated its benefit and efficiency in the localisation and detection of different types of human brain tumours. Clinical dMRI data suffer from multiple artefacts such as motion and eddy-current distortions, contamination by noise, outliers etc. In order to increase the image quality of the derived diffusion scalar metrics and the accuracy of the subsequent data analysis, various pre-processing approaches are actively developed and used. In the present work we assess the effect of different pre-processing procedures such as a noise correction, different smoothing algorithms and spatial interpolation of raw diffusion data, with respect to the accuracy of brain glioma differentiation. As a set of sensitive biomarkers of the glioma malignancy grades we chose the derived scalar metrics from diffusion and kurtosis tensor imaging as well as the neurite orientation dispersion and density imaging (NODDI) biophysical model. Our results show that the application of noise correction, anisotropic diffusion filtering, and cubic-order spline interpolation resulted in the highest sensitivity and specificity for glioma malignancy grading. Thus, these pre-processing steps are recommended for the statistical analysis in brain tumour studies. Copyright © 2017. Published by Elsevier GmbH.

  15. 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.

    Science.gov (United States)

    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.

  16. Genetic Alterations in Glioma

    International Nuclear Information System (INIS)

    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

  17. TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients

    International Nuclear Information System (INIS)

    Wang, Chao; Cao, Shouqiang; Yan, Ying; Ying, Qiao; Jiang, Tao; Xu, Ke; Wu, Anhua

    2010-01-01

    Our study aims to evaluate the expression of TLR9 in glioma tissues, examine the association between TLR9 expression, clinicopathological variables, and glioma patient outcome, we further characterized the direct effects of TLR9 agonist CpG ODN upon the proliferation and invasion of glioma cells in vitro. RT-PCR and immunofluorescence were used to determine the expression of TLR9 in glioma cell lines and clinical glioma samples. Tissue microarry and immunohistochemistry were applied to evaluated TLR9 expression in 292 newly diagnosed glioma and 13 non-neoplastic brain tissues. We further investigated the effect of CpG ODN on the proliferation and invasion of glioma cells in vitro with MTT assays and matrigel transwell assay respectively. RT-PCR showed that TLR9 expressed in all the glioma samples and glioma cell lines we examined. The tissue array analysis indicated that TLR9 expression is correlated with malignancy of glioma (p < 0.01). Multivariate Cox regression analysis revealed that TLR9 expression is an independent prognostic factor for PFS of GBM patients(P = 0.026). TLR9 agonist CpG ODN has no significant effect on glioma proliferation, but matrigel transwell analysis showed that TLR9 agonist CpG ODN can significantly enhance glioma invasion in vitro. Our data indicated that TLR9 expression increases according to the histopathological grade of glioma, and the TLR9 expression level is related to the PFS of GBM patients. In addition, our findings warrant caution in the directly injection of TLR9 agonist CpG ODN into glioma tissues for the glioma immunotherapy

  18. Anaesthetic management for awake craniotomy in brain glioma ...

    African Journals Online (AJOL)

    The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awakeawake- awake method. We describe ...

  19. Automatic Semantic Segmentation of Brain Gliomas from MRI Images Using a Deep Cascaded Neural Network.

    Science.gov (United States)

    Cui, Shaoguo; Mao, Lei; Jiang, Jingfeng; Liu, Chang; Xiong, Shuyu

    2018-01-01

    Brain tumors can appear anywhere in the brain and have vastly different sizes and morphology. Additionally, these tumors are often diffused and poorly contrasted. Consequently, the segmentation of brain tumor and intratumor subregions using magnetic resonance imaging (MRI) data with minimal human interventions remains a challenging task. In this paper, we present a novel fully automatic segmentation method from MRI data containing in vivo brain gliomas. This approach can not only localize the entire tumor region but can also accurately segment the intratumor structure. The proposed work was based on a cascaded deep learning convolutional neural network consisting of two subnetworks: (1) a tumor localization network (TLN) and (2) an intratumor classification network (ITCN). The TLN, a fully convolutional network (FCN) in conjunction with the transfer learning technology, was used to first process MRI data. The goal of the first subnetwork was to define the tumor region from an MRI slice. Then, the ITCN was used to label the defined tumor region into multiple subregions. Particularly, ITCN exploited a convolutional neural network (CNN) with deeper architecture and smaller kernel. The proposed approach was validated on multimodal brain tumor segmentation (BRATS 2015) datasets, which contain 220 high-grade glioma (HGG) and 54 low-grade glioma (LGG) cases. Dice similarity coefficient (DSC), positive predictive value (PPV), and sensitivity were used as evaluation metrics. Our experimental results indicated that our method could obtain the promising segmentation results and had a faster segmentation speed. More specifically, the proposed method obtained comparable and overall better DSC values (0.89, 0.77, and 0.80) on the combined (HGG + LGG) testing set, as compared to other methods reported in the literature. Additionally, the proposed approach was able to complete a segmentation task at a rate of 1.54 seconds per slice.

  20. Mathematical modeling of human glioma growth based on brain topological structures: study of two clinical cases.

    Directory of Open Access Journals (Sweden)

    Cecilia Suarez

    Full Text Available Gliomas are the most common primary brain tumors and yet almost incurable due mainly to their great invasion capability. This represents a challenge to present clinical oncology. Here, we introduce a mathematical model aiming to improve tumor spreading capability definition. The model consists in a time dependent reaction-diffusion equation in a three-dimensional spatial domain that distinguishes between different brain topological structures. The model uses a series of digitized images from brain slices covering the whole human brain. The Talairach atlas included in the model describes brain structures at different levels. Also, the inclusion of the Brodmann areas allows prediction of the brain functions affected during tumor evolution and the estimation of correlated symptoms. The model is solved numerically using patient-specific parametrization and finite differences. Simulations consider an initial state with cellular proliferation alone (benign tumor, and an advanced state when infiltration starts (malign tumor. Survival time is estimated on the basis of tumor size and location. The model is used to predict tumor evolution in two clinical cases. In the first case, predictions show that real infiltrative areas are underestimated by current diagnostic imaging. In the second case, tumor spreading predictions were shown to be more accurate than those derived from previous models in the literature. Our results suggest that the inclusion of differential migration in glioma growth models constitutes another step towards a better prediction of tumor infiltration at the moment of surgical or radiosurgical target definition. Also, the addition of physiological/psychological considerations to classical anatomical models will provide a better and integral understanding of the patient disease at the moment of deciding therapeutic options, taking into account not only survival but also life quality.

  1. Dynamic CT perfusion imaging of intra-axial brain tumours: differentiation of high-grade gliomas from primary CNS lymphomas

    International Nuclear Information System (INIS)

    Schramm, Peter; Xyda, Argyro; Knauth, Michael; Klotz, Ernst; Tronnier, Volker; Hartmann, Marius

    2010-01-01

    Perfusion computed tomography (PCT) allows to quantitatively assess haemodynamic characteristics of brain tissue. We investigated if different brain tumor types can be distinguished from each other using Patlak analysis of PCT data. PCT data from 43 patients with brain tumours were analysed with a commercial implementation of the Patlak method. Four patients had low-grade glioma (WHO II), 31 patients had glioblastoma (WHO IV) and eight patients had intracerebral lymphoma. Tumour regions of interest (ROIs) were drawn in a morphological image and automatically transferred to maps of cerebral blood flow (CBF), cerebral blood volume (CBV) and permeability (K Trans ). Mean values were calculated, group differences were tested using Wilcoxon and Mann Whitney U-tests. In comparison with normal parenchyma, low-grade gliomas showed no significant difference of perfusion parameters (p > 0.05), whereas high-grade gliomas demonstrated significantly higher values (p Trans , p Trans values compared with unaffected cerebral parenchyma (p = 0.0078) but no elevation of CBV. High-grade gliomas show significant higher CBV values than lymphomas (p = 0.0078). PCT allows to reliably classify gliomas and lymphomas based on quantitative measurements of CBV and K Trans . (orig.)

  2. Tomographic criteria of gliomas in the brain stem in infants

    International Nuclear Information System (INIS)

    Machado Junior, M.A.; Bracchi, M.; D'Incerti, L.; Passerini, A.

    1994-01-01

    The relationship between Computed Tomography Imaging, histopathological and prognostic data is evaluated by reviewing 37 cases of brain stem neoplasm in infants. The results indicate a presence of a cystic lesion with solid mural nodule as the single prognostic criteria of a greater survival rate. Such finding frequently corresponds to Pilocytic Astrocytomas. No correlations between contrast enhancement and prognostic was found. The association between the prognostic value to the densitometric characteristics of the lesions was not possible. It was concluded that the evaluations of the extension of such lesion is fundamental. Therefore, Magnetic Resonance Imaging has more value than computed tomography. (M.A.C.)

  3. Establishment of 9L/F344 rat intracerebral glioma model of brain tumor stem cells

    Directory of Open Access Journals (Sweden)

    Zong-yu XIAO

    2015-04-01

    Full Text Available Objective To establish the 9L/F344 rat intracerebral glioma model of brain tumor stem cells.  Methods Rat 9L gliosarcoma stem-like cells were cultured in serum-free suspension. The expression of CD133 and nestin were tested by immunohistochemistry. A total of 48 inbredline male F344 rats were randomly divided into 2 groups, and 9L tumor sphere cells and 9L monolayer cells were respectively implanted into the right caudate nucleus of F344 rats in 2 groups. Survival time was observed and determined using the method of Kaplan-Meier survival analysis. Fourteen days after implantation or when the rats were dying, their brains were perfused and sectioned for HE staining, and CD133 and nestin were detected by immunohistochemistry.  Results Rat 9L tumor spheres were formed with suspension culture in serum-free medium. The gliomas formed in both groups were invasive without obvious capsule. More new vessels, bleeding and necrosis could be detected in 9L tumor spheres group. The tumor cells in both groups were positive for CD133 and nestin. There was no significant difference in the expression of CD133 and nestin between 2 groups (P > 0.05, for all. According to the expression of nestin, the tumors formed by 9L tumor sphere cells were more invasive. The median survival time of the rats bearing 9L tumor sphere cells was 15 d (95%CI: 15.219-15.781, and the median survival time of the rats bearing 9L monolayer cells was 21 d (95%CI: 20.395-21.605. There was significant difference between 2 groups (χ2 = 12.800, P = 0.000.  Conclusions 9L/F344 rat intracerebral glioma model of brain tumor stem cells is successfully established, which provides a glioma model for the future research. DOI: 10.3969/j.issn.1672-6731.2015.04.012

  4. Lactoferrin conjugated iron oxide nanoparticles for targeting brain glioma cells in magnetic particle imaging

    Science.gov (United States)

    Tomitaka, Asahi; Arami, Hamed; Gandhi, Sonu; Krishnan, Kannan M.

    2015-10-01

    Magnetic Particle Imaging (MPI) is a new real-time imaging modality, which promises high tracer mass sensitivity and spatial resolution directly generated from iron oxide nanoparticles. In this study, monodisperse iron oxide nanoparticles with median core diameters ranging from 14 to 26 nm were synthesized and their surface was conjugated with lactoferrin to convert them into brain glioma targeting agents. The conjugation was confirmed with the increase of the hydrodynamic diameters, change of zeta potential, and Bradford assay. Magnetic particle spectrometry (MPS), performed to evaluate the MPI performance of these nanoparticles, showed no change in signal after lactoferrin conjugation to nanoparticles for all core diameters, suggesting that the MPI signal is dominated by Néel relaxation and thus independent of hydrodynamic size difference or presence of coating molecules before and after conjugations. For this range of core sizes (14-26 nm), both MPS signal intensity and spatial resolution improved with increasing core diameter of nanoparticles. The lactoferrin conjugated iron oxide nanoparticles (Lf-IONPs) showed specific cellular internalization into C6 cells with a 5-fold increase in MPS signal compared to IONPs without lactoferrin, both after 24 h incubation. These results suggest that Lf-IONPs can be used as tracers for targeted brain glioma imaging using MPI.

  5. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

    Science.gov (United States)

    Bao, Zhao-Shi; Chen, Hui-Min; Yang, Ming-Yu; Zhang, Chuan-Bao; Yu, Kai; Ye, Wan-Lu; Hu, Bo-Qiang; Yan, Wei; Zhang, Wei; Akers, Johnny; Ramakrishnan, Valya; Li, Jie; Carter, Bob; Liu, Yan-Wei; Hu, Hui-Min; Wang, Zheng; Li, Ming-Yang; Yao, Kun; Qiu, Xiao-Guang; Kang, Chun-Sheng; You, Yong-Ping; Fan, Xiao-Long; Song, Wei Sonya; Li, Rui-Qiang; Su, Xiao-Dong; Chen, Clark C; Jiang, Tao

    2014-11-01

    Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs. © 2014 Bao et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Effect of brain- and tumor-derived connective tissue growth factor on glioma invasion.

    Science.gov (United States)

    Edwards, Lincoln A; Woolard, Kevin; Son, Myung Jin; Li, Aiguo; Lee, Jeongwu; Ene, Chibawanye; Mantey, Samuel A; Maric, Dragan; Song, Hua; Belova, Galina; Jensen, Robert T; Zhang, Wei; Fine, Howard A

    2011-08-03

    Tumor cell invasion is the principal cause of treatment failure and death among patients with malignant gliomas. Connective tissue growth factor (CTGF) has been previously implicated in cancer metastasis and invasion in various tumors. We explored the mechanism of CTGF-mediated glioma cell infiltration and examined potential therapeutic targets. Highly infiltrative patient-derived glioma tumor-initiating or tumor stem cells (TIC/TSCs) were harvested and used to explore a CTGF-induced signal transduction pathway via luciferase reporter assays, chromatin immunoprecipitation (ChIP), real-time polymerase chain reaction, and immunoblotting. Treatment of TIC/TSCs with small-molecule inhibitors targeting integrin β1 (ITGB1) and the tyrosine kinase receptor type A (TrkA), and short hairpin RNAs targeting CTGF directly were used to reduce the levels of key protein components of CTGF-induced cancer infiltration. TIC/TSC infiltration was examined in real-time cell migration and invasion assays in vitro and by immunohistochemistry and in situ hybridization in TIC/TSC orthotopic xenograft mouse models (n = 30; six mice per group). All statistical tests were two-sided. Treatment of TIC/TSCs with CTGF resulted in CTGF binding to ITGB1-TrkA receptor complexes and nuclear factor kappa B (NF-κB) transcriptional activation as measured by luciferase reporter assays (mean relative luciferase activity, untreated vs CTGF(200 ng/mL): 0.53 vs 1.87, difference = 1.34, 95% confidence interval [CI] = 0.69 to 2, P < .001). NF-κB activation resulted in binding of ZEB-1 to the E-cadherin promoter as demonstrated by ChIP analysis with subsequent E-cadherin suppression (fold increase in ZEB-1 binding to the E-cadherin promoter region: untreated + ZEB-1 antibody vs CTGF(200 ng/mL) + ZEB-1 antibody: 1.5 vs 6.4, difference = 4.9, 95% CI = 4.8 to 5.0, P < .001). Immunohistochemistry and in situ hybridization revealed that TrkA is selectively expressed in the most infiltrative glioma cells in situ

  7. Patient-specific metrics of invasiveness reveal significant prognostic benefit of resection in a predictable subset of gliomas.

    Directory of Open Access Journals (Sweden)

    Anne L Baldock

    Full Text Available Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas.In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patient's tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness.We demonstrate that patients with more diffuse tumors showed no survival benefit (P = 0.532 from gross total resection over subtotal/biopsy, while those with nodular (less diffuse tumors showed a significant benefit (P = 0.00142 with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors.These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection.

  8. Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors

    International Nuclear Information System (INIS)

    Server, Andres; Schellhorn, Till; Haakonsen, Monika; Nakstad, Per H.; Josefsen, Roger; Kulle, Bettina; Maehlen, Jan; Kumar, Theresa; Gadmar, Oeystein; Langberg, Carl W.

    2010-01-01

    Background: Brain metastases and primary high-grade gliomas, including glioblastomas multiforme (GBM) and anaplastic astrocytomas (AA), may be indistinguishable by conventional magnetic resonance (MR) imaging. Identification of these tumors may have therapeutic consequences. Purpose: To assess the value of MR spectroscopy (MRS) using short and intermediate echo time (TE) in differentiating solitary brain metastases and high-grade gliomas on the basis of differences in metabolite ratios in the intratumoral and peritumoral region. Material and Methods: We performed MR imaging and MRS in 73 patients with histologically verified intraaxial brain tumors: 53 patients with high-grade gliomas (34 GBM and 19 AA) and 20 patients with metastatic brain tumors. The metabolite ratios of Cho/Cr, Cho/NAA, and NAA/Cr at intermediate TE and the presence of lipids at short TE were assessed from spectral maps in the tumoral core, peritumoral edema, and contralateral normal-appearing white matter. The differences in the metabolite ratios between high-grade gliomas/GBM/AA and metastases were analyzed statistically. Cutoff values of Cho/Cr, Cho/NAA, and NAA/Cr ratios in the peritumoral edema, as well as Cho/Cr and NAA/Cr ratios in the tumoral core for distinguishing high-grade gliomas/GBM/AA from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Significant differences were noted in the peritumoral Cho/Cr, Cho/NAA, and NAA/ Cr ratios between high-grade gliomas/GBM/AA and metastases. ROC analysis demonstrated a cutoff value of 1.24 for peritumoral Cho/Cr ratio to provide sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 100%, 88.9%, 80.0%, and 100%, respectively, for discrimination between high-grade gliomas and metastases. By using a cutoff value of 1.11 for peritumoral Cho/NAA ratio, the sensitivity was 100%, the specificity was 91.1%, the PPV was 83.3%, and the NPV was 100%. Conclusion: The results of this

  9. miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma

    International Nuclear Information System (INIS)

    Põlajeva, Jelena; Swartling, Fredrik J; Jiang, Yiwen; Singh, Umashankar; Pietras, Kristian; Uhrbom, Lene; Westermark, Bengt; Roswall, Pernilla

    2012-01-01

    MicroRNAs (miRNAs) and their role during tumor development have been studied in great detail during the last decade, albeit their expression pattern and regulation during normal development are however not so well established. Previous studies have shown that miRNAs are differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF) signaling is known to be involved in normal development of the brain as well as in malignant primary brain tumors, gliomas, but the complete mechanism is still lacking. We decided to investigate the expression of the oncogenic miR-21 during normal mouse development and glioma, focusing on PDGF signaling as a potential regulator of miR-21. We generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression in a cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain were assessed using Northern blot analysis and in situ hybridization. Immunohistochemistry and Western blot analysis were used to investigate SOX2 expression. LNA-modified siRNA was used for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec (imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statistical significance was calculated using double-sided unpaired Student´s t-test. We identified miR-21 to be highly expressed during embryonic and newborn brain development followed by a gradual decrease until undetectable at postnatal day 7 (P7), this pattern correlated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation and overlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Upon irreversible depletion of miR-21 the expression of SOX2 was strongly diminished in both mouse primary glioma cultures and human glioma cell lines. Interestingly, in normal fibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGF signaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting that mi

  10. Effects of anticancer drugs on glia-glioma brain tumor model characterized by acoustic impedance microscopy

    Science.gov (United States)

    Soon, Thomas Tiong Kwong; Chean, Tan Wei; Yamada, Hikari; Takahashi, Kenta; Hozumi, Naohiro; Kobayashi, Kazuto; Yoshida, Sachiko

    2017-07-01

    An ultrasonic microscope is a useful tool for observing living tissue without chemical fixation or histochemical processing. Two-dimensional (2D) acoustic impedance microscopy developed in our previous study for living cell observation was employed to visualize intracellular changes. We proposed a brain tumor model by cocultivating rat glial cells and C6 gliomas to quantitatively analyze the effects of two types of anticancer drugs, cytochalasin B (CyB) and temozolomide (TMZ), when they were applied. We reported that CyB treatment (25 µg/ml, T = 90 min) significantly reduced the acoustic impedance of gliomas and has little effect on glial cells. Meanwhile, TMZ treatment (2 mg/ml, T = 90 min) impacted both cells equally, in which both cells’ acoustic impedances were decreased. As CyB targets the actin filament polymerization of the cells, we have concluded that the decrease in acoustic impedance was in fact due to actin filament depolymerization and the data can be quantitatively assessed for future studies in novel drug development.

  11. Increased seroreactivity to glioma-expressed antigen 2 in brain tumor patients under radiation.

    Directory of Open Access Journals (Sweden)

    Sabrina M Heisel

    Full Text Available BACKGROUND: Surgery and radiation are the mainstays of therapy for human gliomas that are the most common primary brain tumors. Most recently, cell culture and animal studies provided the first convincing evidence that radiation not only eliminates tumor cells, but also modulates the immune response and likely improves anti-tumor immunotherapy. METHODOLOGY/PRINCIPAL FINDINGS: We present an in vivo study that analyzes the effects of radiation on the immune response in tumor patients. As readout system, we utilized the reactivity of glioma patients' sera against antigen GLEA2 as the most frequent antigen immunogenic in glioblastoma patients. We established an ELISA assay to analyze reactivity of 24 glioblastoma patients over a period of several months. As control we used 30 sera from healthy donors as well as 30 sera from lung cancer patients. We compared the course of GLEA2 seroreactivity at different times prior, during and after radiation. The GLEA2 seroreactivity was increased by the time of surgery, decreased after surgery, increased again under radiation, and slightly decreased after radiation. CONCLUSIONS/SIGNIFICANCE: Our results provide in vivo evidence for an increased antibody response against tumor antigens under radiation. Antigens that become immunogenic with an increased antibody response as result of radiation can serve as ideal targets for immunotherapy of human tumors.

  12. Influence of blood-brain barrier permeability on O-(2-{sup 18}F-fluoroethyl)-L-tyrosine uptake in rat gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Stegmayr, Carina; Bandelow, Ulrike; Oliveira, Dennis; Lohmann, Philipp; Willuweit, Antje; Galldiks, Norbert; Luebke, Joachim H.R. [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); Filss, Christian; Ermert, Johannes; Langen, Karl-Josef [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Shah, N. Jon [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain, Aachen (Germany)

    2017-03-15

    O-(2-{sup 18}F-fluoroethyl)-L-tyrosine ({sup 18}F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on {sup 18}F-FET uptake in two rat glioma models and one human xenograft model. F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent {sup 18}F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of {sup 18}F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs. In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of {sup 18}F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010). Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of {sup 18}F-FET uptake were noted in this experimental study. Thus, {sup 18}F-FET uptake in gliomas appears to be widely independent of the

  13. Generalized q-sampling imaging fiber tractography reveals displacement and infiltration of fiber tracts in low-grade gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Celtikci, Pinar; Fernandes-Cabral, David T.; Yeh, Fang-Cheng; Panesar, Sandip S.; Fernandez-Miranda, Juan C. [University of Pittsburgh Medical Center, Department of Neurological Surgery, Pittsburgh, PA (United States)

    2018-03-15

    Low-grade gliomas (LGGs) are slow growing brain tumors that often cause displacement and/or infiltration of the surrounding white matter pathways. Differentiation between infiltration and displacement of fiber tracts remains a challenge. Currently, there is no reliable noninvasive imaging method capable of revealing such white matter alteration patterns. We employed quantitative anisotropy (QA) derived from generalized q-sampling imaging (GQI) to identify patterns of fiber tract alterations by LGGs. Sixteen patients with a neuropathological diagnosis of LGG (WHO grade II) were enrolled. Peritumoral fiber tracts underwent qualitative and quantitative evaluation. Contralateral hemisphere counterparts were used for comparison. Tracts were qualitatively classified as unaffected, displaced, infiltrated or displaced, and infiltrated at once. The average QA of whole tract (W), peritumoral tract segment (S), and their ratio (S/W) were obtained and compared to the healthy side for quantitative evaluation. Qualitative analysis revealed 9 (13.8%) unaffected, 24 (36.9%) displaced, 13 (20%) infiltrated, and 19 (29.2%) tracts with a combination of displacement and infiltration. There were no disrupted tracts. There was a significant increase in S/W ratio among displaced tracts in the pre-operative scans in comparison with the contralateral side. QA values of peritumoral tract segments (S) were significantly lower in infiltrated tracts. WHO grade II LGGs might displace, infiltrate, or cause a combination of displacement and infiltration of WM tracts. QA derived from GQI provides valuable information that helps to differentiate infiltration from displacement. Anisotropy changes correlate with qualitative alterations, which may serve as a potential biomarker of fiber tract integrity. (orig.)

  14. Application of Awake Craniotomy and Intraoperative Brain Mapping for Surgical Resection of Insular Gliomas of the Dominant Hemisphere.

    Science.gov (United States)

    Alimohamadi, Maysam; Shirani, Mohammad; Shariat Moharari, Reza; Pour-Rashidi, Ahmad; Ketabchi, Mehdi; Khajavi, Mohammadreza; Arami, Mohamadali; Amirjamshidi, Abbas

    2016-08-01

    Radical resection of dominant insular gliomas is difficult because of their close vicinity with internal capsule, basal ganglia, and speech centers. Brain mapping techniques can be used to maximize the extent of tumor removal and to minimize postoperative morbidities by precise localization of eloquent cortical and subcortical areas. Patients with newly diagnosed gliomas of dominant insula were enrolled. The exclusion criteria were severe cognitive disturbances, communication difficulty, age greater than 75 years, severe obesity, difficult airways for intubation and severe cardiopulmonary diseases. All were evaluated preoperatively with contrast-enhanced brain magnetic resonance imaging (MRI), functional brain MRI, and diffusion tensor tractography of language and motor systems. All underwent awake craniotomy with the same anesthesiology protocol. Intraoperative monitoring included continuous motor-evoked potential, electromyography, electrocorticography, direct electrical stimulation of cortex, and subcortical tracts. The patients were followed with serial neurologic examination and imaging. Ten patients were enrolled (4 men, 6 women) with a mean age of 43.6 years. Seven patients suffered from low-grade glioma, and 3 patients had high-grade glioma. The most common clinical presentation was seizure followed by speech disturbance, hemiparesis, and memory loss. Extent of tumor resection ranged from 73% to 100%. No mortality or new major postoperative neurologic deficit was encountered. Seizure control improved in three fourths of patients with medical refractory epilepsy. In one patient with speech disorder at presentation, the speech problem became worse after surgery. Brain mapping during awake craniotomy helps to maximize extent of tumor resection while preserving neurologic function in patients with dominant insular lobe glioma. Copyright © 2016. Published by Elsevier Inc.

  15. Glioma in a goat

    International Nuclear Information System (INIS)

    Marshall, C.L.; Weinstock, D.; Kramer, R.W.; Bagley, R.S.

    1995-01-01

    An adult goat was examined because of behavioral changes and circling. Results of neurologic examination, CSF analysis, hematologic evaluation, and computed tomography of the brain were suggestive of an intra-axial mass. The goat was euthanatized because of worsening neurologic condition and poor prognosis. Necropsy revealed a large mass in the right cerebral hemisphere and caudal brain herniation through the foramen magnum. The mass was diagnosed as a glioma, with oligodendrocyte differentiation. Results of immunohistochemical evaluation were compatible with a malignant, poorly differentiated tumor

  16. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma

    Science.gov (United States)

    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, Shiyung; Rao, Arjun A.; Grifford, Mia; Cherniack, Andrew D.; Zhang, Hailei; Poisson, Laila; Carlotti, Carlos Gilberto; Pretti da Cunha Tirapelli, Daniela; 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.

    2015-01-01

    SUMMARY 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-wildtype diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes. PMID:26824661

  17. Neuronavigator-guided glioma surgery.

    Science.gov (United States)

    Du, Guhong; Zhou, Liangfu; Mao, Ying

    2003-10-01

    To evaluate the effectiveness of neuronavigator-guided surgery for the resection of gliomas. A total of 80 patients with gliomas underwent surgical treatment under the StealthStation neuronavigator to estimate the extent of the tumors. In 27 cases, the measurements of brain shifts at the dura, cortical surface and lesion margin were recorded during the operations. A technique termed "micro-catheter fence post" was used in superficial gliomas to compensate for brain shift. Mean fiducial error and predicted accuracy in the 80 cases were 2.03 mm +/- 0.89 mm and 2.43 mm +/- 0.99 mm, respectively. The shifts at the dura, cortical surface and lesion margin were 3.44 mm +/- 2.39 mm, 7.58 mm +/- 3.75 mm, and 6.55 mm +/- 3.19 mm, respectively. Although neuronavigation revealed residual tumors, operations were discontinued in 5 cases of deep-seated gliomas. In the other 75 cases, total tumor removals were achieved in 62 (82.7%), and subtotal removals were achieved in 13 (17.3%). Post-operation, neurological symptoms were improved or unchanged in 68 cases (85.0%), and worsened in 12 (15.0%). No deaths occurred during the operations and post-operations. Intraoperative brain shifts mainly contribute to the fail of spatial accuracy during neuronavigator-guided glioma surgery. The "micro-catheter fence post" technique used for glioma surgery is shown to be useful for compensating for intraoperative brain shifts. This technique, thus, contributes to an increase in total tumor removal and a decrease in surgical complications.

  18. A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brain stem glioma

    International Nuclear Information System (INIS)

    Dutton, S.C.; Pomeroy, S.L.; Billett, A.L.; Barnes, P.; Kuhlman, C.; Riese, N.E.; Goumnerova, L.; Scott, R.M.; Coleman, C.N.; Tarbell, N.J.

    1997-01-01

    Objective: Prospective phase I study to evaluate the toxicity and maximum tolerated dose of etanidazole administered concurrently with hyperfractionated radiation therapy (HRT) for children with brain stem glioma. Materials and Methods: Eighteen patients with brain stem glioma were treated with etanidazole and HRT from 1990-1996. Eligibility required MRI confirmation of diffuse glioma of medulla, pons or mesencephalon, and signs/symptoms of cranial nerve deficit, ataxia or long tract signs of ≤ 6 months duration. Cervico-medullary tumors were excluded. Patients (median age 8.5 years; 11 males, 7 females) received HRT to the tumor volume plus a 2 cm margin with parallel opposed 6-15 MV photons. The total dose was 66 Gy for the first 3 patients, followed by 63 Gy over 4.2 weeks (1.5 Gy BID with 6 hours between fractions) for the subsequent 15 patients. Etanidazole was administered as a rapid IV infusion 30 minutes prior to the morning fraction of HRT at doses of 1.8 gm/m2 x 17 doses (30.6 gm/m2) at step 1 to a maximum of 2.4 gm/m2 x 21 doses (50.4 gm/m2) at step 8. Dose escalation was planned with 3 patients at each of the 8 levels. Results: Three patients were treated at each dose level except level 2, on which only one patient was treated. The highest dose level achieved was step 7 which delivered a total etanidazole dose of 46.2 gm/m2. Two patients were treated at this level, and both patients experienced grade 3 toxicity in the form of a diffuse cutaneous rash. Three patients received a lower dose of 42 gm/m2 without significant toxicity, and this represents the maximum tolerated dose (MTD). There were 24 cases of grade 1 toxicity (10 vomiting, 5 peripheral neuropathy, 2 rash, 2 constipation, 1 skin erythema, 1 weight loss, 3 other), eleven cases of grade 2 toxicity (4 vomiting, 2 skin erythema, 2 constipation, 1 arthalgia, 1 urinary retention, 1 hematologic), and four grade b 3 toxicities (2 rash, 1 vomiting, 1 skin desquamation). Grade 2 or 3 peripheral

  19. Radiation and misonidazole in children with brain stem gliomas and supratentorial glioblastoma

    International Nuclear Information System (INIS)

    Bloom, H.J.G.; Bugden, R.D.

    1982-01-01

    In a series of 484 children with intracranial tumors referred to the Royal Marsden Hospital for radiotherapy, there were 47 (12%) examples of inoperable pontine and medullary tumors for which the 5-year survival rate was 17%. The limited local tumor mass in brain stem tumors, the absence of cerebro-spinal or distant metastases, and their often initial good but short-lived response to irradiation, all support the trial of a chemical radiosensitizing agent with which to try and achieve greater and more prolonged local control of the disease. Since the prognosis for cerebral hemisphere glioblastoma, which is relatively uncommon in children, is also extremely poor, such cases were included in this pilot study. The problems and possible risks associated with combined radiotherapy and a chemical radiosensitizer in children with brain tumors is discussed. So far, 8 children with brain stem tumors and 3 children with cerebral hemisphere gliomas heave been treated in this study. In addtion, data is also available on 3 children re-treated for incurrent medulloblastomas. Preliminary observations regarding experience with this small series will be reported including blood misonidazole levels, drug tolerance and the possible influence of anticonvulsants and steriods on toxicity

  20. Perfusion imaging of brain gliomas using arterial spin labeling: correlation with histopathological vascular density in MRI-guided biopsies

    Energy Technology Data Exchange (ETDEWEB)

    Di, Ningning; Pang, Haopeng; Ren, Yan; Yao, Zhenwei; Feng, Xiaoyuan [Huashan Hospital Fudan University, Department of Radiology, Shanghai (China); Dang, Xuefei [Shang Hai Gamma Knife Hospital, Shanghai (China); Cheng, Wenna [Binzhou Medical University Affiliated Hospital, Department of Pharmacy, Binzhou (China); Wu, Jingsong; Yao, Chengjun [Huashan Hospital Fudan University, Department of Neurosurgery, Shanghai (China)

    2017-01-15

    This study was designed to determine if cerebral blood flow (CBF) derived from arterial spin labeling (ASL) perfusion imaging could be used to quantitatively evaluate the microvascular density (MVD) of brain gliomas on a ''point-to-point'' basis by matching CBF areas and surgical biopsy sites as accurate as possible. The study enrolled 47 patients with treatment-naive brain gliomas who underwent preoperative ASL, 3D T1-weighted imaging with gadolinium contrast enhancement (3D T1C+), and T2 fluid acquisition of inversion recovery (T2FLAIR) sequences before stereotactic surgery. We histologically quantified MVD from CD34-stained sections of stereotactic biopsies and co-registered biopsy locations with localized CBF measurements. The correlation between CBF and MVD was determined using Spearman's correlation coefficient. P ≤.05 was considered statistically significant. Of the 47 patients enrolled in the study, 6 were excluded from the analysis because of brain shift or poor co-registration and localization of the biopsy site during surgery. Finally, 84 biopsies from 41 subjects were included in the analysis. CBF showed a statistically significant positive correlation with MVD (ρ = 0.567; P =.029). ASL can be a useful noninvasive perfusion MR method for quantitative evaluation of the MVD of brain gliomas. (orig.)

  1. Molecular and metabolic pattern classification for detection of brain glioma progression

    Energy Technology Data Exchange (ETDEWEB)

    Imani, Farzin, E-mail: imanif@upmc.edu [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Boada, Fernando E. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Lieberman, Frank S. [Department of Neurology, University of Pittsburgh Medical Center, PA (United States); Davis, Denise K.; Mountz, James M. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States)

    2014-02-15

    Objectives: The ability to differentiate between brain tumor progression and radiation therapy induced necrosis is critical for appropriate patient management. In order to improve the differential diagnosis, we combined fluorine-18 2-fluoro-deoxyglucose positron emission tomography ({sup 18}F-FDG PET), proton magnetic resonance spectroscopy ({sup 1}H MRS) and histological data to develop a multi-parametric machine-learning model. Methods: We enrolled twelve post-therapy patients with grade 2 and 3 gliomas that were suspicious of tumor progression. All patients underwent {sup 18}F-FDG PET and {sup 1}H MRS. Maximal standardized uptake value (SUVmax) of the tumors and reference regions were obtained. Multiple 2D maps of choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) of the tumors were generated. A support vector machine (SVM) learning model was established to take imaging biomarkers and histological data as input vectors. A combination of clinical follow-up and multiple sequential MRI studies served as the basis for assessing the clinical outcome. All vector combinations were evaluated for diagnostic accuracy and cross validation. The optimal cutoff value of individual parameters was calculated using Receiver operating characteristic (ROC) plots. Results: The SVM and ROC analyses both demonstrated that SUVmax of the lesion was the most significant single diagnostic parameter (75% accuracy) followed by Cho concentration (67% accuracy). SVM analysis of all paired parameters showed SUVmax and Cho concentration in combination could achieve 83% accuracy. SUVmax of the lesion paired with SUVmax of the white matter as well as the tumor Cho paired with the tumor Cr both showed 83% accuracy. These were the most significant paired diagnostic parameters of either modality. Combining all four parameters did not improve the results. However, addition of two more parameters, Cho and Cr of brain parenchyma contralateral to the tumor, increased the accuracy to 92

  2. In Silico Neuro-Oncology: Brownian Motion-Based Mathematical Treatment as a Potential Platform for Modeling the Infiltration of Glioma Cells into Normal Brain Tissue

    Science.gov (United States)

    Antonopoulos, Markos; Stamatakos, Georgios

    2015-01-01

    Intensive glioma tumor infiltration into the surrounding normal brain tissues is one of the most critical causes of glioma treatment failure. To quantitatively understand and mathematically simulate this phenomenon, several diffusion-based mathematical models have appeared in the literature. The majority of them ignore the anisotropic character of diffusion of glioma cells since availability of pertinent truly exploitable tomographic imaging data is limited. Aiming at enriching the anisotropy-enhanced glioma model weaponry so as to increase the potential of exploiting available tomographic imaging data, we propose a Brownian motion-based mathematical analysis that could serve as the basis for a simulation model estimating the infiltration of glioblastoma cells into the surrounding brain tissue. The analysis is based on clinical observations and exploits diffusion tensor imaging (DTI) data. Numerical simulations and suggestions for further elaboration are provided. PMID:26309390

  3. Differentiation of malignant glioma and metastatic brain tumor by thallium-201 single photon emission computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kojima, Yasuhiro; Kuwana, Nobumasa; Noji, Masato; Tosa, Junichi [Yokohama Minami Kyosai Hospital (Japan)

    1994-09-01

    The use of superdelayed thallium-201 single photon emission computed tomography ([sup 201]Tl SPECT) for differentiating malignant gliomas from cerebral metastases was investigated in 23 patients (7 with meningioma, 6 with glioma, 7 with cerebral metastasis, 1 with each of neurinoma, abscess, and necrosis). 4 mCi of [sup 201]Tl was injected intravenously, and gamma camera scans were performed after 10 minutes and 4, 24, 72, and 96 hours (superdelayed scan). The mean thallium index of meningiomas was significantly higher than those of gliomas and cerebral metastases after 10 minutes, while the mean thallium indices of meningiomas and gliomas were significantly higher than those of cerebral metastases after 96 hours. The combination of early and superdelayed [sup 201]Tl SPECT may be useful in differentiating malignant gliomas from cerebral metastases. (author).

  4. Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Karunamuni, Roshan [Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California (United States); Bartsch, Hauke; White, Nathan S. [Department of Radiology, University of California San Diego, La Jolla, California (United States); Moiseenko, Vitali; Carmona, Ruben; Marshall, Deborah C.; Seibert, Tyler M. [Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California (United States); McDonald, Carrie R. [Department of Psychiatry, University of California San Diego, La Jolla, California (United States); Farid, Nikdokht; Krishnan, Anithapriya; Kuperman, Joshua [Department of Radiology, University of California San Diego, La Jolla, California (United States); Mell, Loren [Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California (United States); Brewer, James B.; Dale, Anders M. [Department of Radiology, University of California San Diego, La Jolla, California (United States); Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu [Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California (United States)

    2016-02-01

    Purpose: Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. Methods and Materials: We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thickness between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. Results: Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by −0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. Conclusions: We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.

  5. Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication.

    Science.gov (United States)

    Lin, Qingtang; Liu, Zhao; Ling, Feng; Xu, Geng

    2016-02-01

    Gliomas are the most common type of primary brain tumor. Using current standard treatment regimens, the prognosis of patients with gliomas remains poor, which is predominantly due to the resistance of glioma cells to chemotherapy. The organ microenvironment has been implicated in the pathogenesis and survival of tumor cells. Thus, the aim of the present study was to test the hypothesis that astrocytes (the housekeeping cells of the brain microenvironment) may protect glioma cells from chemotherapy and to investigate the underlying mechanism. Immunofluorescent and scanning electron microscopy demonstrated that glioma cells were surrounded and infiltrated by activated astrocytes. In vitro co-culture of glioma cells with astrocytes significantly reduced the cytotoxic effects on glioma cells caused by various chemotherapeutic agents, as demonstrated by fluorescein isothiocyanate-propidium iodide flow cytometry. Transwell experiments indicated that this protective effect was dependent on physical contact and the gap junctional communication (GJC) between astrocytes and glioma cells. Microarray expression profiling further revealed that astrocytes upregulated the expression levels of various critical survival genes in the glioma cells via GJC. The results of the present study indicated that the organ microenvironment may affect the biological behavior of tumor cells and suggest a novel mechanism of resistance in glioma cells, which may be of therapeutic relevance clinically.

  6. Anaesthetic management for awake craniotomy in brain glioma resection: initial experience in Military Hospital Mohamed V of Rabat.

    Science.gov (United States)

    Meziane, Mohammed; Elkoundi, Abdelghafour; Ahtil, Redouane; Guazaz, Miloudi; Mustapha, Bensghir; Haimeur, Charki

    2017-01-01

    The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awake-awake-awake method. We describe our first experience with anesthetic management for awake craniotomy, which was a combination of these techniques with scalp nerve block, and propofol/rémifentanil target controlled infusion. A 28-year-oldmale underwent an awake craniotomy for brain glioma resection. The scalp nerve block was performed and a low sedative state was maintained until removal of bone flap. During brain glioma resection, the patient awake state was maintained without any complications. Once, the tumorectomy was completed, the level of anesthesia was deepened and a laryngeal mask airway was inserted. A well psychological preparation, a reasonable choice of anesthetic techniques and agents, and continuous team communication were some of the key challenges for successful outcome in our patient.

  7. Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.

    Science.gov (United States)

    Johnson, Adrienne; Severson, Eric; Gay, Laurie; Vergilio, Jo-Anne; Elvin, Julia; Suh, James; Daniel, Sugganth; Covert, Mandy; Frampton, Garrett M; Hsu, Sigmund; Lesser, Glenn J; Stogner-Underwood, Kimberly; Mott, Ryan T; Rush, Sarah Z; Stanke, Jennifer J; Dahiya, Sonika; Sun, James; Reddy, Prasanth; Chalmers, Zachary R; Erlich, Rachel; Chudnovsky, Yakov; Fabrizio, David; Schrock, Alexa B; Ali, Siraj; Miller, Vincent; Stephens, Philip J; Ross, Jeffrey; Crawford, John R; Ramkissoon, Shakti H

    2017-12-01

    Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF , QKI-RAF1 , FGFR3-TACC3 , CEP85L-ROS1 , and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK , DGKB-ETV1 , ATG7-RAF1 , and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE , and POLD1 genes (78% of cases). Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for

  8. A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas.

    Science.gov (United States)

    Li, Yan; He, Hai; Jia, Xinru; Lu, Wan-Liang; Lou, Jinning; Wei, Yen

    2012-05-01

    A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Sestamibi technetium-99m brain single-photon emission computed tomography to identify recurrent glioma in adults: 201 studies.

    Science.gov (United States)

    Le Jeune, Florence Prigent; Dubois, François; Blond, Serge; Steinling, Marc

    2006-04-01

    In the follow-up of treated gliomas, CT and MRI can often not differentiate radionecrosis from recurrent tumor. The aim of this study was to assess the interest of functional imaging with (99m)Tc-MIBI SPECT in a large series of 201 examinations. MIBI SPECT were performed in 81 patients treated for brain gliomas. A MIBI uptake index was computed as the ratio of counts in the lesion to counts in the controlateral region. SPECT was compared to stereotactic biopsy in 14 cases, or in the others cases to imaging evolution or clinical course at 6 months after the last tomoscintigraphy Two hundred and one tomoscintigraphies were performed. One hundred and two scans were true positive, 82 scans were true negative. Six scans were false positive (corresponding to 3 patients): 2 patients with an inflammatory reaction after radiosurgery, 1 with no explanation up to now. Eleven scans were false negative (5 patients): 1 patient with a deep peri-ventricular lesion, 2 patients with no contrast enhancement on MRI, 2 patients with a temporal tumor. The sensitivity for tumor recurrence was 90%, specificity 91.5% and accuracy 90.5%. We studied separately low and high grade glioma: sensitivity for tumor recurrence was respectively 91% and 89%, specificity 100% and 83% and accuracy 95% and 87%. MIBI SPECT allowed the diagnose of anaplasic degenerence of low grade sometimes earlier than clinical (5 cases) or MRI signs (7 cases). Our results confirm the usefullness of MIBI SPECT in the follow-up of treated gliomas for the differential diagnosis between radiation necrosis and tumor recurrence.

  10. Boron neutron capture therapy (BNCT) for high-grade gliomas of the brain: a cautionary note

    International Nuclear Information System (INIS)

    Laramore, George E.; Spence, Alexander M.

    1996-01-01

    Purpose/Objective: Boron neutron capture therapy (BNCT) is a method of treating high-grade gliomas of the brain that involves incorporating 10 B into the tumor using appropriate pharmacological agents and then irradiating the tumor with thermal or epithermal neutron beams. To date, over 120 patients have been treated in this manner by Japanese investigators using a thermal neutron beam from a nuclear reactor. Favorable reports on outcome have motivated considerable current research in BNCT. The purpose of this study is to provide an independent analysis of the Japanese data by identifying the subset of patients from the United States who received this treatment in Japan and comparing their outcomes relative to a matched cohort who received conventional therapy in various Radiation Therapy Oncology Group (RTOG) studies. Methods and Materials: The principal referral sources of patients to Japan for BNCT were identified and the names of patients sent for treatment obtained. The treating physicians in Japan were also contacted to see if additional patients from the United States had been treated. Either the patients or their next of kin were contacted, and permission was obtained to retrieve medical records including tumor pathology for central review. Prognostic variables according to an analysis of the RTOG brain tumor database by Curran et al. were determined from these records and used to construct a matched cohort of patients treated conventionally. Results: A total of 14 patients were identified who had traveled to Japan for BNCT treatment between July, 1987 and June, 1994. In the case of one patient (deceased), it was not possible to contact the next of kin. Material was obtained on the other 13 patients and review of the pathology indicated that 1 patient had a central nervous system lymphoma rather than a high-grade glioma. Survival data was analyzed for the other 12 patients on an actuarial basis, and this showed no difference compared to survival data for a

  11. Sublethal dose of irradiation enhances invasion of malignant glioma cells through p53-MMP 2 pathway in U87MG mouse brain tumor model

    International Nuclear Information System (INIS)

    Pei, Jian; Park, In-Ho; Ryu, Hyang-Hwa; Li, Song-Yuan; Li, Chun-Hao; Lim, Sa-Hoe; Wen, Min; Jang, Woo-Youl; Jung, Shin

    2015-01-01

    Glioblastoma is a highly lethal neoplasm that frequently recurs locally after radiotherapy, and most of these recurrences originate from near the irradiated target field. In the present study, we identified the effects of radiation on glioma invasion and p53, TIMP-2, and MMP-2 expression through in vitro and in vivo experiments. The U87MG (wt p53) and U251 (mt p53) human malignant glioma cell lines were prepared, and the U2OS (wt 53) and Saos2 (del p53) osteosarcoma cell lines were used as p53 positive and negative controls. The four cell lines and p53 knock-downed U87MG cells received radiation (2–6 Gy) and were analyzed for expression of p53 and TIMP-2 by Western blot, and MMP-2 activity was detected by zymography. In addition, the effects of irradiation on directional invasion of malignant glioma were evaluated by implanting nude mice with bioluminescent u87-Fluc in vivo followed by MMP-2, p53, and TIMP-2 immunohisto-chemistry and in situ zymography. MMP-2 activity and p53 expression increased in proportional to the radiation dose in cell lines with wt p53, but not in the cell lines with del or mt p53. TIMP-2 expression did not increase in U87MG cells. MMP-2 activity decreased in p53 knock-downed U87MG cells but increased in the control group. Furthermore, radiation enhanced MMP-2 activity and increased tumor margin invasiveness in vivo. Tumor cells invaded by radiation overexpressed MMP-2 and p53 and revealed high gelatinolytic activity compared with those of non-radiated tumor cells. Radiation-induced upregulation of p53 modulated MMP-2 activity, and the imbalance between MMP-2 and TIMP-2 may have an important role in glioblastoma invasion by degrading the extracellular matrix. Bioluminescent “U87-Fluc”was useful for observing tumor formation without sacrifice after implanting tumor cells in the mouse brain. These findings suggest that the radiotherapy involved field for malignant glioma needs to be reconsidered, and that future trials should investigate

  12. 11C-CHO PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas

    International Nuclear Information System (INIS)

    Li Fangming; Nie Qing; Wang Ruimin; Chang, Susan M.; Zhao Wenrui; Zhu Qi; Liang Yingkui; Yang Ping; Zhang Jun; Jia Haiwei; Fang Henghu

    2012-01-01

    Objective: We explored the clinical values of 11 C-choline ( 11 C-CHO) PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas. Methods: Sixteen patients with the pathological confirmation of the diagnosis of gliomas prior to receiving radiotherapy (postoperative) were included, and on whom both MRI and CHO PET scans were performed at the same position for comparison of residual tumors with the two techniques. 11 C-CHO was used as the tracer in the PET scan. A plain T1-weighted, T2-weighted and contrast-enhanced T1-weighted imaging scans were performed in the MRI scan sequence. The gliomas' residual tumor volume was defined as the area with CHO-PET high-affinity uptake and metabolism (V CHO ) and one with MRI T1-weighted imaging high signal intensity (V Gd ), and was determined by a group of experienced professionals and clinicians. Results: (1) In CHO-PET images, the tumor target volume, i.e., the highly metabolic area with a high concentration of isotopes (SUV 1.016–4.21) and the corresponding contralateral normal brain tissues (SUV0.1–0.62), was well contrasted, and the boundary between lesions and surrounding normal brain tissues was better defined compared with MRI and 18 F-FDG PET images. (2) For patients with brain gliomas of WHO Grade II, the SUV was 1.016–2.5; for those with WHO Grades III and IV, SUVs were >26–4.2. (3) Both CHO PET and MRI were positive for 10 patients and negative for 2 patients. The residual tumor consistency between these two studies was 75%. Four of the 10 CHO-PET-positive patients were negative on MRI scans. The maximum distance between V Gd and V CHO margins was 1.8 cm. (4) The gross tumor volumes (GTVs) and the ensuing treatment regimens were changed for 31.3% (5/16) of patients based on the CHO-PET high-affinity uptake and metabolism, in which the change rate was 80% (4/5), 14.3 % (1/7) and 0% (0/4) for patients with WHO Grade II III, and IV gliomas

  13. 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

    Science.gov (United States)

    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

  14. The value of diffusion tensor imaging in differentiating high-grade gliomas from brain metastases: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Rui Jiang

    Full Text Available Differentiation of high-grade gliomas and solitary brain metastases is an important clinical issue because the treatment strategies differ greatly. Our study aimed to investigate the potential value of diffusion tensor imaging (DTI in differentiating high-grade gliomas from brain metastases using a meta-analytic approach.We searched Pubmed, Embase and the Cochrane Library for relevant articles published in English. Studies that both investigated high-grade gliomas and brain metastases using DTI were included. Random effect model was used to compare fractional anisotropy (FA and mean diffusivity (MD values in the two tumor entities.Nine studies were included into the meta-analysis. In the peritumoral region, compared with brain metastases, high-grade gliomas had a significant increase of FA (SMD  = 0.47; 95% CI, 0.22-0.71; P<0.01 and a significant decrease of MD (SMD  = -1.49; 95% CI, -1.91 to -1.06; P<0.01. However, in the intratumoral area, no significant change in FA (SMD  = 0.16; 95% CI, -0.49 to 0.82; P = 0.73 or MD (SMD  = 0.34; 95% CI, -0.91 to 1.60; P = 0.59 was detected between gliomas and metastases.High-grade gliomas may be distinguished from brain metastases by comparing the peritumoral FA and MD values. DTI appears to be a promising tool in diagnosing solitary intracranial lesions.

  15. Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines

    Directory of Open Access Journals (Sweden)

    Holz David

    2008-01-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is the most common primary intracranial tumor and despite recent advances in treatment regimens, prognosis for affected patients remains poor. Active cell migration and invasion of GBM cells ultimately lead to ubiquitous tumor recurrence and patient death. To further understand the genetic mechanisms underlying the ability of glioma cells to migrate, we compared the matched transcriptional profiles of migratory and stationary populations of human glioma cells. Using a monolayer radial migration assay, motile and stationary cell populations from seven human long term glioma cell lines and three primary GBM cultures were isolated and prepared for expression analysis. Results Gene expression signatures of stationary and migratory populations across all cell lines were identified using a pattern recognition approach that integrates a priori knowledge with expression data. Principal component analysis (PCA revealed two discriminating patterns between migrating and stationary glioma cells: i global down-regulation and ii global up-regulation profiles that were used in a proband-based rule function implemented in GABRIEL to find subsets of genes having similar expression patterns. Genes with up-regulation pattern in migrating glioma cells were found to be overexpressed in 75% of human GBM biopsy specimens compared to normal brain. A 22 gene signature capable of classifying glioma cultures based on their migration rate was developed. Fidelity of this discovery algorithm was assessed by validation of the invasion candidate gene, connective tissue growth factor (CTGF. siRNA mediated knockdown yielded reduced in vitro migration and ex vivo invasion; immunohistochemistry on glioma invasion tissue microarray confirmed up-regulation of CTGF in invasive glioma cells. Conclusion Gene expression profiling of migratory glioma cells induced to disperse in vitro affords discovery of genomic signatures; selected

  16. Molecular fingerprinting reflects different histotypes and brain region in low grade gliomas

    International Nuclear Information System (INIS)

    Mascelli, Samantha; Fasulo, Daniel; Noy, Karin; Wittemberg, Gayle; Pignatelli, Sara; Piatelli, Gianluca; Cama, Armando; Garré, Maria Luisa; Capra, Valeria; Verri, Alessandro; Barla, Annalisa; Raso, Alessandro; Mosci, Sofia; Nozza, Paolo; Biassoni, Roberto; Morana, Giovanni; Huber, Martin; Mircean, Cristian

    2013-01-01

    Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency. Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l 1 l 2 that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR. We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs

  17. A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas?

    International Nuclear Information System (INIS)

    Freeman, Carolyn R.; Kepner, Jim; Kun, Larry E.; Sanford, Robert A.; Kadota, Richard; Mandell, Lynda; Friedman, Henry

    2000-01-01

    Purpose: To compare the proportion of patients that survive at least 1 year following treatment with hyperfractionated radiotherapy (HRT) to a dose of 70.2 Gy on Pediatric Oncology Group (POG) study no. 8495 with that of patients treated with similar radiotherapy plus cisplatinum given by continuous infusion on weeks 1, 3, and 5 of radiotherapy on POG no. 9239. Methods and Materials: The eligibility criteria for the two studies were identical and included age 3 to 21 years, previously untreated tumor involving the brain stem of which two-thirds was in the pons, history less than 6 months, and clinical findings typical for diffuse intrinsic brain stem glioma, including cranial nerve deficits, long tract signs, and ataxia. The outcome of 57 patients who were treated at the 70.2 Gy dose level of POG no. 8495 between May 1986 and February 1988 was compared with that of 64 patients treated with identical radiotherapy plus cisplatinum on POG no. 9239 between June 1992 and March 1996. Results: The number of patients accrued to POG no. 9239 was determined to guarantee that the probability was at least 0.80 of correctly detecting that the 1-year survival rate exceeded that of patients on POG no. 8495 by 0.2. However, the z value for this test was -1.564, giving a p value of 0.9411. That is, there is almost sufficient evidence to conclude that survival for patients receiving HRT plus cisplatinum on POG no. 9239 was worse than that for patients receiving the same radiotherapy alone on POG no. 8495. Conclusion: The finding that patients who received cisplatinum given as a radiosensitizing agent concurrent with HRT fared less well than those receiving the same dose of HRT alone was unexpected and is clearly a cause for concern as many current protocols for patients with diffuse intrinsic brain stem gliomas call for use of chemotherapeutic and/or biological agents given concurrent with radiotherapy

  18. T1-T2 dual-modal MRI of brain gliomas using PEGylated Gd-doped iron oxide nanoparticles.

    Science.gov (United States)

    Xiao, Ning; Gu, Wei; Wang, Hao; Deng, Yunlong; Shi, Xin; Ye, Ling

    2014-03-01

    To overcome the negative contrast limitations of iron oxide-based contrast agents and to improve the biocompatibility of Gd-chelate contrast agents, PEGylated Gd-doped iron oxide (PEG-GdIO) NPs as a T1-T2 dual-modal contrast agent were synthesized by the polyol method. The transverse relaxivity (r2) and longitudinal relaxivity (r1) of PEG-GdIO were determined to be 66.9 and 65.9 mM(-1) s(-1), respectively. The high r1 value and low r2/r1 ratio make PEG-GdIO NPs suitable as a T1-T2 dual-modal contrast agent. The in vivo MRI demonstrated a brighter contrast enhancement in T1-weighted image and a simultaneous darken effect in T2-weighted MR image compared to the pre-contrast image in the region of glioma. Furthermore, the biocompatibility of PEG-GdIO NPs was confirmed by the in vitro MTT cytotoxicity and in vivo histological analyses (H&E). Therefore, PEG-GdIO NPs hold great potential in T1-T2 dual-modal imaging for the diagnosis of brain glioma. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Dynamic Contrast-Enhanced Perfusion MRI of High Grade Brain Gliomas Obtained with Arterial or Venous Waveform Input Function.

    Science.gov (United States)

    Filice, Silvano; Crisi, Girolamo

    2016-01-01

    The aim of this study was to evaluate the differences in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) perfusion estimates of high-grade brain gliomas (HGG) due to the use of an input function (IF) obtained respectively from arterial (AIF) and venous (VIF) approaches by two different commercially available software applications. This prospective study includes 20 patients with pathologically confirmed diagnosis of high-grade gliomas. The data source was processed by using two DCE dedicated commercial packages, both based on the extended Toft model, but the first customized to obtain input function from arterial measurement and the second from sagittal sinus sampling. The quantitative parametric perfusion maps estimated from the two software packages were compared by means of a region of interest (ROI) analysis. The resulting input functions from venous and arterial data were also compared. No significant difference has been found between the perfusion parameters obtained with the two different software packages (P-value < .05). The comparison of the VIFs and AIFs obtained by the two packages showed no statistical differences. Direct comparison of DCE-MRI measurements with IF generated by means of arterial or venous waveform led to no statistical difference in quantitative metrics for evaluating HGG. However, additional research involving DCE-MRI acquisition protocols and post-processing would be beneficial to further substantiate the effectiveness of venous approach as the IF method compared with arterial-based IF measurement. Copyright © 2015 by the American Society of Neuroimaging.

  20. Revisit the Candidacy of Brain Cell Types as the Cell(s of Origin for Human High-Grade Glioma

    Directory of Open Access Journals (Sweden)

    Fangjie Shao

    2018-02-01

    Full Text Available High-grade glioma, particularly, glioblastoma, is the most aggressive cancer of the central nervous system (CNS in adults. Due to its heterogeneous nature, glioblastoma almost inevitably relapses after surgical resection and radio-/chemotherapy, and is thus highly lethal and associated with a dismal prognosis. Identifying the cell of origin has been considered an important aspect in understanding tumor heterogeneity, thereby holding great promise in designing novel therapeutic strategies for glioblastoma. Taking advantage of genetic lineage-tracing techniques, performed mainly on genetically engineered mouse models (GEMMs, multiple cell types in the CNS have been suggested as potential cells of origin for glioblastoma, among which adult neural stem cells (NSCs and oligodendrocyte precursor cells (OPCs are the major candidates. However, it remains highly debated whether these cell types are equally capable of transforming in patients, given that in the human brain, some cell types divide so slowly, therefore may never have a chance to transform. With the recent advances in studying adult NSCs and OPCs, particularly from the perspective of comparative biology, we now realize that notable differences exist among mammalian species. These differences have critical impacts on shaping our understanding of the cell of origin of glioma in humans. In this perspective, we update the current progress in this field and clarify some misconceptions with inputs from important findings about the biology of adult NSCs and OPCs. We propose to re-evaluate the cellular origin candidacy of these cells, with an emphasis on comparative studies between animal models and humans.

  1. Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood-brain barrier and targeted fluorescence imaging of glioma and tumor vasculature.

    Science.gov (United States)

    Huang, Ning; Cheng, Si; Zhang, Xiang; Tian, Qi; Pi, Jiangli; Tang, Jun; Huang, Qing; Wang, Feng; Chen, Jin; Xie, Zongyi; Xu, Zhongye; Chen, Weifu; Zheng, Huzhi; Cheng, Yuan

    2017-01-01

    Delivery of imaging agents to brain glioma is challenging because the blood-brain barrier (BBB) functions as a physiological checkpoint guarding the central nervous system from circulating large molecules. Moreover, the ability of existing probes to target glioma has been insufficient and needs to be improved. In present study, PEG-based long circulation, CdSe/ZnS quantum dots (QDs)-based nanoscale and fluorescence, asparagines-glycine-arginine peptides (NGR)-based specific CD13 recognition were integrated to design and synthesize a novel nanoprobe by conjugating biotinylated NGR peptides to avidin-PEG-coated QDs. Our data showed that the NGR-PEG-QDs were nanoscale with less than 100 nm and were stable in various pH (4.0~8.0). These nanomaterials with non-toxic concentrations could cross the BBB and target CD13-overexpressing glioma and tumor vasculature in vitro and in vivo, contributing to fluorescence imaging of this brain malignancy. These achievements allowed groundbreaking technological advances in targeted fluorescence imaging for the diagnosis and surgical removal of glioma, facilitating potential transformation toward clinical nanomedicine. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Evaluation of D-isomers of 4-borono-2-18F-fluoro-phenylalanine and O-11C-methyl-tyrosine as brain tumor imaging agents: a comparative PET study with their L-isomers in rat brain glioma.

    Science.gov (United States)

    Kanazawa, Masakatsu; Nishiyama, Shingo; Hashimoto, Fumio; Kakiuchi, Takeharu; Tsukada, Hideo

    2018-06-13

    The potential of the D-isomerization of 4-borono-2- 18 F-fluoro-phenylalanine ( 18 F-FBPA) to improve its target tumor to non-target normal brain tissue ratio (TBR) was evaluated in rat brain glioma and compared with those of L- and D- 11 C-methyl-tyrosine ( 11 C-CMT). The L- or D-isomer of 18 F-FBPA was injected into rats through the tail vein, and their whole body kinetics and distributions were assessed using the tissue dissection method up to 90 min after the injection. The kinetics of L- and D- 18 F-FBPA or L- and D- 11 C-CMT in the C-6 glioma-inoculated rat brain were measured for 90 or 60 min, respectively, using high-resolution animal PET, and their TBRs were assessed. Tissue dissection analyses showed that D- 18 F-FBPA uptake was significantly lower than that of L- 18 F-FBPA in the brain and abdominal organs, except for the kidney and bladder, reflecting the faster elimination rate of D- 18 F-FBPA than L- 18 F-FBPA from the blood to the urinary tract. PET imaging using 18 F-FBPA revealed that although the brain uptake of D- 18 F-FBPA was significantly lower than that of L- 18 F-FBPA, the TBR of the D-isomer improved to 6.93 from 1.45 for the L-isomer. Similar results were obtained with PET imaging using 11 C-CMT with a smaller improvement in TBR to 1.75 for D- 11 C-CMT from 1.33 for L- 11 C-CMT. The present results indicate that D- 18 F-FBPA is a better brain tumor imaging agent with higher TBR than its original L-isomer and previously reported tyrosine-based PET imaging agents. This improved TBR of D- 18 F-FBPA without any pre-treatments, such as tentative blood-brain barrier disruption using hyperosmotic agents or sonication, suggests that the D-isomerization of BPA results in the more selective accumulation of 10 B in tumor cells that is more effective and less toxic than conventional L-BPA.

  3. FasL and FADD delivery by a glioma-specific and cell cycle-dependent HSV-1 amplicon virus enhanced apoptosis in primary human brain tumors

    Directory of Open Access Journals (Sweden)

    Lam Paula Y

    2010-10-01

    Full Text Available Abstract Background Glioblastoma multiforme is the most malignant cancer of the brain and is notoriously difficult to treat due to the highly proliferative and infiltrative nature of the cells. Herein, we explored the combination treatment of pre-established human glioma xenograft using multiple therapeutic genes whereby the gene expression is regulated by both cell-type and cell cycle-dependent transcriptional regulatory mechanism conferred by recombinant HSV-1 amplicon vectors. Results We demonstrated for the first time that Ki67-positive proliferating primary human glioma cells cultured from biopsy samples were effectively induced into cell death by the dual-specific function of the pG8-FasL amplicon vectors. These vectors were relatively stable and exhibited minimal cytotoxicity in vivo. Intracranial implantation of pre-transduced glioma cells resulted in better survival outcome when compared with viral vectors inoculated one week post-implantation of tumor cells, indicating that therapeutic efficacy is dependent on the viral spread and mode of viral vectors administration. We further showed that pG8-FasL amplicon vectors are functional in the presence of commonly used treatment regimens for human brain cancer. In fact, the combined therapies of pG8-FasL and pG8-FADD in the presence of temozolomide significantly improved the survival of mice bearing intracranial high-grade gliomas. Conclusion Taken together, our results showed that the glioma-specific and cell cycle-dependent HSV-1 amplicon vector is potentially useful as an adjuvant therapy to complement the current gene therapy strategy for gliomas.

  4. Overexpression of NIMA-related kinase 2 is associated with poor prognoses in malignant glioma.

    Science.gov (United States)

    Liu, Huajie; Liu, Bin; Hou, Xianzeng; Pang, Bo; Guo, Pengbo; Jiang, Wanli; Ding, Qian; Zhang, Rui; Xin, Tao; Guo, Hua; Xu, Shangchen; Pang, Qi

    2017-05-01

    Eleated expression of NIMA-related kinase 2 (NEK2) was frequently observed in a variety of malignant cancers, and it appears to be involved in the initiation, maintenance, progression, metastasis of cancer and is positively associated with poor prognosis. We sought to investigate NEK2 expression and its predictive roles in malignant gliomas, and study the correlation of NEK2 protein expression with proliferation, clinical parameters, overall survival and some other parameters. We investigate NEK2 protein expression in 99 samples of malignant gliomas, including 35 WHO grade II, 22 grade III, and 42 grade IV gliomas, by immunohistochemistry and western blot (n = 50). We then made correlative analysis of protein overexpression using the Kaplan-Meier method, Log rank test, and Cox proportional-hazards model analysis. NEK2 protein was overexpressed in malignant gliomas, but not in normal brain tissues. Overexpression of NEK2 correlated with malignancy, proliferation and adverse overall survival in gliomas. Moreover, chemotherapy, resection extent and WHO grade also correlate with overall survival in gliomas. However, within WHO grade II glioma subgroup, NEK2 overexpression showed no impact on overall survival. The present study firstly reveals that NEK2 protein is widely overexpressed in gliomas. NEK2 overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki-67) and prognosis in malignant gliomas. NEK2 is a potential gene therapy target and prognostic indicator.

  5. Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas.

    Science.gov (United States)

    Chen, Ning; Shao, Chen; Li, Shuai; Wang, Zihao; Qu, Yanming; Gu, Wei; Yu, Chunjiang; Ye, Ling

    2015-11-01

    The fusion of molecular and anatomical modalities facilitates more reliable and accurate detection of tumors. Herein, we prepared the PEG-Cy5.5 conjugated MnO nanoparticles (MnO-PEG-Cy5.5 NPs) with magnetic resonance (MR) and near-infrared fluorescence (NIRF) imaging modalities. The applicability of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe for the detection of brain gliomas was investigated. In vivo MR contrast enhancement of the MnO-PEG-Cy5.5 nanoprobe in the tumor region was demonstrated. Meanwhile, whole-body NIRF imaging of glioma bearing nude mouse exhibited distinct tumor localization upon injection of MnO-PEG-Cy5.5 NPs. Moreover, ex vivo CLSM imaging of the brain slice hosting glioma indicated the preferential accumulation of MnO-PEG-Cy5.5 NPs in the glioma region. Our results therefore demonstrated the potential of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe in improving the diagnostic efficacy by simultaneously providing anatomical information from deep inside the body and more sensitive information at the cellular level. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Motor network plasticity and low-frequency oscillations abnormalities in patients with brain gliomas: a functional MRI study.

    Directory of Open Access Journals (Sweden)

    Chen Niu

    Full Text Available Brain plasticity is often associated with the process of slow-growing tumor formation, which remodels neural organization and optimizes brain network function. In this study, we aimed to investigate whether motor function plasticity would display deficits in patients with slow-growing brain tumors located in or near motor areas, but who were without motor neurological deficits. We used resting-state functional magnetic resonance imaging to probe motor networks in 15 patients with histopathologically confirmed brain gliomas and 15 age-matched healthy controls. All subjects performed a motor task to help identify individual motor activity in the bilateral primary motor cortex (PMC and supplementary motor area (SMA. Frequency-based analysis at three different frequencies was then used to investigate possible alterations in the power spectral density (PSD of low-frequency oscillations. For each group, the average PSD was determined for each brain region and a nonparametric test was performed to determine the difference in power between the two groups. Significantly reduced inter-hemispheric functional connectivity between the left and right PMC was observed in patients compared with controls (P<0.05. We also found significantly decreased PSD in patients compared to that in controls, in all three frequency bands (low: 0.01-0.02 Hz; middle: 0.02-0.06 Hz; and high: 0.06-0.1 Hz, at three key motor regions. These findings suggest that in asymptomatic patients with brain tumors located in eloquent regions, inter-hemispheric connection may be more vulnerable. A comparison of the two approaches indicated that power spectral analysis is more sensitive than functional connectivity analysis for identifying the neurological abnormalities underlying motor function plasticity induced by slow-growing tumors.

  7. Standardized orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics and tumor cell heterogeneity

    Directory of Open Access Journals (Sweden)

    Alessandra M. Welker

    2016-02-01

    Full Text Available Glioblastoma (GBM is a deadly brain cancer, for which few effective drug treatments are available. Several studies have used zebrafish models to study GBM, but a standardized approach to modeling GBM in zebrafish was lacking to date, preventing comparison of data across studies. Here, we describe a new, standardized orthotopic xenotransplant model of GBM in zebrafish. Dose-response survival assays were used to define the optimal number of cells for tumor formation. Techniques to measure tumor burden and cell spread within the brain over real time were optimized using mouse neural stem cells as control transplants. Applying this standardized approach, we transplanted two patient-derived GBM cell lines, serum-grown adherent cells and neurospheres, into the midbrain region of embryonic zebrafish and analyzed transplanted larvae over time. Progressive brain tumor growth and premature larval death were observed using both cell lines; however, fewer transplanted neurosphere cells were needed for tumor growth and lethality. Tumors were heterogeneous, containing both cells expressing stem cell markers and cells expressing markers of differentiation. A small proportion of transplanted neurosphere cells expressed glial fibrillary acidic protein (GFAP or vimentin, markers of more differentiated cells, but this number increased significantly during tumor growth, indicating that these cells undergo differentiation in vivo. By contrast, most serum-grown adherent cells expressed GFAP and vimentin at the earliest times examined post-transplant. Both cell types produced brain tumors that contained Sox2+ cells, indicative of tumor stem cells. Transplanted larvae were treated with currently used GBM therapeutics, temozolomide or bortezomib, and this resulted in a reduction in tumor volume in vivo and an increase in survival. The standardized model reported here facilitates robust and reproducible analysis of glioblastoma tumor cells in real time and provides a

  8. Comparative Genomic Hybridization of Human Malignant Gliomas Reveals Multiple Amplification Sites and Nonrandom Chromosomal Gains and Losses

    Science.gov (United States)

    Schròck, Evelin; Thiel, Gundula; Lozanova, Tanka; du Manoir, Stanislas; Meffert, Marie-Christine; Jauch, Anna; Speicher, Michael R.; Nürnberg, Peter; Vogel, Siegfried; Janisch, Werner; Donis-Keller, Helen; Ried, Thomas; Witkowski, Regine; Cremer, Thomas

    1994-01-01

    Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue ImagesFigure 1Figure 4Figure 6 PMID:8203461

  9. Molecular markers in glioma.

    Science.gov (United States)

    Ludwig, Kirsten; Kornblum, Harley I

    2017-09-01

    Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular heterogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they may have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC's (CD133, CD15, A2B5, nestin, ALDH1, proteasome activity, ABC transporters, and label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas.

  10. Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

    Directory of Open Access Journals (Sweden)

    Garcia Juan L

    2010-08-01

    Full Text Available Abstract Background Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow in vitro forming neurospheres and that can be isolated in vivo using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM. Methods Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA; Results Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders. Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups

  11. The value of intraoperative ultrasonography during the resection of relapsed irradiated malignant gliomas in the brain

    International Nuclear Information System (INIS)

    Mursch, Kay; Mursch, Julianne Behnke; Scholz, Martin; Brueck, Wolfgang

    2017-01-01

    The aim of this study was to investigate whether intraoperative ultrasonography (IOUS) helped the surgeon navigate towards the tumor as seen in preoperative magnetic resonance imaging and whether IOUS was able to distinguish between tumor margins and the surrounding tissue. Twenty-five patients suffering from high-grade gliomas who were previously treated by surgery and radiotherapy were included. Intraoperatively, two histopathologic samples were obtained a sample of unequivocal tumor tissue (according to anatomical landmarks and the surgeon's visual and tactile impressions) and a small tissue sample obtained using a navigated needle when the surgeon decided to stop the resection. This specimen was considered to be a boundary specimen, where no tumor tissue was apparent. The decision to take the second sample was not influenced by IOUS. The effect of IOUS was analyzed semi-quantitatively. All 25 samples of unequivocal tumor tissue were histopathologically classified as tumor tissue and were hyperechoic on IOUS. Of the boundary specimens, eight were hypoechoic. Only one harbored tumor tissue (P=0.150). Seventeen boundaries were moderately hyperechoic, and these samples contained all possible histological results (i.e., tumor, infiltration, or no tumor). During surgery performed on relapsed, irradiated, high-grade gliomas, IOUS provided a reliable method of navigating towards the core of the tumor. At borders, it did not reliably distinguish between remnants or tumor-free tissue, but hypoechoic areas seldom contained tumor tissue

  12. The value of intraoperative ultrasonography during the resection of relapsed irradiated malignant gliomas in the brain

    Energy Technology Data Exchange (ETDEWEB)

    Mursch, Kay; Mursch, Julianne Behnke [Dept. of Neurosurgery, Zentralklinik, Bad Berka (Germany); Scholz, Martin [Dept. of Neurosurgery, Klinikum Duisburg, Duisburg (Germany); Brueck, Wolfgang [Dept. of Neuropathology, Georg August Universitaet, Goettingen (Germany)

    2017-01-15

    The aim of this study was to investigate whether intraoperative ultrasonography (IOUS) helped the surgeon navigate towards the tumor as seen in preoperative magnetic resonance imaging and whether IOUS was able to distinguish between tumor margins and the surrounding tissue. Twenty-five patients suffering from high-grade gliomas who were previously treated by surgery and radiotherapy were included. Intraoperatively, two histopathologic samples were obtained a sample of unequivocal tumor tissue (according to anatomical landmarks and the surgeon's visual and tactile impressions) and a small tissue sample obtained using a navigated needle when the surgeon decided to stop the resection. This specimen was considered to be a boundary specimen, where no tumor tissue was apparent. The decision to take the second sample was not influenced by IOUS. The effect of IOUS was analyzed semi-quantitatively. All 25 samples of unequivocal tumor tissue were histopathologically classified as tumor tissue and were hyperechoic on IOUS. Of the boundary specimens, eight were hypoechoic. Only one harbored tumor tissue (P=0.150). Seventeen boundaries were moderately hyperechoic, and these samples contained all possible histological results (i.e., tumor, infiltration, or no tumor). During surgery performed on relapsed, irradiated, high-grade gliomas, IOUS provided a reliable method of navigating towards the core of the tumor. At borders, it did not reliably distinguish between remnants or tumor-free tissue, but hypoechoic areas seldom contained tumor tissue.

  13. The value of intraoperative ultrasonography during the resection of relapsed irradiated malignant gliomas in the brain

    Directory of Open Access Journals (Sweden)

    Kay Mursch

    2017-01-01

    Full Text Available Purpose The aim of this study was to investigate whether intraoperative ultrasonography (IOUS helped the surgeon navigate towards the tumor as seen in preoperative magnetic resonance imaging and whether IOUS was able to distinguish between tumor margins and the surrounding tissue. Methods Twenty-five patients suffering from high-grade gliomas who were previously treated by surgery and radiotherapy were included. Intraoperatively, two histopathologic samples were obtained a sample of unequivocal tumor tissue (according to anatomical landmarks and the surgeon’s visual and tactile impressions and a small tissue sample obtained using a navigated needle when the surgeon decided to stop the resection. This specimen was considered to be a boundary specimen, where no tumor tissue was apparent. The decision to take the second sample was not influenced by IOUS. The effect of IOUS was analyzed semi-quantitatively. Results All 25 samples of unequivocal tumor tissue were histopathologically classified as tumor tissue and were hyperechoic on IOUS. Of the boundary specimens, eight were hypoechoic. Only one harbored tumor tissue (P=0.150. Seventeen boundaries were moderately hyperechoic, and these samples contained all possible histological results (i.e., tumor, infiltration, or no tumor. Conclusion During surgery performed on relapsed, irradiated, high-grade gliomas, IOUS provided a reliable method of navigating towards the core of the tumor. At borders, it did not reliably distinguish between remnants or tumor-free tissue, but hypoechoic areas seldom contained tumor tissue.

  14. Antibody guided irradiation of brain glioma by arterial infusion of radioactive monoclonal antibody against epidermal growth factor receptor and blood group A antigen

    Energy Technology Data Exchange (ETDEWEB)

    Epenetos, A.A.; Courtenay-Luck, N.; Pickering, D.; Hooker, G.; Lavender, J.P.; McKenzie, C.G. (Hammersmith Hospital, London (UK)); Durbin, H. (Imperial Cancer Research Fund, London (UK). Labs.)

    1985-05-18

    In a patient with recurrent grade IV glioma of the brain resistant to conventional treatment an antibody guided isotopic scan showed uptake by the tumour of a monoclonal antibody (9A) that was developed against epidermal growth factor receptor but cross reacted with blood group A antigen. As a therapeutic attempt antibody labelled with 1665 MBq (45.0 mCi) iodine-131 was delivered to the tumour area by infusion into the internal carotid artery. Computed tomography showed regression of the tumour after treatment, and an appreciable and sustained clinical improvement was noted without any toxicity. Delivery of irradiation guided by monoclonal antibody delivered by arterial infusion of the tumour area may be of clinical value in the treatment of brain gliomas resistant to conventional forms of treatment.

  15. Glutamate/glutamine metabolism coupling between astrocytes and glioma cells: neuroprotection and inhibition of glioma growth.

    Science.gov (United States)

    Yao, Pei-Sen; Kang, De-Zhi; Lin, Ru-Ying; Ye, Bing; Wang, Wei; Ye, Zu-Cheng

    2014-07-18

    Glioma glutamate release has been shown to promote the growth of glioma cells and induce neuronal injuries from epilepsy to neuronal death. However, potential counteractions from normal astrocytes against glioma glutamate release have not been fully evaluated. In this study, we investigated the glutamate/glutamine cycling between glioma cells and astrocytes and their impact on neuronal function. Co-cultures of glioma cells with astrocytes (CGA) in direct contact were established under different mix ratio of astrocyte/glioma. Culture medium conditioned in these CGAs were sampled for HPLC measurement, for neuronal ratiometric calcium imaging, and for neuronal survival assay. We found: (1) High levels of glutaminase expression in glioma cells, but not in astrocytes, glutaminase enables glioma cells to release large amount of glutamate in the presence of glutamine. (2) Glutamate levels in CGAs were directly determined by the astrocyte/glioma ratios, indicating a balance between glioma glutamate release and astrocyte glutamate uptake. (3) Culture media from CGAs of higher glioma/astrocyte ratios induced stronger neuronal Ca(2+) response and more severe neuronal death. (4) Co-culturing with astrocytes significantly reduced the growth rate of glioma cells. These results indicate that normal astrocytes in the brain play pivotal roles in glioma growth inhibition and in reducing neuronal injuries from glioma glutamate release. However, as tumor growth, the protective role of astrocytes gradually succumb to glioma cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Radiobiological effect of different irradiation fractionated regimens in human brain glioma

    International Nuclear Information System (INIS)

    Gai Xue; Yang Weizhi; Gao Li; Jiang Heng; Wang Mianrong; Shi Huizhen

    2010-01-01

    Objective: To evaluate the radiobiological effect of different irradiation fractionated regimens in human glioma cells (BT 325 cell line). Methods: The xenografts in Balb/c-nude mice were irradiated with different single and fractionated regimens. The single fraction dose was 10, 20, 30, 40 and 60 Gy, respectively. The fractionated regimens were 2 Gy x 5 fractions ( irradiated every day), and 3 Gy x 3 fractions (irradiated every other day), 3 Gy x 5 fractions (irradiated every day) and 4 Gy x 3 fractions (irradiated every other day), with total doses of 125 Gy, 114 Gy, 126 Gy and 112 Gy, respectively. The growth curve was used to evaluate the tumor doubling time. clonogenic assays was performed to draw the cell survival curve and analyze the radiobiological parameters with doses of 1, 2, 4, 6, 8 and 10 Gy. T 1/2 was measured by comet assay. Results: Tumor regression were not observed by single fraction irradiation, 2 Gy x 5 fractions and 3 Gy x 3 fractions irradiation regimens. The tumor regress was more significant with the increas of fraction dose. The 4 Gy x 3 fractions inhibited tumor more though not curing tumor. The cell doubling time of the BT 325 cell was 30. 16 h and the tumor doubling time of the xenograft was 43 days.When fitted with L-Q model, α was 0. 36 Gy -1 and β was 0. 057 Gy -2 . When fitted with the single-hit multi target model, D 0 was 1. 394 Gy, Dq was 2. 127 Gy and SF 2 was 0.714, respectively. The T 1/2 was 9.999 min. Conclusions: Glioma is a radioresistant tumor. Increase of the fraction dose improves recent effect.Further study is needed to control the tumor stem cells. (authors)

  17. Molecular Alterations of KIT Oncogene in Gliomas

    Directory of Open Access Journals (Sweden)

    Ana L. Gomes

    2007-01-01

    Full Text Available Gliomas are the most common and devastating primary brain tumours. Despite therapeutic advances, the majority of gliomas do not respond either to chemo or radiotherapy. KIT, a class III receptor tyrosine kinase (RTK, is frequently involved in tumourigenic processes. Currently, KIT constitutes an attractive therapeutic target. In the present study we assessed the frequency of KIT overexpression in gliomas and investigated the genetic mechanisms underlying KIT overexpression. KIT (CD117 immunohistochemistry was performed in a series of 179 gliomas of various grades. KIT activating gene mutations (exons 9, 11, 13 and 17 and gene amplification analysis, as defined by chromogenic in situ hybridization (CISH and quantitative real-time PCR (qRT-PCR were performed in CD117 positive cases. Tumour cell immunopositivity was detected in 15.6% (28/179 of cases, namely in 25% (1/4 of pilocytic astrocytomas, 25% (5/20 of diffuse astrocytomas, 20% (1/5 of anaplastic astrocytomas, 19.5% (15/77 of glioblastomas and one third (3/9 of anaplastic oligoastrocytomas. Only 5.7% (2/35 of anaplastic oligodendrogliomas showed CD117 immunoreactivity. No association was found between tumour CD117 overexpression and patient survival. In addition, we also observed CD117 overexpression in endothelial cells, which varied from 0–22.2% of cases, being more frequent in high-grade lesions. No KIT activating mutations were identified. Interestingly, CISH and/or qRT-PCR analysis revealed the presence of KIT gene amplification in 6 glioblastomas and 2 anaplastic oligoastrocytomas, corresponding to 33% (8/24 of CD117 positive cases. In conclusion, our results demonstrate that KIT gene amplification rather than gene mutation is a common genetic mechanism underlying KIT expression in subset of malignant gliomas. Further studies are warranted to determine whether glioma patients exhibiting KIT overexpression and KIT gene amplification may benefit from therapy with anti-KIT RTK

  18. Angiogenesis in gliomas.

    Directory of Open Access Journals (Sweden)

    Elzbieta Czykier

    2008-02-01

    Full Text Available Brain gliomas are characterized by invasive growth and neovascularisation potential. Angiogenesis plays a major role in the progression of gliomas and its determination has a great prognostic value. The aim of the study was to assess the vascularisation of chosen brain gliomas and to estimate how it is correlated with tumour histological type, malignancy grade, location and size, and with age and sex of patients. Tumour vascularisation analysis was based on the determination of microvascular proliferation (MVP and microvessel density (MVD. Microvascular proliferation was measured with immunohistochemical methods using mouse monoclonal antibodies to detect cell proliferation antigens. The following antibodies were used Ki-67 and PCNA (DAKO. Identification of vessels was performed by CD31 antibody and anti-human von Willebrand factor (DAKO. The highest microvascular proliferation and microvascular density were observed in multiform glioblastomas and the lowest in oligodendrogliomas. Significant correlation was observed between the vascularisation and malignancy grade.

  19. PET pharmacokinetic analysis to estimate boron concentration in tumor and brain as a guide to plan BNCT for malignant cerebral glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nariai, Tadashi [Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo (Japan)], E-mail: nariai.nsrg@tmd.ac.jp; Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1, Nakacho, Itabashi-ku, Tokyo (Japan); Kimura, Yuichi [Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba (Japan); Inaji, Motoki; Momose, Toshiya [Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo (Japan); Yamamoto, Tetsuya; Matsumura, Akira [Department of Neurosurgery, University of Tsukuba, Tennodai, Tsukuba, Igaraki (Japan); Ishii, Kenji [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1, Nakacho, Itabashi-ku, Tokyo (Japan); Ohno, Kikuo [Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo (Japan)

    2009-07-15

    Introduction: To plan the optimal BNCT for patients with malignant cerebral glioma, estimation of the ratio of boron concentration in tumor tissue against that in the surrounding normal brain (T/N ratio of boron) is important. We report a positron emission tomography (PET) imaging method to estimate T/N ratio of tissue boron concentration based on pharmacokinetic analysis of amino acid probes. Methods: Twelve patients with cerebral malignant glioma underwent 60 min dynamic PET scanning of brain after bolus injection of {sup 18}F-borono-phenyl-alanine (FBPA) with timed arterial blood sampling. Using kinetic parameter obtained by this scan, T/N ratio of boron concentration elicited by one-hour constant infusion of BPA, as performed in BNCT, was simulated on Runge-Kutta algorithm. {sup 11}C-methionine (MET) PET scan, which is commonly used in worldwide PET center as brain tumor imaging tool, was also performed on the same day to compare the image characteristics of FBPA and that of MET. Result: PET glioma images obtained with FBPA and MET are almost identical in all patients by visual inspection. Estimated T/N ratio of tissue boron concentration after one-hour constant infusion of BPA, T/N ratio of FBPA on static condition, and T/N ratio of MET on static condition showed significant linear correlation between each other. Conclusion: T/N ratio of boron concentration that is obtained by constant infusion of BPA during BNCT can be estimated by FBPA PET scan. This ratio can also be estimated by MET-PET imaging. As MET-PET study is available in many clinical PET center, selection of candidates for BNCT may be possible by MET-PET images. Accurate planning of BNCT may be performed by static images of FBPA PET. Use of PET imaging with amino acid probes may contribute very much to establish an appropriate application of BNCT for patients with malignant glioma.

  20. PET pharmacokinetic analysis to estimate boron concentration in tumor and brain as a guide to plan BNCT for malignant cerebral glioma

    International Nuclear Information System (INIS)

    Nariai, Tadashi; Ishiwata, Kiichi; Kimura, Yuichi; Inaji, Motoki; Momose, Toshiya; Yamamoto, Tetsuya; Matsumura, Akira; Ishii, Kenji; Ohno, Kikuo

    2009-01-01

    Introduction: To plan the optimal BNCT for patients with malignant cerebral glioma, estimation of the ratio of boron concentration in tumor tissue against that in the surrounding normal brain (T/N ratio of boron) is important. We report a positron emission tomography (PET) imaging method to estimate T/N ratio of tissue boron concentration based on pharmacokinetic analysis of amino acid probes. Methods: Twelve patients with cerebral malignant glioma underwent 60 min dynamic PET scanning of brain after bolus injection of 18 F-borono-phenyl-alanine (FBPA) with timed arterial blood sampling. Using kinetic parameter obtained by this scan, T/N ratio of boron concentration elicited by one-hour constant infusion of BPA, as performed in BNCT, was simulated on Runge-Kutta algorithm. 11 C-methionine (MET) PET scan, which is commonly used in worldwide PET center as brain tumor imaging tool, was also performed on the same day to compare the image characteristics of FBPA and that of MET. Result: PET glioma images obtained with FBPA and MET are almost identical in all patients by visual inspection. Estimated T/N ratio of tissue boron concentration after one-hour constant infusion of BPA, T/N ratio of FBPA on static condition, and T/N ratio of MET on static condition showed significant linear correlation between each other. Conclusion: T/N ratio of boron concentration that is obtained by constant infusion of BPA during BNCT can be estimated by FBPA PET scan. This ratio can also be estimated by MET-PET imaging. As MET-PET study is available in many clinical PET center, selection of candidates for BNCT may be possible by MET-PET images. Accurate planning of BNCT may be performed by static images of FBPA PET. Use of PET imaging with amino acid probes may contribute very much to establish an appropriate application of BNCT for patients with malignant glioma.

  1. Portable Intraoperative Computed Tomography Scan in Image-Guided Surgery for Brain High-grade Gliomas: Analysis of Technical Feasibility and Impact on Extent of Tumor Resection.

    Science.gov (United States)

    Barbagallo, Giuseppe M V; Palmucci, Stefano; Visocchi, Massimiliano; Paratore, Sabrina; Attinà, Giancarlo; Sortino, Giuseppe; Albanese, Vincenzo; Certo, Francesco

    2016-03-01

    Intraoperative magnetic resonance imaging is the gold standard among image-guided techniques for glioma surgery. Scant data are available on the role of intraoperative computed tomography (i-CT) in high-grade glioma (HGG) surgery. To verify the technical feasibility and usefulness of portable i-CT in image-guided surgical resection of HGGs. This is a retrospective series control analysis of prospectively collected data. Twenty-five patients (Group A) with HGGs underwent surgery using i-CT and 5-aminolevulinic acid (5-ALA) fluorescence. A second cohort of 25 patients (Group B) underwent 5-ALA fluorescence-guided surgery but without i-CT. We used a portable 8-slice CT scanner and, in both groups, neuronavigation. Extent of tumor resection (ETOR) and pre- and postoperative Karnofsky performance status (KPS) scores were measured; the impact of i-CT on overall survival (OS) and progression-free survival (PFS) was also analyzed. In 8 patients (32%) in Group A, i-CT revealed residual tumor, and in 4 of them it helped to also resect pathological tissue detached from the main tumor. EOTR in these 8 patients was 97.3% (96%-98.6%). In Group B, residual tumor was found in 6 patients, whose tumor's mean resection was 98% (93.5-99.7). The Student t test did not show statistically significant differences in EOTR in the 2 groups. The KPS score decreased from 67 to 69 after surgery in Group A and from 74 to 77 in Group B (P = .07 according to the Student t test). Groups A and B did not show statistically significant differences in OS and PFS (P = .61 and .46, respectively, by the log-rank test). No statistically significant differences in EOTR, KPS, PFS, and OS were observed in the 2 groups. However, i-CT helped to verify EOTR and to update the neuronavigator with real-time images, as well as to identify and resect pathological tissue in multifocal tumors. i-CT is a feasible and effective alternative to intraoperative magnetic resonance imaging. Portable i-CT can provide useful

  2. Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies against epidermal growth factor receptor and placental alkaline phosphatase

    International Nuclear Information System (INIS)

    Kalofonos, H.P.; Pawlikowska, T.R.; Hemingway, A.

    1989-01-01

    Twenty-seven patients with brain glioma were scanned using 123 I-labeled monoclonal antibodies against epidermal growth factor receptor (EGFR1) or placental alkaline phosphatase (H17E2). Successful localization was achieved in 18 out of 27 patients. Eleven out of 27 patients were also studied using a nonspecific control antibody (11.4.1) of the same immunoglobulin subclass and observable tumor localization was also achieved in five patients. The specificity of targeting was assessed by comparing images obtained with specific and nonspecific antibodies and by examining tumor and normal tissue biopsies after dual antibody administration. Ten patients with recurrent grade III or IV glioma who showed good localization of radiolabeled antibody were treated with 40-140 mCi of 131 I-labeled antibody delivered to the tumor area intravenously (n = 5) or by infusion into the internal carotid artery (n = 5). Six patients showed clinical improvement lasting from 6 mo to 3 yr. One patient continues in remission (3 yr after therapy), but the other five who responded initially relapsed 6-9 mo after therapy and died. No major toxicity was attributable to antibody-guided irradiation. Targeted irradiation by monoclonal antibody may be clinically useful and should be explored further in the treatment of brain gliomas resistant to conventional forms of treatment

  3. Accurate classification of brain gliomas by discriminate dictionary learning based on projective dictionary pair learning of proton magnetic resonance spectra.

    Science.gov (United States)

    Adebileje, Sikiru Afolabi; Ghasemi, Keyvan; Aiyelabegan, Hammed Tanimowo; Saligheh Rad, Hamidreza

    2017-04-01

    Proton magnetic resonance spectroscopy is a powerful noninvasive technique that complements the structural images of cMRI, which aids biomedical and clinical researches, by identifying and visualizing the compositions of various metabolites within the tissues of interest. However, accurate classification of proton magnetic resonance spectroscopy is still a challenging issue in clinics due to low signal-to-noise ratio, overlapping peaks of metabolites, and the presence of background macromolecules. This paper evaluates the performance of a discriminate dictionary learning classifiers based on projective dictionary pair learning method for brain gliomas proton magnetic resonance spectroscopy spectra classification task, and the result were compared with the sub-dictionary learning methods. The proton magnetic resonance spectroscopy data contain a total of 150 spectra (74 healthy, 23 grade II, 23 grade III, and 30 grade IV) from two databases. The datasets from both databases were first coupled together, followed by column normalization. The Kennard-Stone algorithm was used to split the datasets into its training and test sets. Performance comparison based on the overall accuracy, sensitivity, specificity, and precision was conducted. Based on the overall accuracy of our classification scheme, the dictionary pair learning method was found to outperform the sub-dictionary learning methods 97.78% compared with 68.89%, respectively. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Diffusion Tensor Tractography Reveals Disrupted Structural Connectivity during Brain Aging

    Science.gov (United States)

    Lin, Lan; Tian, Miao; Wang, Qi; Wu, Shuicai

    2017-10-01

    Brain aging is one of the most crucial biological processes that entail many physical, biological, chemical, and psychological changes, and also a major risk factor for most common neurodegenerative diseases. To improve the quality of life for the elderly, it is important to understand how the brain is changed during the normal aging process. We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 75 healthy old subjects by using graph theory metrics to describe the anatomical networks and connectivity patterns, and network-based statistic (NBS) analysis was used to identify pairs of regions with altered structural connectivity. The NBS analysis revealed a significant network comprising nine distinct fiber bundles linking 10 different brain regions showed altered white matter structures in young-old group compare with middle-aged group (p < .05, family-wise error-corrected). Our results might guide future studies and help to gain a better understanding of brain aging.

  5. Long Non-coding RNA LINC00339 Stimulates Glioma Vasculogenic Mimicry Formation by Regulating the miR-539-5p/TWIST1/MMPs Axis

    Directory of Open Access Journals (Sweden)

    Junqing Guo

    2018-03-01

    Full Text Available Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma.

  6. 18F-FDOPA PET-CT vs 99mTc-GHA SPECT-CT in evaluation of recurrent brain gliomas

    International Nuclear Information System (INIS)

    Karunanithi, Sellam; Bal, C.; Malhotra, A.; Kumar, Abhishek; Bandopadhyay, G.P.; Gupta, D.

    2010-01-01

    Full text: Purpose of this study was to compare the role of 18 F-FDOPA PET-CT(FDOPA) and 99m Tc-GHA SPECT-CT (GHA) in detecting recurrence in glioma patients. Materials and Methods: Thirty patients of clinically suspected recurrent glioma of varying grades (ten with low grade and twenty with high grade primary tumor), previously treated with surgery and/or radiotherapy were evaluated using FDOPA and GHA. FDOPA images were interpreted positive for any abnormal tracer uptake noted in brain parenchyma. GHA images were interpreted as positive for abnormal tracer uptake noted in brain parenchyma. Final outcome was judged on the basis of biopsy report and/or clinical follow-up and serial MRI/MR spectroscopy imaging results. Results: Twenty- three patients were considered positive (death in 5, biopsy in 2, clinical progression in 6 and progression on imaging in 10) while 7 were negative for recurrence. FDOPA scan was positive in 22, negative in 8 patients. GHA was positive in 21, negative in 9 patients. Sensitivity, specificity, PPV and NPV of FDOPA were 95.6%, 100%, 100% and 87.5%, respectively. Sensitivity, specificity, PPV and NPV of GHA were 82.6%, 71.4%, 90.4% and 55.5%, respectively. Conclusions: FDOPA has the highest detection rate for recurrent glioma irrespective of the grade. FDOPA was found to be superior especially in detecting low grade viable gliomas. GHA, however due to high occurrence of false-positive results, prospective differentiation of recurrent tumor from treatment-induced changes is not possible in most patients

  7. Epileptic seizures in patients with glioma: A single centre- based ...

    African Journals Online (AJOL)

    were used for analysis of seizure incidence differences as per WHO Grades, histology, location ... Keywords: Brain tumour, Epilepsy, Glioma, Seizures, Levetiracetam, .... glioma patients. Characteristics. N (%). Gender. Male. Female. Histology.

  8. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

    Directory of Open Access Journals (Sweden)

    Susanna J E Veringa

    Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

  9. History and current state of immunotherapy in glioma and brain metastasis.

    Science.gov (United States)

    McGranahan, Tresa; Li, Gordon; Nagpal, Seema

    2017-05-01

    Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

  10. Perturbation of whole-brain dynamics in silico reveals mechanistic differences between brain states

    NARCIS (Netherlands)

    Deco, Gustavo; Cabral, Joana; Saenger, Victor M; Boly, Melanie; Tagliazucchi, Enzo; Laufs, Helmut; Van Someren, Eus; Jobst, Beatrice; Stevner, Angus; Kringelbach, Morten L

    2017-01-01

    Human neuroimaging research has revealed that wakefulness and sleep involve very different activity patterns. Yet, it is not clear why brain states differ in their dynamical complexity, e.g. in the level of integration and segregation across brain networks over time. Here, we investigate the

  11. Perturbation of whole-brain dynamics in silico reveals mechanistic differences between brain states

    NARCIS (Netherlands)

    Deco, Gustavo; Cabral, Joana; Saenger, Victor M; Boly, Melanie; Tagliazucchi, Enzo; Laufs, Helmut; Van Someren, Eus; Jobst, Beatrice M; Stevner, Angus B A; Kringelbach, Morten L

    2018-01-01

    Human neuroimaging research has revealed that wakefulness and sleep involve very different activity patterns. Yet, it is not clear why brain states differ in their dynamical complexity, e.g. in the level of integration and segregation across brain networks over time. Here, we investigate the

  12. An Interindividual Comparison of O-(2- [18F]Fluoroethyl)-L-Tyrosine (FET)– and L-[Methyl-11C]Methionine (MET)–PET in Patients With Brain Gliomas and Metastases

    International Nuclear Information System (INIS)

    Grosu, Anca-Ligia; Astner, Sabrina T.; Riedel, Eva; Nieder, Carsten; Wiedenmann, Nicole; Heinemann, Felix; Schwaiger, Markus

    2011-01-01

    Purpose: L-[methyl- 11 C]methionine (MET)–positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of 11 C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2- [ 18 F]fluoroethyl)-L-tyrosine (FET) is labeled with 18 F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI). Methods and Materials: We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion–to–gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up. Results: There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p 18 F]fluoroethyl)-L-tyrosine–PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas.

  13. Characteristics of MR imaging of brain stem glioma for the treatment of combination chemotherapy with interferon-. beta. and ACNU in addition to radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Wakabayashi, Toshihiko; Yoshida, Jun; Sugita, Kenichiro (Nagoya Univ. (Japan). Faculty of Medicine)

    1990-08-01

    In an attempt to improve the prognosis of brain stem glioma patients, a new treatment using a combination of chemotherapy of interferon-{beta}, ACNU, (1) - (4 - Amino - 2 - methyl - 5 - primidinyl) - methyl - 3 - (2-chloroethyl) - 3 -nitrosourea hydrochloride, and radiation, so called IAR therapy, was utilized on 19 patients who were diagnosed through CT and/or MRI findings as having pontine glioma. Eight of these patients were given IAR therapy at four week intervals and the changes were checked on MRI. The MRI response was classified into 3 types, that is, type 1: diffuse low intensity lesion on T{sub 1} WI changing to isodensity and tumor mass disappearing rapidly; type 2: located high intensity lesion in low intensity on T{sub 1} WI once appearing on decreasing the whole tumor size, then this lesion disappearing gradually; type 3: spotted low and/or iso mosaic intensity lesion appearing on and after treatment, with little change in tumor mass. The type 1 patients showed rapid improvement of neurological deficits and good recovery was obtained. Type 2 patients also recovered well but at recurrent periods tended to show disseminated sings intraspinally. The type 3 patients did not recover from neurological deficits well. But there were no significant differences of prognosis among these 3 types. Furthermore, MRI showed more precise data than CT scan on brain stem lesions and seemed to be more useful for diagnosis and follow-up treatment than CT scan. Though it is suggested that IAR combination therapy should be respected as the first choice for the treatment of brain stem glioma, it is strongly requested that some maintenance therapy is established for continuing the reduction time after induction of complete or partial remission with IAR therapy. (author).

  14. Awake Craniotomy with Noninvasive Brain Mapping by 3-Tesla Functional Magnetic Resonance Imaging for Excision of Low-grade Glioma: A Case of a Young Patient from Pakistan.

    Science.gov (United States)

    Aleem Bhatti, Atta Ul; Jakhrani, Nasir Khan; Parekh, Maria Adnan

    2018-01-01

    The past few years have seen increasing support for gross total resection in the management of low-grade gliomas (LGGs), with a greater extent of resection correlated with better overall survival, progression-free survival, and time to malignant transformation. There is consistent evidence in literature supporting extent of safe resection as a good prognostic indicator as well as positively affecting seizure control, symptomatic relief in pressure symptoms, and longer progression-free and total survival. The operative goal in most LGG cases is to maximize the extent of resection for these benefits while avoiding postoperative neurologic deficits. Several advanced invasive and noninvasive surgical techniques such as intraoperative magnetic resonance imaging (MRI), fluorescence-guided surgery, intraoperative functional pathway mapping, and neuronavigation have been developed in an attempt to better achieve maximal safe resection. We present a case of LGG in a young patient with a 5-year history of refractory seizures and gradual onset walking difficulty. Serial MRI brain scans revealed a progressive increase in right frontal tumor size with substantial edema and parafalcine herniation. Noninvasive brain mapping by functional MRI (fMRI) and sleep-awake-sleep type of anesthesia with endotracheal tube insertion was utilized during an awake craniotomy. Histopathology confirmed a Grade II oligodendroglioma, and genetic analysis revealed no codeletion at 1p/19q. Neurological improvement was remarkable in terms of immediate motor improvement, and the patient remained completely seizure free on a single antiepileptic drug. There is no radiologic or clinical evidence of recurrence 6 months postoperatively. This is the first published report of an awake craniotomy for LGG in Pakistan. The contemporary concept of supratotal resection in LGGs advocates generous functional resection even beyond MRI findings rather than mere excision of oncological boundaries. This relatively

  15. 7-Tesla Susceptibility-Weighted Imaging to Assess the Effects of Radiotherapy on Normal-Appearing Brain in Patients With Glioma

    International Nuclear Information System (INIS)

    Lupo, Janine M.; Chuang, Cynthia F.; Chang, Susan M.; Barani, Igor J.; Jimenez, Bert; Hess, Christopher P.; Nelson, Sarah J.

    2012-01-01

    Purpose: To evaluate the intermediate- and long-term imaging manifestations of radiotherapy on normal-appearing brain tissue in patients with treated gliomas using 7T susceptibility-weighted imaging (SWI). Methods and Materials: SWI was performed on 25 patients with stable gliomas on a 7 Tesla magnet. Microbleeds were identified as discrete foci of susceptibility that did not correspond to vessels. The number of microbleeds was counted within and outside of the T2-hyperintense lesion. For 3 patients, radiation dosimetry maps were reconstructed and fused with the 7T SWI data. Results: Multiple foci of susceptibility consistent with microhemorrhages were observed in patients 2 years after chemoradiation. These lesions were not present in patients who were not irradiated. The prevalence of microhemorrhages increased with the time since completion of radiotherapy, and these lesions often extended outside the boundaries of the initial high-dose volume and into the contralateral hemisphere. Conclusions: High-field SWI has potential for visualizing the appearance of microbleeds associated with long-term effects of radiotherapy on brain tissue. The ability to visualize these lesions in normal-appearing brain tissue may be important in further understanding the utility of this treatment in patients with longer survival.

  16. Novel drugs in pediatric gliomas

    OpenAIRE

    Zhang, Dongli; Liu, Xiaoming; Fan, Conghai; Chen, Jiao

    2017-01-01

    Astrocytomas (gliomas) are the most common primary brain tumors among adults and second most frequent neoplasm among children. New ideas and novel approaches are being explored world over with aim to devise better management strategeies for this deadly pathological state. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting importance of various therapeutic drugs against gliomas. It was observed clearly that this approach of using therape...

  17. Frequent Nek1 overexpression in human gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Jun [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Cai, Yu, E-mail: aihaozuqiu22@163.com [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Liu, Pin [Med-X Research Institute, Shanghai Jiao Tong University, Shanghai (China); Zhao, Weiguo [Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

    2016-08-05

    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, 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.

  18. Frequent Nek1 overexpression in human gliomas

    International Nuclear Information System (INIS)

    Zhu, Jun; Cai, Yu; Liu, Pin; Zhao, Weiguo

    2016-01-01

    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, 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.

  19. Atypical nuclear localization of VIP receptors in glioma cell lines and patients

    Energy Technology Data Exchange (ETDEWEB)

    Barbarin, Alice; Séité, Paule [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France); Godet, Julie [Laboratoire d’anatomie et de cytologie pathologiques, CHU de Poitiers, 2 rue de la Milétrie, 86000 Poitiers (France); Bensalma, Souheyla; Muller, Jean-Marc [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France); Chadéneau, Corinne, E-mail: corinne.chadeneau@univ-poitiers.fr [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France)

    2014-11-28

    Highlights: • The VIP receptor VPAC1 contains a putative NLS signal. • VPAC1 is predominantly nuclear in GBM cell lines but not VPAC2. • Non-nuclear VPAC1/2 protein expression is correlated with glioma grade. • Nuclear VPAC1 is observed in 50% of stage IV glioma (GBM). - Abstract: An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression.

  20. Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

    Science.gov (United States)

    Wegner, Florian; Wilke, Florian; Raab, Peter; Tayeb, Said Ben; Boeck, Anna-Lena; Haense, Cathleen; Trebst, Corinna; Voss, Elke; Schrader, Christoph; Logemann, Frank; Ahrens, Jörg; Leffler, Andreas; Rodriguez-Raecke, Rea; Dengler, Reinhard; Geworski, Lilli; Bengel, Frank M; Berding, Georg; Stangel, Martin; Nabavi, Elham

    2014-06-20

    Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

  1. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Li, Qiuping [Zhongshan Hospital of Fudan University, Shanghai 200032 (China); Yang, Zhiyuan; Wu, Guoqiang [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Sun, Shuhui [Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Gu, Jianxin [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Institutes of Biomedical Sciences of Fudan University, Shanghai 200032 (China); Wei, Yuanyan, E-mail: yywei@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Jiang, Jianhai, E-mail: jianhaijiang@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China)

    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 a 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.

  2. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

    International Nuclear Information System (INIS)

    Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan; Li, Qiuping; Yang, Zhiyuan; Wu, Guoqiang; Sun, Shuhui; Gu, Jianxin; Wei, Yuanyan; Jiang, Jianhai

    2010-01-01

    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 a 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.

  3. Digital tissue and what it may reveal about the brain.

    Science.gov (United States)

    Morgan, Josh L; Lichtman, Jeff W

    2017-10-30

    Imaging as a means of scientific data storage has evolved rapidly over the past century from hand drawings, to photography, to digital images. Only recently can sufficiently large datasets be acquired, stored, and processed such that tissue digitization can actually reveal more than direct observation of tissue. One field where this transformation is occurring is connectomics: the mapping of neural connections in large volumes of digitized brain tissue.

  4. Penetration of blood–brain barrier and antitumor activity and nerve repair in glioma by doxorubicin-loaded monosialoganglioside micelles system

    Directory of Open Access Journals (Sweden)

    Zou D

    2017-07-01

    Full Text Available Dan Zou,1 Wei Wang,1 Daoxi Lei,1 Ying Yin,1 Peng Ren,1 Jinju Chen,2 Tieying Yin,1 Bochu Wang,1 Guixue Wang,1 Yazhou Wang1 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People’s Republic of China; 2School of Mechanical and System Engineering, Newcastle University, Newcastle Upon Tyne, UK Abstract: For the treatment of glioma and other central nervous system diseases, one of the biggest challenges is that most therapeutic drugs cannot be delivered to the brain tumor tissue due to the blood–brain barrier (BBB. The goal of this study was to construct a nanodelivery vehicle system with capabilities to overcome the BBB for central nervous system administration. Doxorubicin as a model drug encapsulated in ganglioside GM1 micelles was able to achieve up to 9.33% loading efficiency and 97.05% encapsulation efficiency by orthogonal experimental design. The in vitro study demonstrated a slow and sustainable drug release in physiological conditions. In the cellular uptake studies, mixed micelles could effectively transport into both human umbilical vein endothelial cells and C6 cells. Furthermore, biodistribution imaging of mice showed that the DiR/GM1 mixed micelles were accumulated sustainably and distributed centrally in the brain. Experiments on zebrafish confirmed that drug-loaded GM1 micelles can overcome the BBB and enter the brain. Among all the treatment groups, the median survival time of C6-bearing rats after administering DOX/GM1 micelles was significantly prolonged. In conclusion, the ganglioside nanomicelles developed in this work can not only penetrate BBB effectively but also repair nerves and kill tumor cells at the same time. Keywords: blood–brain barrier, GM1, nanovesicles, doxorubicin, glioma, zebrafish

  5. PEGylated Polyamidoamine dendrimer conjugated with tumor homing peptide as a potential targeted delivery system for glioma.

    Science.gov (United States)

    Jiang, Yan; Lv, Lingyan; Shi, Huihui; Hua, Yabing; Lv, Wei; Wang, Xiuzhen; Xin, Hongliang; Xu, Qunwei

    2016-11-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system (CNS) tumor with a short survival time. The failure of chemotherapy is ascribed to the low transport of chemotherapeutics across the Blood Brain Tumor Barrier (BBTB) and poor penetration into tumor tissue. In order to overcome the two barriers, small nanoparticles with active targeted capability are urgently needed for GBM drug delivery. In this study, we proposed PEGylated Polyamidoamine (PAMAM) dendrimer nanoparticles conjugated with glioma homing peptides (Pep-1) as potential glioma targeting delivery system (Pep-PEG-PAMAM), where PEGylated PAMAM dendrimer nanoparticle was utilized as carrier due to its small size and perfect penetration into tumor and Pep-1 was used to overcome BBTB via interleukin 13 receptor α2 (IL-13Rα2) mediated endocytosis. The preliminary availability and safety of Pep-PEG-PAMAM as a nanocarrier for glioma was evaluated. In vitro results indicated that a significantly higher amount of Pep-PEG-PAMAM was endocytosed by U87 MG cells. In vivo fluorescence imaging of U87MG tumor-bearing mice confirmed that the fluorescence intensity at glioma site of targeted group was 2.02 folds higher than that of untargeted group (**p<0.01), and glioma distribution experiment further revealed that Pep-PEG-PAMAM exhibited a significantly enhanced accumulation and improved penetration at tumor site. In conclusion, Pep-1 modified PAMAM was a promising nanocarrier for targeted delivery of brain glioma. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer.

    Directory of Open Access Journals (Sweden)

    Nina P Connolly

    Full Text Available Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS virus / tumor virus receptor-A (tv-a transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  7. The Glioma International Case-Control Study

    DEFF Research Database (Denmark)

    Amirian, E. Susan; Armstrong, Georgina N; Zhou, Renke

    2016-01-01

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly...... describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen...

  8. Symbolic joint entropy reveals the coupling of various brain regions

    Science.gov (United States)

    Ma, Xiaofei; Huang, Xiaolin; Du, Sidan; Liu, Hongxing; Ning, Xinbao

    2018-01-01

    The convergence and divergence of oscillatory behavior of different brain regions are very important for the procedure of information processing. Measurements of coupling or correlation are very useful to study the difference of brain activities. In this study, EEG signals were collected from ten subjects under two conditions, i.e. eyes closed state and idle with eyes open. We propose a nonlinear algorithm, symbolic joint entropy, to compare the coupling strength among the frontal, temporal, parietal and occipital lobes and between two different states. Instead of decomposing the EEG into different frequency bands (theta, alpha, beta, gamma etc.), the novel algorithm is to investigate the coupling from the entire spectrum of brain wave activities above 4Hz. The coupling coefficients in two states with different time delay steps are compared and the group statistics are presented as well. We find that the coupling coefficient of eyes open state with delay consistently lower than that of eyes close state across the group except for one subject, whereas the results without delay are not consistent. The differences between two brain states with non-zero delay can reveal the intrinsic inter-region coupling better. We also use the well-known Hénon map data to validate the algorithm proposed in this paper. The result shows that the method is robust and has a great potential for other physiologic time series.

  9. Differential expression of splicing variants of the human caldesmon gene (CALD1) in glioma neovascularization versus normal brain microvasculature

    NARCIS (Netherlands)

    P.P. Zheng (Pingpin); A.M. Sieuwerts (Anieta); T.M. Luider (Theo); M.M. van der Weiden (Marcel); J.M. Kros (Johan); P.A.E. Sillevis Smitt (Peter)

    2004-01-01

    textabstractCaldesmon is a cytoskeleton-associated protein which has not yet been related to neoplastic angiogenesis. In this study we investigated the expression of the caldesmon gene (CALD1) splicing variants and the protein expression level in glioma microvessels versus normal

  10. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis

    Science.gov (United States)

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1+ tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the “classical-like” (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients’ outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1+ cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1- cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1+ cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  11. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

    Science.gov (United States)

    Boockvar, John A; Tsiouris, Apostolos J; Hofstetter, Christoph P; Kovanlikaya, Ilhami; Fralin, Sherese; Kesavabhotla, Kartik; Seedial, Stephen M; Pannullo, Susan C; Schwartz, Theodore H; Stieg, Philip; Zimmerman, Robert D; Knopman, Jared; Scheff, Ronald J; Christos, Paul; Vallabhajosula, Shankar; Riina, Howard A

    2011-03-01

    The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. A total of 30 patients with recurrent malignant glioma were included in the current study. The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

  12. Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

    Science.gov (United States)

    2017-10-23

    Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

  13. Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

    Science.gov (United States)

    Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

    2012-02-01

    Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

  14. Reproducibility of O-(2-{sup 18}F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Stegmayr, Carina; Schoeneck, Michael; Oliveira, Dennis; Willuweit, Antje [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); Filss, Christian; Coenen, Heinz H.; Langen, Karl-Josef [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Galldiks, Norbert [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Cologne, Department of Neurology, Cologne (Germany); Shah, N. Jon [Institute of Neuroscience and Medicine, Research Center Juelich, Juelich (Germany); University of Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain, Juelich (Germany)

    2016-06-15

    Positron emission tomography (PET) using O-(2-{sup 18}F-fluoroethyl)-L-tyrosine ({sup 18}F-FET) is a well-established method for the diagnostics of brain tumors. This study investigates reproducibility of {sup 18}F-FET uptake kinetics in rat gliomas and the influence of the frequently used dexamethasone (Dex) therapy. F98 glioma or 9L gliosarcoma cells were implanted into the striatum of 31 Fischer rats. After 10-11 days of tumor growth, the animals underwent dynamic PET after injection of {sup 18}F-FET (baseline). Thereafter, animals were divided into a control group and a group receiving Dex injections, and all animals were reinvestigated 2 days later. Tumor-to-brain ratios (TBR) of {sup 18}F-FET uptake (18-61 min p.i.) and the slope of the time-activity-curves (TAC) (18-61 min p.i.) were evaluated using a Volume-of-Interest (VOI) analysis. Data were analyzed by two-way repeated measures ANOVA and reproducibility by the intraclass correlation coefficient (ICC). The slope of the tumor TACs showed high reproducibility with an ICC of 0.93. A systematic increase of the TBR in the repeated scans was noted (3.7 ± 2.8 %; p < 0.01), and appeared to be related to tumor growth as indicated by a significant correlation of TBR and tumor volume (r = 0.77; p < 0.0001). After correction for tumor growth TBR showed high longitudinal stability with an ICC of 0.84. Dex treatment induced a significant decrease of the TBR (-8.2 ± 6.1 %; p < 0.03), but did not influence the slope of the tumor TAC. TBR of {sup 18}F-FET uptake and tracer kinetics in brain tumors showed high longitudinal stability. Dex therapy may induce a minor decrease of the TBR; this needs further investigation. (orig.)

  15. Chemo-enzymatic Synthesis of Propionyl-ester-linked Taxol-monosaccharide Conjugate and its Drug Delivery System Using Hybrid-Bio-nanocapsules Targeting Brain Glioma Cells

    Directory of Open Access Journals (Sweden)

    Hiroki Hamada

    2013-01-01

    Full Text Available Taxol is recognized as one of the most potent anticancer agents used in the treatment of breast and ovarian cancers, which are common cancers in women. To overcome its shortcomings, that is, its low water-solubility that reduces drug loading capacity of DDS carriers when incorporating taxol, chemo-enzymatic synthesis of ester-linked taxol-glucose conjugate, i.e., 7-propionyltaxol 2′- O -α-D-glucoside, as a water soluble taxol prodrug was achieved by using a-glucosidase as a glucosylation catalyst. The water-solubility of 7-propionyltaxol 2′- O -α-D-glucoside (25 mM was 63 fold higher than that of taxol (0.4 mM. The pre-S1 peptide which displays on the surface of bio-nanocapsules, which are nanoparticles composed of the hepatitis B virus surface antigen, was replaced with the antibody affinity motif of protein A. Conjugation of such bio-nanocapsules with anti-human epidermal growth factor receptor antibody gave hybrid bio-nanocapsules. The hybrid bio-nanocapsules were effective for delivering 7-propionyltaxol 2′- O -α-D-glucoside to human brain glioma cells. 7-Propionyltaxol 2′- O -α-D-glucoside was effectively hydrolyzed to give taxol in 95% by human glioma cells. The drug loading capacity of hybrid bio-nanocapsules incorporating 7-propionyltaxol 2′- O -α-D-glucoside was 120 times higher than that incorporating taxol itself.

  16. 5-Fluorouracil and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) followed by hydroxyurea, misonidazole, and irradiation for brain stem gliomas: a pilot study of the Brain Tumor Research Center and the Childrens Cancer Group

    International Nuclear Information System (INIS)

    Levin, V.A.; Edwards, M.S.; Wara, W.M.; Allen, J.; Ortega, J.; Vestnys, P.

    1984-01-01

    Twenty-eight evaluable children with the diagnosis of brain stem glioma were treated with 5-fluorouracil and CCNU before posterior fossa irradiation (5500 rads); during irradiation, the children received hydroxyurea and misonidazole. The treatment was well tolerated, and minimal toxicity was produced. The median relapse-free survival was 32 weeks, and the median survival was 44 weeks. Analysis of covariates showed that, in patients between the ages of 2 and 19 years, survival was longest in the older children (P less than 0.02). Tumor histology, sex, extent of operation (if any), Karnofsky score, and radiation dose did not correlate with survival

  17. Penetration of blood-brain barrier and antitumor activity and nerve repair in glioma by doxorubicin-loaded monosialoganglioside micelles system.

    Science.gov (United States)

    Zou, Dan; Wang, Wei; Lei, Daoxi; Yin, Ying; Ren, Peng; Chen, Jinju; Yin, Tieying; Wang, Bochu; Wang, Guixue; Wang, Yazhou

    2017-01-01

    For the treatment of glioma and other central nervous system diseases, one of the biggest challenges is that most therapeutic drugs cannot be delivered to the brain tumor tissue due to the blood-brain barrier (BBB). The goal of this study was to construct a nanodelivery vehicle system with capabilities to overcome the BBB for central nervous system administration. Doxorubicin as a model drug encapsulated in ganglioside GM1 micelles was able to achieve up to 9.33% loading efficiency and 97.05% encapsulation efficiency by orthogonal experimental design. The in vitro study demonstrated a slow and sustainable drug release in physiological conditions. In the cellular uptake studies, mixed micelles could effectively transport into both human umbilical vein endothelial cells and C6 cells. Furthermore, biodistribution imaging of mice showed that the DiR/GM1 mixed micelles were accumulated sustainably and distributed centrally in the brain. Experiments on zebrafish confirmed that drug-loaded GM1 micelles can overcome the BBB and enter the brain. Among all the treatment groups, the median survival time of C6-bearing rats after administering DOX/GM1 micelles was significantly prolonged. In conclusion, the ganglioside nanomicelles developed in this work can not only penetrate BBB effectively but also repair nerves and kill tumor cells at the same time.

  18. ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARα -mediated inhibition of Glioma cell motility in vitro

    Directory of Open Access Journals (Sweden)

    Del Valle Luis

    2010-06-01

    Full Text Available Abstract Background Glioblastomas are characterized by rapid cell growth, aggressive CNS infiltration, and are resistant to all known anticancer regimens. Recent studies indicate that fibrates and statins possess anticancer potential. Fenofibrate is a potent agonist of peroxisome proliferator activated receptor alpha (PPARα that can switch energy metabolism from glycolysis to fatty acid β-oxidation, and has low systemic toxicity. Fenofibrate also attenuates IGF-I-mediated cellular responses, which could be relevant in the process of glioblastoma cell dispersal. Methods The effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR signaling, PPARα activity, reactive oxygen species (ROS metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines. Results Fenofibrate treatment attenuated IGF-I signaling responses and repressed cell motility of LN-229 and T98G Glioma cell lines. In the absence of fenofibrate, specific inhibition of the IGF-IR had only modest effects on Glioma cell motility. Further experiments revealed that PPARα-dependent accumulation of ROS is a strong contributing factor in Glioma cell lines responses to fenofibrate. The ROS scavenger, N-acetyl-cysteine (NAC, restored cell motility, improved mitochondrial potential, and increased ATP levels in fenofibrate treated Glioma cell lines. Conclusions Our results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARα-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.

  19. Noninvasive quantification of 18F-FLT human brain PET for the assessment of tumour proliferation in patients with high-grade glioma

    International Nuclear Information System (INIS)

    Backes, Heiko; Ullrich, Roland; Neumaier, Bernd; Kracht, Lutz; Wienhard, Klaus; Jacobs, Andreas H.

    2009-01-01

    Compartmental modelling of 3 ' -deoxy-3 ' -[ 18 F]-fluorothymidine ( 18 F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18 F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Based on the analysis of 11 patients with glioma (WHO grade II-IV) a procedure for the automated extraction of an input function from 18 F-FLT brain PET data was derived. The time-activity curve of the volume of interest with the maximum difference in 18 F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18 F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K 1 (transport across the blood-brain barrier) and K i (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K 1,img and K 1,sample , r = 0.95, p -5 ; K i,img and K i,sample , r = 0.86, p 1,img and K 1,sample , p = 0.20; K i,img and K i,sample , p = 0.92). Furthermore, a significant correlation between K i,img and the percentage of Ki-67-positive cells was observed (r = 0.73, p = 0.01). Kinetic modelling of 18 F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical

  20. CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1α

    International Nuclear Information System (INIS)

    Esencay, Mine; Sarfraz, Yasmeen; Zagzag, David

    2013-01-01

    Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion. In order to perform the studies, we employed optimal cell culture methods and hypoxic conditions, lentivirus-mediated knockdown of protein expression, Western Blot analysis, migration assays and immunoprecipitation. We determined statistical significance by unpaired t-test. In this report, we show that U87MG, LN229 and LN308 glioma cells express CXCR7 and that exposure to hypoxia upregulates CXCR7 protein expression in these cell lines. CXCR7-expressing U87MG, LN229 and LN308 glioma cells migrated towards stromal-derived factor (SDF)-1α/CXCL12 in hypoxic conditions in the Boyden chamber assays. While shRNA-mediated knockdown of CXCR7 expression did not affect the migration of any of the three cell lines in normoxic conditions, we observed a reduction in the migration of LN229 and LN308, but not U87MG, glioma cells towards SDF-1α in hypoxic conditions. In addition, knockdown of CXCR7 expression in LN229 and LN308 glioma cells decreased levels of SDF-1α-induced phosphorylation of ERK1/2 and Akt. Inhibiting CXCR4 in LN229 and LN308 glioma cells that were knocked down for CXCR7 did not further reduce migration towards SDF-1α in hypoxic conditions and did not affect the levels of phosphorylated ERK1/2 and Akt. Analysis of immunoprecipitated CXCR4 from LN229 and LN308 glioma cells revealed co-precipitated CXCR7. Taken together, our findings indicate that both CXCR4 and CXCR7 mediate glioma cell migration towards SDF-1α in hypoxic conditions and support the development of therapeutic agents targeting these receptors

  1. Comparative evaluation of gadoteridol versus gadopentetate dimeglumine for contrast-enhanced MRI in a rat brain glioma model at 1.5 and 3.0 T

    International Nuclear Information System (INIS)

    Ai Fei; Qi Jianpin; Li Xiaoming; Runge, Val M.; Morelli, John N.; Vu, Lan.; Cannel, Jeremy; Loynachan, Alan T.

    2010-01-01

    Objective: To compare gadoteridol and gadopentetate dimeglumine (Gd-DTPA) with respect to lesion enhancement in a rat brain glioma model at 1. 5 and 3.0 T. Methods: Glioma cells were injected into the brains of 42 male CDF (Fisher 344) rats through implanted cannula to create Glioma animal model. One week after implantation, all rats were randomly divided in to four groups which included 12, 10, 10, 10 rats. The comparisons included the contrast effect of gadoteridol versus gadopentetate dimeglumine at both 1.5 and 3.0 T. In addition, gadoteridol alone was evaluated by comparing the standard dose at both two field strengths and half dose at 3.0 T to a standard full dose at 1.5 T. Two MRI scans for different contrast agent injections were performed in each animal model with an interval of 24 hours. T 1 -weighted images were analyzed pre-contrast and at five time points (1, 3, 5, 7 and 9 min) post-contrast with respect to lesion signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and contrast enhancement (CE). Student t test was used for statistics. Results: The mean SNR, CNR, and CE were respectively 54.4±3.2, 17.0±3.3 and 20.8±3.4 with gadopentetate dimeglumine versus 53.2±3.2, 17.2±3.1 and 20.8±3.2 with gadoteridol at 1.5 T at every postconuast time point (t=2.247, 0.403, 0.076, P>0.05). The mean SNR, CNR, and CE were respectively 94.8±7.1, 38.0±6.0 and 45.0±6.3 with gadopentetate dimeglumine versus 95.5±2.9, 37.2±2.7 and 45.6±2.8 with gadoteridol at 3.0 T (t= 0.303, 0.573, 0.357, P>0.05). No statistically significant differences were found in these parameters between the two agents at any time point at either field strength. Standard dose gadoteridol demonstrated significant improvements in SNR (51.9±3.0 at 1.5 T vs 86.1±4.9 at 3.0 T), CNR (15.6±3.0 at 1.5 T vs 27.4±5.0 at 3.0 T) and CE (18.6±3.0 at 1.5 T vs 37.3±5.3 at 3.0 T) at 3.0 T as compared to 1.5 T at every time post-contrast (t=36.227, 11.977, 17.106, P 0.05). Conclusions

  2. Terahertz reflectometry imaging for low and high grade gliomas

    Science.gov (United States)

    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

    2016-01-01

    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. PMID:27782153

  3. Upregulation of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 Promotes Radioresistance of Glioma by Repressing Semaphorin 5A

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Rong [Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong (China); Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian (China); Yao, Qiwei [Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong (China); Department of Radiation Oncology, Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou, Fujian (China); Ren, Chen; Liu, Ying; Yang, Hongli; Xie, Guozhu; Du, Shasha [Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong (China); Yang, Kaijun [Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong (China); Yuan, Yawei, E-mail: yuanyawei2015@outlook.com [Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong (China); Department of Radiation Oncology, Cancer Hospital Center of Guangzhou Medical University, Guangzhou, Guangdong (China)

    2016-11-15

    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), 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.

  4. Upregulation of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 Promotes Radioresistance of Glioma by Repressing Semaphorin 5A

    International Nuclear Information System (INIS)

    Zheng, Rong; Yao, Qiwei; Ren, Chen; Liu, Ying; Yang, Hongli; Xie, Guozhu; Du, Shasha; Yang, Kaijun; Yuan, Yawei

    2016-01-01

    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), 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.

  5. Dosimetric comparison of the related parameters between simultaneous integrated boost intensity-modulated radiotherapy and sequential boost conformal radiotherapy for postoperative malignant glioma of the brain

    International Nuclear Information System (INIS)

    Shao Qian; Lu Jie; Li Jianbin; Sun Tao; Bai Tong; Liu Tonghai; Yin Yong

    2011-01-01

    Objective: To compare the dosimetric of different parameter of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with sequential boost conformal radiotherapy (SB-CRT) for postoperative malignant glioma of the brain. Methods: Ten patients with malignant glioma of brain were selected to study. Each patient was simulated all by CT and MRI, and the imagings of CT and MRI were all sent to Pinnacle 3 planning system. The fusion technology with MR-CT imaging was used on Pinnacle 3 planning system. The target volume was delineated and defined based on MRI. The postoperative residual lesion and resection cavity were defined as gross tumor volume (GTV) and expanded GTV some scope was defined as clinical target volume (CTV). The margins of GTV expanded 10 mm and 25 mm were defined as CTV1 and CTV2 respectively. CTV1 and CTV2 all enlarged 5 mm were defined as PTV1 and PTV2 respectively. The plans of simultaneous integrated boost intensity-modulated radiotherapy and sequential boost conformal radiotherapy were respectively designed for each patient using Pinnacle 3 planning system and the dosimetric of different parameter was compared. The prescribe dose of SIB-IMRT was PTV1: 62.5 Gy/25 f, PTV2: 50.0 Gy/25 f; and SB-CRT was PTV1: 66.0 Gy/33 f, PTV2: 50.0 Gy/25 f. The dosimetries of different parameters of SIB-IMRT and SB-CRT were compared by using Paired-Samples T Test. Results: The maximum and mean dose of PTV1, PTV2, and brainstem were of significant difference (P 0.05). Conclusion: The SIB-IMRT plan is better than the SB-CRT plan. The CI and HI of SIB-IMRT are superior to SB-CRT. At the same time, it can preserve the important organs such as brainstem and reduce the mean dose of whole brain. On the other hand it can shorten the total period of therapy time. (authors)

  6. Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway

    Directory of Open Access Journals (Sweden)

    Wang R

    2017-07-01

    Full Text Available Ronglin Wang,1,* Yuqian Li,1,* Gang Zhu,1,* Bo Tian,1 Wen Zeng,1 Yang Yang,2 Zhihong Li1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 2Department of Neurosurgery, The 451th hospital of PLA, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2 is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. Methods: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. Results: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251 compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan–Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt

  7. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model.

    Science.gov (United States)

    Huhndorf, Monika; Moussavi, Amir; Kramann, Nadine; Will, Olga; Hattermann, Kirsten; Stadelmann, Christine; Jansen, Olav; Boretius, Susann

    2016-01-01

    Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization. We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections. In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology. Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

  8. 2-Hydroxyglutarate Detection by Short Echo Time Magnetic Resonance Spectroscopy in Routine Imaging Study of Brain Glioma at 3.0 T.

    Science.gov (United States)

    Crisi, Girolamo; Filice, Silvano; Michiara, Maria; Crafa, Pellegrino; Lana, Silvia

    The objective of this study was to assess the effective performance of short echo time magnetic resonance spectroscopy (short TE MRS) for 2HG detection as biomarker of isocitrate dehydrogenase (IDH) status in all grade glioma (GL). A total of 82 GL patients were prospectively investigated by short TE MRS at 3.0 T as part of a multimodal magnetic resonance imaging study protocol. Spectral analysis was performed using linear combination model. Tumor specimens were diagnosed as IDH mutant or wild type according to the 2016 World Health Organization (WHO) classification of brain tumors. Spectra were analyzed for the presence of 2HG. The performance of short TE MRS was evaluated in terms of sensitivity, specificity, and positive and negative likelihood ratio on the overall sample and on GL WHO grades II and III and glioblastoma separately. The specificity and sensitivity estimated on the overall sample were 88% and 77%, respectively. In GL WHO grades II and III, 100% specificity and 75% sensitivity were estimated. We reiterate the feasibility to identify IDH status of brain GL using short TE MRS at 3.0 T. The method can correctly detect 2HG as expression of IDH mutation in WHO grades II and III GL with a 100% specificity but a 75% sensitivity. In the evaluation of glioblastoma, short TE MRS performs poorly having a 17% false positive rate.

  9. Paediatric and adult malignant glioma

    DEFF Research Database (Denmark)

    Jones, Chris; Perryman, Lara; Hargrave, Darren

    2012-01-01

    Gliomas in children differ from their adult counterparts by their distribution of histological grade, site of presentation and rate of malignant transformation. Although rare in the paediatric population, patients with high-grade gliomas have, for the most part, a comparably dismal clinical outcome...... to older patients with morphologically similar lesions. Molecular profiling data have begun to reveal the major genetic alterations underpinning these malignant tumours in children. Indeed, the accumulation of large datasets on adult high-grade glioma has revealed key biological differences between...... the adult and paediatric disease. Furthermore, subclassifications within the childhood age group can be made depending on age at diagnosis and tumour site. However, challenges remain on how to reconcile clinical data from adult patients to tailor novel treatment strategies specifically for paediatric...

  10. The Art of Intraoperative Glioma Identification

    Directory of Open Access Journals (Sweden)

    Zoe Z Zhang

    2015-07-01

    Full Text Available A major dilemma in brain tumor surgery is the identification of tumor boundaries to maximize tumor excision and minimize postoperative neurological damage. Gliomas, especially low-grade tumors, and normal brain have a similar color and texture which poses a challenge to the neurosurgeon. Advances in glioma resection techniques combine the experience of the neurosurgeon and various advanced technologies. Intraoperative methods to delineate gliomas from normal tissue consist of 1 image-based navigation, 2 intraoperative sampling, 3 electrophysiological monitoring, and 4 enhanced visual tumor demarcation. The advantages and disadvantages of each technique are discussed. A combination of these methods is becoming widely accepted in routine glioma surgery. Gross total resection in conjunction with radiation, chemotherapy, or immune/gene therapy may increase the rates of cure in this devastating disease.

  11. Vascular Gene Expression in Nonneoplastic and Malignant Brain

    Science.gov (United States)

    Madden, Stephen L.; Cook, Brian P.; Nacht, Mariana; Weber, William D.; Callahan, Michelle R.; Jiang, Yide; Dufault, Michael R.; Zhang, Xiaoming; Zhang, Wen; Walter-Yohrling, Jennifer; Rouleau, Cecile; Akmaev, Viatcheslav R.; Wang, Clarence J.; Cao, Xiaohong; St. Martin, Thia B.; Roberts, Bruce L.; Teicher, Beverly A.; Klinger, Katherine W.; Stan, Radu-Virgil; Lucey, Brenden; Carson-Walter, Eleanor B.; Laterra, John; Walter, Kevin A.

    2004-01-01

    Malignant gliomas are uniformly lethal tumors whose morbidity is mediated in large part by the angiogenic response of the brain to the invading tumor. This profound angiogenic response leads to aggressive tumor invasion and destruction of surrounding brain tissue as well as blood-brain barrier breakdown and life-threatening cerebral edema. To investigate the molecular mechanisms governing the proliferation of abnormal microvasculature in malignant brain tumor patients, we have undertaken a cell-specific transcriptome analysis from surgically harvested nonneoplastic and tumor-associated endothelial cells. SAGE-derived endothelial cell gene expression patterns from glioma and nonneoplastic brain tissue reveal distinct gene expression patterns and consistent up-regulation of certain glioma endothelial marker genes across patient samples. We define the G-protein-coupled receptor RDC1 as a tumor endothelial marker whose expression is distinctly induced in tumor endothelial cells of both brain and peripheral vasculature. Further, we demonstrate that the glioma-induced gene, PV1, shows expression both restricted to endothelial cells and coincident with endothelial cell tube formation. As PV1 provides a framework for endothelial cell caveolar diaphragms, this protein may serve to enhance glioma-induced disruption of the blood-brain barrier and transendothelial exchange. Additional characterization of this extensive brain endothelial cell gene expression database will provide unique molecular insights into vascular gene expression. PMID:15277233

  12. Quantitative proteomics and transcriptomics reveals metabolic differences in attracting and non-attracting human-in-mouse glioma stem cell xenografts and stromal cells

    Directory of Open Access Journals (Sweden)

    Norelle C. Wildburger

    2015-09-01

    Full Text Available Bone marrow-derived human mesenchymal stem cells (BM-hMSCs show promise as cell-based delivery vehicles for anti-glioma therapeutics, due to innate tropism for gliomas. However, in clinically relevant human-in-mouse glioma stem cell xenograft models, BM-hMSCs tropism is variable. We compared the proteomic profile of cancer and stromal cells in GSCXs that attract BM-hMSCs (“attractors” with those to do not (“non-attractors” to identify pathways that may modulate BM-hMSC homing, followed by targeted transcriptomics. The results provide the first link between fatty acid metabolism, glucose metabolism, ROS, and N-glycosylation patterns in attractors. Reciprocal expression of these pathways in the stromal cells suggests microenvironmental cross-talk.

  13. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

    Science.gov (United States)

    El Sayed, S M; Abou El-Magd, R M; Shishido, Y; Chung, S P; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

    2012-01-01

    Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

  14. Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma

    International Nuclear Information System (INIS)

    Evers, Patrick; Lee, Percy P; DeMarco, John; Agazaryan, Nzhde; Sayre, James W; Selch, Michael; Pajonk, Frank

    2010-01-01

    Glioblastoma is the most common brain tumor in adults. The mechanisms leading to glioblastoma are not well understood but animal studies support that inactivation of tumor suppressor genes in neural stem cells (NSC) is required and sufficient to induce glial cancers. This suggests that the NSC niches in the brain may harbor cancer stem cells (CSCs), Thus providing novel therapy targets. We hypothesize that higher radiation doses to these NSC niches improve patient survival by eradicating CSCs. 55 adult patients with Grade 3 or Grade 4 glial cancer treated with radiotherapy at UCLA between February of 2003 and May of 2009 were included in this retrospective study. Using radiation planning software and patient radiological records, the SVZ and SGL were reconstructed for each of these patients and dosimetry data for these structures was calculated. Using Kaplan-Meier analysis we show that patients whose bilateral subventricular zone (SVZ) received greater than the median SVZ dose (= 43 Gy) had a significant improvement in progression-free survival if compared to patients who received less than the median dose (15.0 vs 7.2 months PFS; P = 0.028). Furthermore, a mean dose >43 Gy to the bilateral SVZ yielded a hazard ratio of 0.73 (P = 0.019). Importantly, similarly analyzing total prescription dose failed to illustrate a statistically significant impact. Our study leads us to hypothesize that in glioma targeted radiotherapy of the stem cell niches in the adult brain could yield significant benefits over radiotherapy of the primary tumor mass alone and that damage caused by smaller fractions of radiation maybe less efficiently detected by the DNA repair mechanisms in CSCs

  15. Isocitrate dehydrogenase 1 and 2 genes mutations and MGMT methylation in gliomas

    Directory of Open Access Journals (Sweden)

    D. V. Tabakov

    2017-01-01

    Full Text Available Gliomas are the most common brain tumors. It is difficult to detect them at early stages of disease and there is a few available therapies providing significant improvement in survival. Mutations of isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2 play significant role in gliomogenesis, diagnostics and selection of patient therapy. We tested the distribution of IDH1 and IDH2 mutations in gliomas of different histological types and grades of malignancy by DNA melting analysis using our protocol with a sensitivity of 5 %. The results of this assay were confirmed by conventional Sanger sequencing. IDH1/2 mutations were detected in 74 % of lower grade gliomas (II and III, World Health Organization and in 14 % of glioblastomas (IV, World Health Organization. Mutation rate in gliomas with oligodendroglioma component were significantly higher then in other glioma types (р = 0.014. The IDH1 mutations was the most common (79 % of general mutation number. IDH1/2 mutations can induce aberrant gene methylation. Detection of methylation rate of the gene encoding for O6-methylguanine-DNA-methyltransferase (MGMT, predictive biomarker for treatment of gliomas with the alkylating agents, has demonstrated a partial association with IDH1/2 mutations. In 73 % of IDH1/2-mutant tumors MGMT promoter methylation were observed. At the same time IDH1/2 mutations were not revealed in 67 % tumors with MGMT promoter methylation. These results indicate existence of another mechanism of MGMT methylation in gliomas. Our data strong support for necessity of both markers testing when patient therapy is selected.

  16. Retrospective analysis of 104 histologically proven adult brainstem gliomas: clinical symptoms, therapeutic approaches and prognostic factors

    International Nuclear Information System (INIS)

    Reithmeier, Thomas; Kuzeawu, Aanyo; Hentschel, Bettina; Loeffler, Markus; Trippel, Michael; Nikkhah, Guido

    2014-01-01

    Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically proven brainstem gliomas. Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS ≤ 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age ≥ 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age ≥ 40 and higher tumor grade have a negative impact on overall survival

  17. Brain-to-brain hyperclassification reveals action-specific motor mapping of observed actions in humans.

    Science.gov (United States)

    Smirnov, Dmitry; Lachat, Fanny; Peltola, Tomi; Lahnakoski, Juha M; Koistinen, Olli-Pekka; Glerean, Enrico; Vehtari, Aki; Hari, Riitta; Sams, Mikko; Nummenmaa, Lauri

    2017-01-01

    Seeing an action may activate the corresponding action motor code in the observer. It remains unresolved whether seeing and performing an action activates similar action-specific motor codes in the observer and the actor. We used novel hyperclassification approach to reveal shared brain activation signatures of action execution and observation in interacting human subjects. In the first experiment, two "actors" performed four types of hand actions while their haemodynamic brain activations were measured with 3-T functional magnetic resonance imaging (fMRI). The actions were videotaped and shown to 15 "observers" during a second fMRI experiment. Eleven observers saw the videos of one actor, and the remaining four observers saw the videos of the other actor. In a control fMRI experiment, one of the actors performed actions with closed eyes, and five new observers viewed these actions. Bayesian canonical correlation analysis was applied to functionally realign observers' and actors' fMRI data. Hyperclassification of the seen actions was performed with Bayesian logistic regression trained on actors' data and tested with observers' data. Without the functional realignment, between-subjects accuracy was at chance level. With the realignment, the accuracy increased on average by 15 percentage points, exceeding both the chance level and the accuracy without functional realignment. The highest accuracies were observed in occipital, parietal and premotor cortices. Hyperclassification exceeded chance level also when the actor did not see her own actions. We conclude that the functional brain activation signatures underlying action execution and observation are partly shared, yet these activation signatures may be anatomically misaligned across individuals.

  18. Unusual combination of Cis platinum and radiotherapy followed by a three fractions per day irradiation in splitcourse: a phase I-II study in brain glioma patients

    International Nuclear Information System (INIS)

    Ben-Hassel, M.; Lesimple, T.; Gedouin, D.; Chenal, C.; Guegan, Y.; Darcel, F.

    1992-01-01

    An unusual protocol based on a preliminary clinical study on cylindromas metastasized to the lung was proposed to brain glioma patients: Day 2 100 mg/m 2 i.v. Cis platinum (Cis P II) followed at days 3 and 5 by 6 Gy irradiation (RT) in two fractions and three days. Five cycles were scheduled at 21 days interval. On disease progression a three fractions per day radiotherapy regimen (3 FRT) in split-course (two series of 22.50 Gy in 15 fractions and five days separated by a two weeks period of rest) was then delivered to the patients. All patients had a measurable mass on the CT scan. 19 were entered into the study: 13 as first line therapy (group A) and six for salvage treatment (group B). Tolerance was globally good. Eight patients were considered responders at the end of five cycles of Cis II-RT. They were all group A patients. Median symptom-free interval was six months for the whole population. Survival was twelve months. The 3 FRT was well tolerated but does not seem to have improved the therapeutic gain of the chemoradiotherapy combination. The present study concerns patients whose prognosis was poor on inclusion: Surgery unadvisable or unsatisfactory and diagnosis mainly based on biopsy only. The number and the duration of responses justify further study into Cis P II as first line therapy as either an effective cytotoxic drug or a potential radio enhancer. (orig.) [de

  19. Outcome of secondary high-grade glioma in children previously treated for a malignant condition: A study of the Canadian Pediatric Brain Tumour Consortium

    International Nuclear Information System (INIS)

    Carret, Anne-Sophie; Tabori, Uri; Crooks, Bruce; Hukin, Juliette; Odame, Isaac; Johnston, Donna L.; Keene, Daniel L.; Freeman, Carolyn; Bouffet, Eric

    2006-01-01

    Background and purpose: Reports of secondary high-grade glioma (HGG) in survivors of childhood cancer are scarce. The aim of this study was to review the pattern of diagnosis, the treatment, and outcome of secondary pediatric HGG. Patients and methods: We performed a multi-center retrospective study among the 17 paediatric institutions participating in the Canadian Pediatric Brain Tumour Consortium (CPBTC). Results: We report on 18 patients (14 males, 4 females) treated in childhood for a primary cancer, who subsequently developed a HGG as a second malignancy. All patients had previously received radiation therapy +/- chemotherapy for either acute lymphoblastic leukaemia (n = 9) or solid tumour (n = 9). All HGG occurred within the previous radiation fields. At the last follow-up, 17 patients have died and the median survival time is 9.75 months. Conclusion: Although aggressive treatment seems to provide sustained remissions in some patients, the optimal management is still to be defined. Further documentation of such cases is necessary in order to better understand the pathogenesis, the natural history and the prevention of these tumours

  20. Protein tyrosine phosphatases in glioma biology.

    NARCIS (Netherlands)

    Navis, A.C.; Eijnden, M. van den; Schepens, J.T.G.; Hooft van Huijsduijnen, R.; Wesseling, P.; Hendriks, W.J.A.J.

    2010-01-01

    Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic

  1. Kynurenic acid synthesis by human glioma

    DEFF Research Database (Denmark)

    Vezzani, A; Gramsbergen, J B; Versari, P

    1990-01-01

    Biopsy material from human gliomas obtained during neurosurgery was used to investigate whether pathological human brain tissue is capable of producing kynurenic acid (KYNA), a natural brain metabolite which can act as an antagonist at excitatory amino acid receptors. Upon in vitro exposure to 40...

  2. Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.

    Science.gov (United States)

    Meng, Qingying; Ying, Zhe; Noble, Emily; Zhao, Yuqi; Agrawal, Rahul; Mikhail, Andrew; Zhuang, Yumei; Tyagi, Ethika; Zhang, Qing; Lee, Jae-Hyung; Morselli, Marco; Orozco, Luz; Guo, Weilong; Kilts, Tina M; Zhu, Jun; Zhang, Bin; Pellegrini, Matteo; Xiao, Xinshu; Young, Marian F; Gomez-Pinilla, Fernando; Yang, Xia

    2016-05-01

    Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient-host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part 1: stimulatory effects on blood monocytes and monocyte-derived cells of the brain

    Directory of Open Access Journals (Sweden)

    Kushchayev SV

    2012-09-01

    Full Text Available Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,4,5 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USAObjectives: Immunotherapy with immunostimulants is an attractive therapy against gliomas. C-type lectin receptors specific for galactose/N-acetylgalactosamine (GCLR regulate cellular differentiation, recognition, and trafficking of monocyte-derived cells. A peptide mimetic of GCLR ligands (GCLRP was used to activate blood monocytes and populations of myeloid-derived cells against a murine glioblastoma.Methods: The ability of GCLRP to stimulate phagocytosis by human microglia and monocyte-derived cells of the brain (MDCB isolated from a human glioblastoma was initially assessed in vitro. Induction of activation markers on blood monocytes was assayed by flow cytometry after administration of GCLRP to naive mice. C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells and were randomized for tumor size by magnetic resonance imaging, which was also used to assess increase in tumor size. Brain tumor tissues were analyzed using flow cytometry, histology, and enzyme-linked immunosorbent assay with respect to tumor, peritumoral area, and contralateral hemisphere regions.Results: GCLRP exhibited strong stimulatory effect on MDCBs and blood monocytes in vitro and in vivo. GCLRP was associated with an increased percentage of precursors of dendritic cells in the blood (P = 0.003, which differentiated into patrolling macrophages in tumoral (P = 0.001 and peritumoral areas (P = 0.04, rather than into dendritic cells

  4. The musical brain: brain waves reveal the neurophysiological basis of musicality in human subjects.

    Science.gov (United States)

    Tervaniemi, M; Ilvonen, T; Karma, K; Alho, K; Näätänen, R

    1997-04-18

    To reveal neurophysiological prerequisites of musicality, auditory event-related potentials (ERPs) were recorded from musical and non-musical subjects, musicality being here defined as the ability to temporally structure auditory information. Instructed to read a book and to ignore sounds, subjects were presented with a repetitive sound pattern with occasional changes in its temporal structure. The mismatch negativity (MMN) component of ERPs, indexing the cortical preattentive detection of change in these stimulus patterns, was larger in amplitude in musical than non-musical subjects. This amplitude enhancement, indicating more accurate sensory memory function in musical subjects, suggests that even the cognitive component of musicality, traditionally regarded as depending on attention-related brain processes, in fact, is based on neural mechanisms present already at the preattentive level.

  5. Targetome Analysis Revealed Involvement of MiR-126 in Neurotrophin Signaling Pathway: A Possible Role in Prevention of Glioma Development.

    Science.gov (United States)

    Rouigari, Maedeh; Dehbashi, Moein; Ghaedi, Kamran; Pourhossein, Meraj

    2018-07-01

    For the first time, we used molecular signaling pathway enrichment analysis to determine possible involvement of miR-126 and IRS-1 in neurotrophin pathway. In this prospective study, Validated and predicted targets (targetome) of miR-126 were collected following searching miRtarbase (http://mirtarbase.mbc.nctu.edu.tw/) and miRWalk 2.0 databases, respectively. Then, approximate expression of miR-126 targeting in Glioma tissue was examined using UniGene database (http://www.ncbi. nlm.nih.gov/unigene). In silico molecular pathway enrichment analysis was carried out by DAVID 6.7 database (http://david. abcc.ncifcrf.gov/) to explore which signaling pathway is related to miR-126 targeting and how miR-126 attributes to glioma development. MiR-126 exerts a variety of functions in cancer pathogenesis via suppression of expression of target gene including PI3K, KRAS, EGFL7, IRS-1 and VEGF. Our bioinformatic studies implementing DAVID database, showed the involvement of miR-126 target genes in several signaling pathways including cancer pathogenesis, neurotrophin functions, Glioma formation, insulin function, focal adhesion production, chemokine synthesis and secretion and regulation of the actin cytoskeleton. Taken together, we concluded that miR-126 enhances the formation of glioma cancer stem cell probably via down regulation of IRS-1 in neurotrophin signaling pathway. Copyright© by Royan Institute. All rights reserved.

  6. A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain

    International Nuclear Information System (INIS)

    Halperin, Edward C.; Herndon, James; Schold, S. Clifford; Brown, Mark; Vick, Nicholas; Cairncross, J. Gregory; Macdonald, David R.; Gaspar, Laurie; Fischer, Barbara; Dropcho, Edward; Rosenfeld, Steven; Morowitz, Richard; Piepmeier, Joseph; Hait, William; Byrne, Thomas; Salter, Merle; Imperato, Joseph; Khandekar, Janardan; Paleologos, Nina; Burger, Peter; Bentel, Gunilla C.; Friedman, Allan

    1996-01-01

    Purpose: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were ≥ 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) ≥ 60%. Methods and Materials: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m 2 ) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m 2 ) given at 6-week intervals or 6-mercaptopurine (6-MP, 750 mg/m 2 IV daily for 3 days every 6 weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average age 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS ≥ 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age ≥ 45 years (b) KPS < 90%; (c) GBM/Gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). Conclusions: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a

  7. Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II. Treatment-related late toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Kortmann, R.D.; Timmermann, B.; Plasswilm, L.; Paulsen, F.; Jeremic, B.; Kay, S.; Bamberg, M. [Dept. of Radiooncology, Univ. of Tuebingen (Germany); Taylor, R.E. [Radiotherapy Dept., Cookridge Hospital, Leeds (United Kingdom); Scarzello, G. [Dept. of Radiotherapy, Padua General Hospital (Italy); Gnekow, A.K. [Children' s Hospital Augsburg (Germany); Dieckmann, K. [Dept. of Radiooncology, General Hospital Vienna (Austria)

    2003-09-01

    Material and Methods: Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms. Results: Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e.g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field - four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects. Conclusions: More studies and clear definitions of clinical endpoints

  8. Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II. Treatment-related late toxicity

    International Nuclear Information System (INIS)

    Kortmann, R.D.; Timmermann, B.; Plasswilm, L.; Paulsen, F.; Jeremic, B.; Kay, S.; Bamberg, M.; Taylor, R.E.; Scarzello, G.; Gnekow, A.K.; Dieckmann, K.

    2003-01-01

    Material and Methods: Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms. Results: Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e.g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field - four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects. Conclusions: More studies and clear definitions of clinical endpoints

  9. [Methods of statistical analysis in differential diagnostics of the degree of brain glioma anaplasia during preoperative stage].

    Science.gov (United States)

    Glavatskiĭ, A Ia; Guzhovskaia, N V; Lysenko, S N; Kulik, A V

    2005-12-01

    The authors proposed a possible preoperative diagnostics of the degree of supratentorial brain gliom anaplasia using statistical analysis methods. It relies on a complex examination of 934 patients with I-IV degree anaplasias, which had been treated in the Institute of Neurosurgery from 1990 to 2004. The use of statistical analysis methods for differential diagnostics of the degree of brain gliom anaplasia may optimize a diagnostic algorithm, increase reliability of obtained data and in some cases avoid carrying out irrational operative intrusions. Clinically important signs for the use of statistical analysis methods directed to preoperative diagnostics of brain gliom anaplasia have been defined

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

    Science.gov (United States)

    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.

  11. FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

    Science.gov (United States)

    Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

    2014-01-01

    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

  12. Integral dose delivered to normal brain with conventional intensity-modulated radiotherapy (IMRT) and helical tomotherapy IMRT during partial brain radiotherapy for high-grade gliomas with and without selective sparing of the hippocampus, limbic circuit and neural stem cell compartment

    International Nuclear Information System (INIS)

    Marsh, James C.; Ziel, Ellis G; Diaz, Aidnag Z; Turian, Julius V; Wendt, Julie A.; Gobole, Rohit

    2013-01-01

    We compared integral dose with uninvolved brain (ID brain ) during partial brain radiotherapy (PBRT) for high-grade glioma patients using helical tomotherapy (HT) and seven field traditional inverse-planned intensity-modulated radiotherapy (IMRT) with and without selective sparing (SPA) of contralateral hippocampus, neural stem cell compartment (NSC) and limbic circuit. We prepared four PBRT treatment plans for four patients with high-grade gliomas (60Gy in 30 fractions delivered to planning treatment volume (PTV60Gy)). For all plans, a structure denoted 'uninvolved brain' was created, which included all brain tissue not part of PTV or standard (STD) organs at risk (OAR). No dosimetric constraints were included for uninvolved brain. Selective SPA plans were prepared with IMRT and HT; contralateral hippocampus, NSC and limbic circuit were contoured; and dosimetric constraints were entered for these structures without compromising dose to PTV or STD OAR. We compared V100 and D95 for PTV46Gy and PTV60Gy, and ID brain for all plans. There were no significant differences in V100 and D95 for PTV46Gy and PTV60Gy. ID brain was lower in traditional IMRT versus HT plans for STD and SPA plans (mean ID brain 23.64Gy vs. 28Gy and 18.7Gy vs. 24.5Gy, respectively) and in SPA versus STD plans both with IMRT and HT (18.7Gy vs. 23.64Gy and 24.5Gy vs. 28Gy, respectively). n the setting of PBRT for high-grade gliomas, IMRT reduces ID brain compared with HT with or without selective SPA of contralateral hippocampus, limbic circuit and NSC, and the use of selective SPA reduces ID brain compared with STD PBRT delivered with either traditional IMRT or HT.

  13. Study Reveals Brain Biology behind Self-Control

    Science.gov (United States)

    Sparks, Sarah D.

    2011-01-01

    A new neuroscience twist on a classic psychology study offers some clues to what makes one student able to buckle down for hours of homework before a test while his classmates party. The study published in the September 2011 edition of "Proceedings of the National Academy of Science," suggests environmental cues may "hijack" the brain's mechanisms…

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

    Science.gov (United States)

    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.

  15. Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

    Directory of Open Access Journals (Sweden)

    Kim Clarke

    2015-07-01

    Full Text Available Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

  16. Epidemiology of glioma

    DEFF Research Database (Denmark)

    Rasmussen, Birthe Krogh; Hansen, Steinbjorn; Laursen, Rene J.

    2017-01-01

    in 15%. The overall male:female ratio was 3:2 and the mean age at onset was 60 years. Data for WHO grade I, II, III and IV glioma showed several important differences regarding age and sex distribution and symptomatology at presentation. The mean age increased with the grade of glioma and males...... duration, and headache rates for glioma grade I-IV showed decreasing survival with increasing grade. Glioma grade I-IV showed...

  17. Direct measurement of the signal intensity of diffusion-weighted magnetic resonance imaging for preoperative grading and treatment guidance for brain gliomas

    Directory of Open Access Journals (Sweden)

    Chih-Chun Wu

    2012-11-01

    Conclusion: The proposed method – direct measuring of tumor signal intensity of DWI on PACS monitors – is feasible for grading gliomas in clinical neuro-oncology imaging services and has a high level of reliability and reproducibility.

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

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Bin [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Hu, Zhiqiang, E-mail: zhiqhutg@126.com [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Huang, Hui; Zhu, Guangtong; Xiao, Zhiyong [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Wan, Weiqing; Zhang, Peng; Jia, Wang; Zhang, Liwei [Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050 (China)

    2014-11-07

    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. 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.

  19. [Multidisciplinar approach to the management of gliomas].

    Science.gov (United States)

    Moura, Bianca; Migliorini, Denis; Bourhis, Jean; Daniel, Roy; Levivier, Marc; Hottinger, Andreas F

    2016-04-27

    Gliomas represent two thirds of all primary brain tumors. Their prognosis depends directly upon their level of differentiation. On MRI, tumoral aggressivity is highlighted by contrast uptake and the infiltrative nature of the lesion. Clinical suspicion must however be confirmed by histology and molecular markers become essential to refine the diagnosis and tailor the treatment. Isocytrate dehydrogenase (IDH) mutations, codeletion of 1p and 19q and the presence of methylation of the MGMT promoter identify a subgroup of gliomas with better prognosis and may help predict response to treatment. Management of patients with primary brain tumors should always be defined in multidisciplinar tumor boards involving neurosurgeons, oncologists, radiation oncologists, neuropathologists and neuroradiologists.

  20. PET imaging reveals brain functional changes in internet gaming disorder

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Mei; Zhang, Ying; Du, Fenglei; Hou, Haifeng; Chao, Fangfang; Zhang, Hong [The Second Hospital of Zhejiang University School of Medicine, Department of Nuclear Medicine, Hangzhou, Zhejiang (China); Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou (China); Chen, Qiaozhen [The Second Hospital of Zhejiang University School of Medicine, Department of Nuclear Medicine, Hangzhou, Zhejiang (China); The Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Psychiatry, Hangzhou (China)

    2014-07-15

    Internet gaming disorder is an increasing problem worldwide, resulting in critical academic, social, and occupational impairment. However, the neurobiological mechanism of internet gaming disorder remains unknown. The aim of this study is to assess brain dopamine D{sub 2} (D{sub 2})/Serotonin 2A (5-HT{sub 2A}) receptor function and glucose metabolism in the same subjects by positron emission tomography (PET) imaging approach, and investigate whether the correlation exists between D{sub 2} receptor and glucose metabolism. Twelve drug-naive adult males who met criteria for internet gaming disorder and 14 matched controls were studied with PET and {sup 11}C-N-methylspiperone ({sup 11}C-NMSP) to assess the availability of D{sub 2}/5-HT{sub 2A} receptors and with {sup 18}F-fluoro-D-glucose ({sup 18}F-FDG) to assess regional brain glucose metabolism, a marker of brain function. {sup 11}C-NMSP and {sup 18}F-FDG PET imaging data were acquired in the same individuals under both resting and internet gaming task states. In internet gaming disorder subjects, a significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D{sub 2} receptors was observed in the striatum, and was correlated to years of overuse. A low level of D{sub 2} receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex. For the first time, we report the evidence that D{sub 2} receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D{sub 2}/5-HT{sub 2A} receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects. (orig.)

  1. PET imaging reveals brain functional changes in internet gaming disorder

    International Nuclear Information System (INIS)

    Tian, Mei; Zhang, Ying; Du, Fenglei; Hou, Haifeng; Chao, Fangfang; Zhang, Hong; Chen, Qiaozhen

    2014-01-01

    Internet gaming disorder is an increasing problem worldwide, resulting in critical academic, social, and occupational impairment. However, the neurobiological mechanism of internet gaming disorder remains unknown. The aim of this study is to assess brain dopamine D 2 (D 2 )/Serotonin 2A (5-HT 2A ) receptor function and glucose metabolism in the same subjects by positron emission tomography (PET) imaging approach, and investigate whether the correlation exists between D 2 receptor and glucose metabolism. Twelve drug-naive adult males who met criteria for internet gaming disorder and 14 matched controls were studied with PET and 11 C-N-methylspiperone ( 11 C-NMSP) to assess the availability of D 2 /5-HT 2A receptors and with 18 F-fluoro-D-glucose ( 18 F-FDG) to assess regional brain glucose metabolism, a marker of brain function. 11 C-NMSP and 18 F-FDG PET imaging data were acquired in the same individuals under both resting and internet gaming task states. In internet gaming disorder subjects, a significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D 2 receptors was observed in the striatum, and was correlated to years of overuse. A low level of D 2 receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex. For the first time, we report the evidence that D 2 receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D 2 /5-HT 2A receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects. (orig.)

  2. Effect of contrast leakage on the detection of abnormal brain tumor vasculature in high-grade glioma.

    Science.gov (United States)

    LaViolette, Peter S; Daun, Mitchell K; Paulson, Eric S; Schmainda, Kathleen M

    2014-02-01

    Abnormal brain tumor vasculature has recently been highlighted by a dynamic susceptibility contrast (DSC) MRI processing technique. The technique uses independent component analysis (ICA) to separate arterial and venous perfusion. The overlap of the two, i.e. arterio-venous overlap or AVOL, preferentially occurs in brain tumors and predicts response to anti-angiogenic therapy. The effects of contrast agent leakage on the AVOL biomarker have yet to be established. DSC was acquired during two separate contrast boluses in ten patients undergoing clinical imaging for brain tumor diagnosis. Three components were modeled with ICA, which included the arterial and venous components. The percentage of each component as well as a third component were determined within contrast enhancing tumor and compared. AVOL within enhancing tumor was also compared between doses. The percentage of enhancing tumor classified as not arterial or venous and instead into a third component with contrast agent leakage apparent in the time-series was significantly greater for the first contrast dose compared to the second. The amount of AVOL detected within enhancing tumor was also significantly greater with the second dose compared to the first. Contrast leakage results in large signal variance classified as a separate component by the ICA algorithm. The use of a second dose mitigates the effect and allows measurement of AVOL within enhancement.

  3. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Gregory J. Baker

    2014-07-01

    Full Text Available As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM, and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.

  4. Involvement of the kynurenine pathway in human glioma pathophysiology.

    Directory of Open Access Journals (Sweden)

    Seray Adams

    Full Text Available The kynurenine pathway (KP is the principal route of L-tryptophan (TRP catabolism leading to the production of kynurenine (KYN, the neuroprotectants, kynurenic acid (KYNA and picolinic acid (PIC, the excitotoxin, quinolinic acid (QUIN and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+. The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1, indoleamine 2,3-dioxygenase-2 (IDO-2 and tryptophan 2,3-dioxygenase (TDO-2 initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1 cultured human glioma cells and 2 plasma from patients with glioblastoma (GBM. Our data revealed that interferon-gamma (IFN-γ stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU, kynurenine hydroxylase (KMO and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD and kynurenine aminotransferase-I (KAT-I expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18 compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+, which is necessary for energy production and DNA repair.

  5. Histogram analysis reveals a better delineation of tumor volume from background in 18F-FET PET compared to CBV maps in a hybrid PET–MR studie in gliomas

    International Nuclear Information System (INIS)

    Filss, Christian P.; Stoffels, Gabriele; Galldiks, Norbert; Sabel, Michael; Wittsack, Hans J.; Coenen, Heinz H.; Shah, Nadim J.; Herzog, Hans

    2014-01-01

    Anatomical imaging with magnetic resonance imaging (MRI) is currently the method of first choice for diagnostic investigation of glial tumors. However, different MR sequences may over- or underestimate tumor size and thus it may not be possible to delineate tumor from adjacent brain. In order to compensate this confinement additonal MR sequences like perfusion weighted MRI (PWI) with regional cerebral blood volume (rCBV) or positron emission tomography (PET) with aminoacids are used to gain further information. Recent studies suggest that both of theses image modalities provide similar diagnostic information. For comparison tumor to brain ratios (TBR) with mean and maximum values are frequently used but results from different studies can often not be checked against each other. Furthermore, especially the maximum TBR in rCBV is at risk to be falsified by artifacts (e.g. blood vessels). These confinements are reduced by the use of histograms since all information of the VOIs are equally displayed. In this study we measured and compared the intersection of tumor and reference tissue histograms in 18 F-FET PET and rCBV maps in glioma patients. Methods: Twenty-seven glioma patients with contrast enhancing lesion on T1-weighted MR images were investigated using static 18 F-FET PET and rCBV in MRI using a PET–MR hybrid scanner. In all patients diagnosis was confirmed histologically (7 grade II gliomas, 6 grade III gliomas and 14 grade IV gliomas). We generated a set of tumor and reference tissue Volumes-of-Interest (VOIs) based on T1 weighted images in MRI with the tumor VOI defined by contrast enhancement and transferred these VOIs to the corresponding 18 F-FET PET scans and rCBV maps. From these VOIs we generated tumor and reference tissue histograms with a unity of one for each curve integral and measured the proportion of the area under the tumor curve that falls into the reference curve for 18 F-FET PET and rCBV maps for each patient. Results: The mean proportion

  6. Optic glioma

    Science.gov (United States)

    ... loss of peripheral vision and eventually leads to blindness The child may show symptoms of diencephalic syndrome, which includes: Daytime sleeping Decreased memory and brain function Headaches Delayed growth Loss of ...

  7. Loss of heterozygosity of TRIM3 in malignant gliomas

    International Nuclear Information System (INIS)

    Boulay, Jean-Louis; Stiefel, Urs; Taylor, Elisabeth; Dolder, Béatrice; Merlo, Adrian; Hirth, Frank

    2009-01-01

    Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ... Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene

  8. Analysis of DTI-Derived Tensor Metrics in Differential Diagnosis between Low-grade and High-grade Gliomas.

    Science.gov (United States)

    Jiang, Liang; Xiao, Chao-Yong; Xu, Quan; Sun, Jun; Chen, Huiyou; Chen, Yu-Chen; Yin, Xindao

    2017-01-01

    Purpose: It is critical and difficult to accurately discriminate between high- and low-grade gliomas preoperatively. This study aimed to ascertain the role of several scalar measures in distinguishing high-grade from low-grade gliomas, especially the axial diffusivity (AD), radial diffusivity (RD), planar tensor (Cp), spherical tensor (Cs), and linear tensor (Cl) derived from diffusion tensor imaging (DTI). Materials and Methods: Fifty-three patients with pathologically confirmed brain gliomas (21 low-grade and 32 high-grade) were included. Contrast-enhanced T1-weighted images and DTI were performed in all patients. The AD, RD, Cp, Cs, and Cl values in the tumor zone, peritumoral edema zone, white matter (WM) adjacent to edema and contralateral normal-appearing white matter (NAWM) were calculated. The DTI parameters and tumor grades were statistically analyzed, and receiver operating characteristic (ROC) curve analysis was also performed. Results: The DTI metrics in the affected hemisphere showed significant differences from those in the NAWM, except for the AD values in the tumor zone and the RD values in WM adjacent to edema in the low-grade groups, as well as the Cp values in WM adjacent to edema in the high-grade groups. AD in the tumor zone as well as Cs and Cl in WM adjacent to edema revealed significant differences between the low- and high-grade gliomas. The areas under the curve (Az) of all three metrics were greater than 0.5 in distinguishing low-grade from high-grade gliomas by ROC curve analysis, and the best DTI metric was Cs in WM adjacent to edema (Az: 0.692). Conclusion: AD in the tumor zone as well as Cs and Cl in WM adjacent to edema will provide additional information to better classify gliomas and can be used as non-invasive reliable biomarkers in glioma grading.

  9. RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop

    Science.gov (United States)

    Giladi, Nis David; Ziv-Av, Amotz; Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Ben-Asher, Hiba Waldman; deCarvalho, Ana; Mikkelsen, Tom; Poisson, Laila; Brodie, Chaya

    2015-01-01

    Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM. PMID:26267319

  10. The effects of gene polymorphisms on glioma prognosis.

    Science.gov (United States)

    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.

  11. An Updated and Comprehensive Meta-Analysis of Association Between Seven Hot Loci Polymorphisms from Eight GWAS and Glioma Risk.

    Science.gov (United States)

    Wu, Qiang; Peng, Yanyan; Zhao, Xiaotao

    2016-09-01

    Eight genome-wide association studies (GWASs) found that seven loci (rs2736100, rs4295627, rs4977756, rs498872, rs11979158, rs2252586, rs6010620) polymorphisms could elevate the risk of glioma, one of the most common types of primary brain cancer in adults. However, the replication studies about these seven loci obtained inconsistent results. In order to derive a more accurate estimation about the relationship between the selected single-nucleotide polymorphism (SNP) and susceptibility to glioma, we conducted a meta-analysis containing all eligible published case control studies to evaluate the association. An overall literature search was conducted using the database of PubMed, Science Direct, China national knowledge infrastructure (CNKI), and Embase. Seventeen articles with 25 studies were included in the meta-analysis. Glioma risk (odds ratio, OR; 95 % confidential interval, 95 %CI) was estimated with the random-effect model or the fixed-effects model. STATA 12.0 was applied to analyze all statistical data. Results showed that seven hot loci were all associated with increased risk of glioma (rs2736100, OR = 1.28, 95 %CI = 1.23-1.32; rs4295627, OR = 1.34, 95 %CI = 1.21-1.47; rs4977756, OR = 1.24, 95 %CI = 1.20-1.28; rs498872, OR = 1.24, 95 %CI = 1.15-1.33; rs6010620, OR = 1.29, 95 %CI = 1.24-1.35; rs11979158: OR = 1.18, 95 %CI = 1.10-1.25; rs2252586: OR = 1.18, 95 %CI = 1.10-1.25). Additionally, subgroup analysis by stages of glioma found that variation of rs11979158 had stronger relationship with high-grade (OR = 1.32, 95 %CI = 1.19-1.45) than low-grade glioma (OR = 1.12, 95 % CI = 1.03-1.21). Similarly, stratified analysis of rs2252586 by stages revealed the similar trend, with OR of 1.26 (95 %CI = 1.17-1.35) in high-grade glioma and OR of 1.15 (95 %CI = 1.08-1.22) in low-grade glioma. In summary, the present study showed that mutations of the seven loci could elevate

  12. Tumor Metabolism of Malignant Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang, E-mail: deliang.guo@osumc.edu [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center & Arthur G James Cancer Hospital, Columbus, OH 43012 (United States)

    2013-11-08

    Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

  13. Tumor Metabolism of Malignant Gliomas

    International Nuclear Information System (INIS)

    Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang

    2013-01-01

    Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation

  14. Radiosurgery in gliomas (middle-line tumors)

    International Nuclear Information System (INIS)

    Betti, O.O.; Rosler, R.

    1989-01-01

    The clinical experience is presented obtained from treatment with high-energy linac radiosurgery of 22 patients with stereotactically biopsed gliomas located in middle-line, from thalamus to brain stem and from infundibulum to pineo-tectal regions, during the period 1982-1987. (H.W.). 10 refs

  15. Neuromyelitis Optica Lesion Mimicking Brainstem Glioma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-12-01

    Full Text Available A 12-year-old girl who presented with weakness of the left extremities and right sided sixth cranial nerve palsy had neuromyelitis optica (NMO mistaken for brainstem glioma on MRI, in a report from Brain Research Institute, Yonsei University College of Medicine,Seoul, Republic of KoreaNeuromyelitis Optica, Optic-Spinal Syndrome, Spectroscopy.

  16. Hormone replacement therapy and risk of glioma

    DEFF Research Database (Denmark)

    Andersen, Lene; Friis, Søren; Hallas, Jesper

    2013-01-01

    Aim: Several studies indicate that use of hormone replacement therapy (HRT) is associated with an increased risk of intracranial meningioma, while associations between HRT use and risk of other brain tumors have been less explored. We investigated the influence of HRT use on the risk of glioma...

  17. [Guidelines for the radiotherapy of gliomas].

    Science.gov (United States)

    Feuvret, L; Antoni, D; Biau, J; Truc, G; Noël, G; Mazeron, J-J

    2016-09-01

    Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  18. Contemporary management of high-grade gliomas.

    Science.gov (United States)

    Sim, Hao-Wen; Morgan, Erin R; Mason, Warren P

    2018-01-01

    High-grade gliomas, including glioblastoma, are the most common malignant brain tumors in adults. Despite intensive efforts to develop new therapies for these diseases, treatment options remain limited and prognosis is poor. Recently, there have been important advances in our understanding of the molecular basis of glioma, leading to refinements in our diagnostic and management approach. There is new evidence to guide the treatment of elderly patients. A multitude of new agents have been investigated, including targeted therapies, immunotherapeutics and tumor-treating fields. This review summarizes the key findings from this research, and presents a perspective on future opportunities to advance the field.

  19. Molecular and Genetic Determinants of Glioma Cell Invasion

    Directory of Open Access Journals (Sweden)

    Kenta Masui

    2017-12-01

    Full Text Available A diffusely invasive nature is a major obstacle in treating a malignant brain tumor, “diffuse glioma”, which prevents neurooncologists from surgically removing the tumor cells even in combination with chemotherapy and radiation. Recently updated classification of diffuse gliomas based on distinct genetic and epigenetic features has culminated in a multilayered diagnostic approach to combine histologic phenotypes and molecular genotypes in an integrated diagnosis. However, it is still a work in progress to decipher how the genetic aberrations contribute to the aggressive nature of gliomas including their highly invasive capacity. Here we depict a set of recent discoveries involving molecular genetic determinants of the infiltrating nature of glioma cells, especially focusing on genetic mutations in receptor tyrosine kinase pathways and metabolic reprogramming downstream of common cancer mutations. The specific biology of glioma cell invasion provides an opportunity to explore the genotype-phenotype correlation in cancer and develop novel glioma-specific therapeutic strategies for this devastating disease.

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

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang, E-mail: md_wzx7189@163.com

    2016-03-18

    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 of 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.

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

    Directory of Open Access Journals (Sweden)

    G. Song

    Full Text Available 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.

  2. Educational games for brain health: revealing their unexplored potential through a neurocognitive approach

    Directory of Open Access Journals (Sweden)

    Patrick eFissler

    2015-07-01

    Full Text Available Educational games link the motivational nature of games with learning of knowledge and skills. Here, we go beyond effects on these learning outcomes. We review two lines of evidence which indicate the currently unexplored potential of educational games to promote brain health: First, gaming with specific neurocognitive demands (e.g., executive control, and second, educational learning experiences (e.g., studying foreign languages improve brain health markers. These markers include cognitive ability, brain function, and brain structure. As educational games allow the combination of specific neurocognitive demands with educational learning experiences, they seem to be optimally suited for promoting brain health. We propose a neurocognitive approach to reveal this unexplored potential of educational games in future research.

  3. Deep brain stimulation reveals emotional impact processing in ventromedial prefrontal cortex

    DEFF Research Database (Denmark)

    Gjedde, Albert; Geday, Jacob

    2009-01-01

    We tested the hypothesis that modulation of monoaminergic tone with deep-brain stimulation (DBS) of subthalamic nucleus would reveal a site of reactivity in the ventromedial prefrontal cortex that we previously identified by modulating serotonergic and noradrenergic mechanisms by blocking serotonin......-noradrenaline reuptake sites. We tested the hypothesis in patients with Parkinson's disease in whom we had measured the changes of blood flow everywhere in the brain associated with the deep brain stimulation of the subthalamic nucleus. We determined the emotional reactivity of the patients as the average impact...

  4. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials

    Science.gov (United States)

    Chamberlain, Marc; Schiff, David; Reijneveld, Jaap C.; Armstrong, Terri S.; Ruda, Roberta; Wen, Patrick Y.; Weller, Michael; Koekkoek, Johan A. F.; Mittal, Sandeep; Arakawa, Yoshiki; Choucair, Ali; Gonzalez-Martinez, Jorge; MacDonald, David R.; Nishikawa, Ryo; Shah, Aashit; Vecht, Charles J.; Warren, Paula; van den Bent, Martin J.; DeAngelis, Lisa M.

    2017-01-01

    Patients with low-grade glioma frequently have brain tumor–related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed. PMID:27651472

  5. Amplitude-modulated stimuli reveal auditory-visual interactions in brain activity and brain connectivity.

    Science.gov (United States)

    Laing, Mark; Rees, Adrian; Vuong, Quoc C

    2015-01-01

    The temporal congruence between auditory and visual signals coming from the same source can be a powerful means by which the brain integrates information from different senses. To investigate how the brain uses temporal information to integrate auditory and visual information from continuous yet unfamiliar stimuli, we used amplitude-modulated tones and size-modulated shapes with which we could manipulate the temporal congruence between the sensory signals. These signals were independently modulated at a slow or a fast rate. Participants were presented with auditory-only, visual-only, or auditory-visual (AV) trials in the fMRI scanner. On AV trials, the auditory and visual signal could have the same (AV congruent) or different modulation rates (AV incongruent). Using psychophysiological interaction analyses, we found that auditory regions showed increased functional connectivity predominantly with frontal regions for AV incongruent relative to AV congruent stimuli. We further found that superior temporal regions, shown previously to integrate auditory and visual signals, showed increased connectivity with frontal and parietal regions for the same contrast. Our findings provide evidence that both activity in a network of brain regions and their connectivity are important for AV integration, and help to bridge the gap between transient and familiar AV stimuli used in previous studies.

  6. Amplitude-modulated stimuli reveal auditory-visual interactions in brain activity and brain connectivity

    Directory of Open Access Journals (Sweden)

    Mark eLaing

    2015-10-01

    Full Text Available The temporal congruence between auditory and visual signals coming from the same source can be a powerful means by which the brain integrates information from different senses. To investigate how the brain uses temporal information to integrate auditory and visual information from continuous yet unfamiliar stimuli, we use amplitude-modulated tones and size-modulated shapes with which we could manipulate the temporal congruence between the sensory signals. These signals were independently modulated at a slow or a fast rate. Participants were presented with auditory-only, visual-only or auditory-visual (AV trials in the scanner. On AV trials, the auditory and visual signal could have the same (AV congruent or different modulation rates (AV incongruent. Using psychophysiological interaction analyses, we found that auditory regions showed increased functional connectivity predominantly with frontal regions for AV incongruent relative to AV congruent stimuli. We further found that superior temporal regions, shown previously to integrate auditory and visual signals, showed increased connectivity with frontal and parietal regions for the same contrast. Our findings provide evidence that both activity in a network of brain regions and their connectivity are important for auditory-visual integration, and help to bridge the gap between transient and familiar AV stimuli used in previous studies.

  7. Beyond Alkylating Agents for Gliomas: Quo Vadimus?

    Science.gov (United States)

    Puduvalli, Vinay K; Chaudhary, Rekha; McClugage, Samuel G; Markert, James

    2017-01-01

    Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier. Novel therapies that circumvent such limitations have been the focus of intense study and include approaches such as immunotherapy, targeting of signaling hubs and metabolic pathways, and use of biologic agents. Immunotherapeutic approaches including tumor-targeted vaccines, immune checkpoint blockade, antibody-drug conjugates, and chimeric antigen receptor-expressing cell therapies are in various stages of clinical trials. Similarly, identification of key metabolic pathways or converging hubs of signaling pathways that are tumor specific have yielded novel targets for therapy of gliomas. In addition, the failure of conventional therapies against gliomas has led to a growing interest among patients in the use of alternative therapies, which in turn has necessitated developing evidence-based approaches to the application of such therapies in clinical studies. The development of these novel approaches bears potential for providing breakthroughs in treatment of more meaningful and improved outcomes for patients with gliomas.

  8. Molecular Therapeutic Targets for Glioma Angiogenesis

    Directory of Open Access Journals (Sweden)

    Shingo Takano

    2010-01-01

    Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

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

    Directory of Open Access Journals (Sweden)

    Saghir Akhtar

    2018-04-01

    Full Text Available 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.

  10. Altered brain structural networks in attention deficit/hyperactivity disorder children revealed by cortical thickness.

    Science.gov (United States)

    Liu, Tian; Chen, Yanni; Li, Chenxi; Li, Youjun; Wang, Jue

    2017-07-04

    This study investigated the cortical thickness and topological features of human brain anatomical networks related to attention deficit/hyperactivity disorder. Data were collected from 40 attention deficit/hyperactivity disorder children and 40 normal control children. Interregional correlation matrices were established by calculating the correlations of cortical thickness between all pairs of cortical regions (68 regions) of the whole brain. Further thresholds were applied to create binary matrices to construct a series of undirected and unweighted graphs, and global, local, and nodal efficiencies were computed as a function of the network cost. These experimental results revealed abnormal cortical thickness and correlations in attention deficit/hyperactivity disorder, and showed that the brain structural networks of attention deficit/hyperactivity disorder subjects had inefficient small-world topological features. Furthermore, their topological properties were altered abnormally. In particular, decreased global efficiency combined with increased local efficiency in attention deficit/hyperactivity disorder children led to a disorder-related shift of the network topological structure toward regular networks. In addition, nodal efficiency, cortical thickness, and correlation analyses revealed that several brain regions were altered in attention deficit/hyperactivity disorder patients. These findings are in accordance with a hypothesis of dysfunctional integration and segregation of the brain in patients with attention deficit/hyperactivity disorder and provide further evidence of brain dysfunction in attention deficit/hyperactivity disorder patients by observing cortical thickness on magnetic resonance imaging.

  11. Lifespan Development of the Human Brain Revealed by Large-Scale Network Eigen-Entropy

    Directory of Open Access Journals (Sweden)

    Yiming Fan

    2017-09-01

    Full Text Available Imaging connectomics based on graph theory has become an effective and unique methodological framework for studying functional connectivity patterns of the developing and aging brain. Normal brain development is characterized by continuous and significant network evolution through infancy, childhood, and adolescence, following specific maturational patterns. Normal aging is related to some resting state brain networks disruption, which are associated with certain cognitive decline. It is a big challenge to design an integral metric to track connectome evolution patterns across the lifespan, which is to understand the principles of network organization in the human brain. In this study, we first defined a brain network eigen-entropy (NEE based on the energy probability (EP of each brain node. Next, we used the NEE to characterize the lifespan orderness trajectory of the whole-brain functional connectivity of 173 healthy individuals ranging in age from 7 to 85 years. The results revealed that during the lifespan, the whole-brain NEE exhibited a significant non-linear decrease and that the EP distribution shifted from concentration to wide dispersion, implying orderness enhancement of functional connectome over age. Furthermore, brain regions with significant EP changes from the flourishing (7–20 years to the youth period (23–38 years were mainly located in the right prefrontal cortex and basal ganglia, and were involved in emotion regulation and executive function in coordination with the action of the sensory system, implying that self-awareness and voluntary control performance significantly changed during neurodevelopment. However, the changes from the youth period to middle age (40–59 years were located in the mesial temporal lobe and caudate, which are associated with long-term memory, implying that the memory of the human brain begins to decline with age during this period. Overall, the findings suggested that the human connectome

  12. Hemispheric Asymmetry of Human Brain Anatomical Network Revealed by Diffusion Tensor Tractography

    Directory of Open Access Journals (Sweden)

    Ni Shu

    2015-01-01

    Full Text Available The topological architecture of the cerebral anatomical network reflects the structural organization of the human brain. Recently, topological measures based on graph theory have provided new approaches for quantifying large-scale anatomical networks. However, few studies have investigated the hemispheric asymmetries of the human brain from the perspective of the network model, and little is known about the asymmetries of the connection patterns of brain regions, which may reflect the functional integration and interaction between different regions. Here, we utilized diffusion tensor imaging to construct binary anatomical networks for 72 right-handed healthy adult subjects. We established the existence of structural connections between any pair of the 90 cortical and subcortical regions using deterministic tractography. To investigate the hemispheric asymmetries of the brain, statistical analyses were performed to reveal the brain regions with significant differences between bilateral topological properties, such as degree of connectivity, characteristic path length, and betweenness centrality. Furthermore, local structural connections were also investigated to examine the local asymmetries of some specific white matter tracts. From the perspective of both the global and local connection patterns, we identified the brain regions with hemispheric asymmetries. Combined with the previous studies, we suggested that the topological asymmetries in the anatomical network may reflect the functional lateralization of the human brain.

  13. The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression

    Directory of Open Access Journals (Sweden)

    Desgagnés Julie

    2006-03-01

    Full Text Available Abstract Background Chlorogenic acid (CHL, the most potent functional inhibitor of the microsomal glucose-6-phosphate translocase (G6PT, is thought to possess cancer chemopreventive properties. It is not known, however, whether any G6PT functions are involved in tumorigenesis. We investigated the effects of CHL and the potential role of G6PT in regulating the invasive phenotype of brain tumor-derived glioma cells. Results RT-PCR was used to show that, among the adult and pediatric brain tumor-derived cells tested, U-87 glioma cells expressed the highest levels of G6PT mRNA. U-87 cells lacked the microsomal catalytic subunit glucose-6-phosphatase (G6Pase-α but expressed G6Pase-β which, when coupled to G6PT, allows G6P hydrolysis into glucose to occur in non-glyconeogenic tissues such as brain. CHL inhibited U-87 cell migration and matrix metalloproteinase (MMP-2 secretion, two prerequisites for tumor cell invasion. Moreover, CHL also inhibited cell migration induced by sphingosine-1-phosphate (S1P, a potent mitogen for glioblastoma multiform cells, as well as the rapid, S1P-induced extracellular signal-regulated protein kinase phosphorylation potentially mediated through intracellular calcium mobilization, suggesting that G6PT may also perform crucial functions in regulating intracellular signalling. Overexpression of the recombinant G6PT protein induced U-87 glioma cell migration that was, in turn, antagonized by CHL. MMP-2 secretion was also inhibited by the adenosine triphosphate (ATP-depleting agents 2-deoxyglucose and 5-thioglucose, a mechanism that may inhibit ATP-mediated calcium sequestration by G6PT. Conclusion We illustrate a new G6PT function in glioma cells that could regulate the intracellular signalling and invasive phenotype of brain tumor cells, and that can be targeted by the anticancer properties of CHL.

  14. MEG network differences between low- and high-grade glioma related to epilepsy and cognition.

    Directory of Open Access Journals (Sweden)

    Edwin van Dellen

    Full Text Available OBJECTIVE: To reveal possible differences in whole brain topology of epileptic glioma patients, being low-grade glioma (LGG and high-grade glioma (HGG patients. We studied functional networks in these patients and compared them to those in epilepsy patients with non-glial lesions (NGL and healthy controls. Finally, we related network characteristics to seizure frequency and cognitive performance within patient groups. METHODS: We constructed functional networks from pre-surgical resting-state magnetoencephalography (MEG recordings of 13 LGG patients, 12 HGG patients, 10 NGL patients, and 36 healthy controls. Normalized clustering coefficient and average shortest path length as well as modular structure and network synchronizability were computed for each group. Cognitive performance was assessed in a subset of 11 LGG and 10 HGG patients. RESULTS: LGG patients showed decreased network synchronizability and decreased global integration compared to healthy controls in the theta frequency range (4-8 Hz, similar to NGL patients. HGG patients' networks did not significantly differ from those in controls. Network characteristics correlated with clinical presentation regarding seizure frequency in LGG patients, and with poorer cognitive performance in both LGG and HGG glioma patients. CONCLUSION: Lesion histology partly determines differences in functional networks in glioma patients suffering from epilepsy. We suggest that differences between LGG and HGG patients' networks are explained by differences in plasticity, guided by the particular lesional growth pattern. Interestingly, decreased synchronizability and decreased global integration in the theta band seem to make LGG and NGL patients more prone to the occurrence of seizures and cognitive decline.

  15. Expression of Zonulin, c-kit, and Glial Fibrillary Acidic Protein in Human Gliomas.

    Science.gov (United States)

    Skardelly, Marco; Armbruster, Franz Paul; Meixensberger, Jürgen; Hilbig, Heidegard

    2009-08-18

    The hallmarks of human malignant gliomas are their marked invasiveness and vascularity. Because angiogenesis and tumor invasion have been associated with extracellular matrix degradation and intercellular tight junctions, the involvement of zonulin in glioma biology is in the focus. We selected for histological examination five cases of glioblastoma WHO IV (nomenclature of the World Health Organization) and one case each from astrocytoma WHO III, meningioma WHO III, and meningioma WHO I as control samples. The meningioma WHO I is regarded as benign, whereas the meningioma WHO III is recognized as the transition form of malignant tumors in humans. The visualization of a newly designed antibody against human zonulin was studied in triple-labeling studies using fluorescence immunocytochemistry and compared with the expression of c-kit and glial fibrillary acidic protein in differently developed human gliomas. We found that increasing the expression of c-kit is accompanied by an increase of zonulin expression. Both are correlated to the degree of malignancy of human brain tumors. The expression of zonulin is correlated to the degradation of the blood-brain barrier as revealed by Griffonia simplicifolia lectin. In differently graded tumors, we found differently graded involvement of blood vessels in the tumor development, explaining patients' survival.

  16. Podoplanin increases migration and angiogenesis in malignant glioma

    OpenAIRE

    Grau, Stefan J; Trillsch, Fabian; Tonn, Joerg-Christian; Goldbrunner, Roland H; Noessner, Elfriede; Nelson, Peter J; von Luettichau, Irene

    2015-01-01

    Expression of podoplanin in glial brain tumors is grade dependent. While serving as a marker for tumor progression and modulating invasion in various neoplasms, little is known about podoplanin function in gliomas. Therefore we stably transfected two human glioma cell lines (U373MG and U87MG) with expression plasmids encoding podoplanin. The efficacy of transfection was confirmed by FACS analysis, PCR and immunocytochemistry. Cells were then sorted for highly podoplanin expressing cells (U373...

  17. Glia to glioma: A wrathful journey

    Directory of Open Access Journals (Sweden)

    Krishnendu Ghosh

    2017-05-01

    Full Text Available Glial cells, unlike neurons in the brain, can undergo cellular division to maintain their functional continuity. However, sometimes this divisional attribute gets uncontrolled, which breaches tissue organization and transforms tissues into neoplasm. The proliferative abnormality of neuroglia results in one of the most dreaded neoplasm amounting to 30% of all brain tumors—the glioma. The abnormal proliferation, high level of progression and invasive potential makes glioma one of the most lethal killers in its class. The pathological scenario becomes more moribund owing to poor prognosis and high mortality rate of the menace. Conventional onco-therapies yield dismal results compared to other soft tissue tumors. In time, with the advent of newer trends of prognosis and treatment modalities in the field of oncology, a hope for betterment is expected, but not yet achieved. These advancements would fetch some better results with proper and minute understanding of the biology of glioma, both at physiological as well as molecular level. In the present context, we have tried to document an insight to glioma biology that can serve as a primer to understand this lethal killer and its killing spree, with some approaches to combat its carnage.

  18. Automated discrimination of lower and higher grade gliomas based on histopathological image analysis

    Directory of Open Access Journals (Sweden)

    Hojjat Seyed Mousavi

    2015-01-01

    Full Text Available Introduction: Histopathological images have rich structural information, are multi-channel in nature and contain meaningful pathological information at various scales. Sophisticated image analysis tools that can automatically extract discriminative information from the histopathology image slides for diagnosis remain an area of significant research activity. In this work, we focus on automated brain cancer grading, specifically glioma grading. Grading of a glioma is a highly important problem in pathology and is largely done manually by medical experts based on an examination of pathology slides (images. To complement the efforts of clinicians engaged in brain cancer diagnosis, we develop novel image processing algorithms and systems to automatically grade glioma tumor into two categories: Low-grade glioma (LGG and high-grade glioma (HGG which represent a more advanced stage of the disease. Results: We propose novel image processing algorithms based on spatial domain analysis for glioma tumor grading that will complement the clinical interpretation of the tissue. The image processing techniques are developed in close collaboration with medical experts to mimic the visual cues that a clinician looks for in judging of the grade of the disease. Specifically, two algorithmic techniques are developed: (1 A cell segmentation and cell-count profile creation for identification of Pseudopalisading Necrosis, and (2 a customized operation of spatial and morphological filters to accurately identify microvascular proliferation (MVP. In both techniques, a hierarchical decision is made via a decision tree mechanism. If either Pseudopalisading Necrosis or MVP is found present in any part of the histopathology slide, the whole slide is identified as HGG, which is consistent with World Health Organization guidelines. Experimental results on the Cancer Genome Atlas database are presented in the form of: (1 Successful detection rates of pseudopalisading necrosis

  19. In-depth mapping of the mouse brain N-glycoproteome reveals widespread N-glycosylation of diverse brain proteins.

    Science.gov (United States)

    Fang, Pan; Wang, Xin-Jian; Xue, Yu; Liu, Ming-Qi; Zeng, Wen-Feng; Zhang, Yang; Zhang, Lei; Gao, Xing; Yan, Guo-Quan; Yao, Jun; Shen, Hua-Li; Yang, Peng-Yuan

    2016-06-21

    N-glycosylation is one of the most prominent and abundant posttranslational modifications of proteins. It is estimated that over 50% of mammalian proteins undergo glycosylation. However, the analysis of N-glycoproteins has been limited by the available analytical technology. In this study, we comprehensively mapped the N-glycosylation sites in the mouse brain proteome by combining complementary methods, which included seven protease treatments, four enrichment techniques and two fractionation strategies. Altogether, 13492 N-glycopeptides containing 8386 N-glycosylation sites on 3982 proteins were identified. After evaluating the performance of the above methods, we proposed a simple and efficient workflow for large-scale N-glycosylation site mapping. The optimized workflow yielded 80% of the initially identified N-glycosylation sites with considerably less effort. Analysis of the identified N-glycoproteins revealed that many of the mouse brain proteins are N-glycosylated, including those proteins in critical pathways for nervous system development and neurological disease. Additionally, several important biomarkers of various diseases were found to be N-glycosylated. These data confirm that N-glycosylation is important in both physiological and pathological processes in the brain, and provide useful details about numerous N-glycosylation sites in brain proteins.

  20. Glioma Association and Balancing Selection of ZFPM2.

    Directory of Open Access Journals (Sweden)

    Shui-Ying Tsang

    Full Text Available ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350, non-glioma cancer (n = 354 and healthy control (n = 463 by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69 of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016, and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005 or non-glioma cancers (P = 0.020. ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002, with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028. In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology.

  1. The 18-kDa mitochondrial translocator protein in gliomas: from the bench to bedside.

    OpenAIRE

    Janczar, Karolina; Su, Zhangjie; Raccagni, Isabella; Anfosso, Andrea; Kelly, Charlotte; Durrenberger, Pascal F; Gerhard, Alexander; Roncaroli, Federic

    2015-01-01

    The 18-kDa mitochondrial translocator protein (TSPO) is known to be highly expressed in several types of cancer, including gliomas, whereas expression in normal brain is low. TSPO functions in glioma are still incompletely understood. The TSPO can be quantified pre-operatively with molecular imaging making it an ideal candidate for personalized treatment of patient with glioma. Studies have proposed to exploit the TSPO as a transporter of chemotherapics to selectively target tumour cells in t...

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

    Science.gov (United States)

    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.

  3. Textural features of dynamic contrast-enhanced MRI derived model-free and model-based parameter maps in glioma grading.

    Science.gov (United States)

    Xie, Tian; Chen, Xiao; Fang, Jingqin; Kang, Houyi; Xue, Wei; Tong, Haipeng; Cao, Peng; Wang, Sumei; Yang, Yizeng; Zhang, Weiguo

    2018-04-01

    Presurgical glioma grading by dynamic contrast-enhanced MRI (DCE-MRI) has unresolved issues. The aim of this study was to investigate the ability of textural features derived from pharmacokinetic model-based or model-free parameter maps of DCE-MRI in discriminating between different grades of gliomas, and their correlation with pathological index. Retrospective. Forty-two adults with brain gliomas. 3.0T, including conventional anatomic sequences and DCE-MRI sequences (variable flip angle T1-weighted imaging and three-dimensional gradient echo volumetric imaging). Regions of interest on the cross-sectional images with maximal tumor lesion. Five commonly used textural features, including Energy, Entropy, Inertia, Correlation, and Inverse Difference Moment (IDM), were generated. All textural features of model-free parameters (initial area under curve [IAUC], maximal signal intensity [Max SI], maximal up-slope [Max Slope]) could effectively differentiate between grade II (n = 15), grade III (n = 13), and grade IV (n = 14) gliomas (P textural features, Entropy and IDM, of four DCE-MRI parameters, including Max SI, Max Slope (model-free parameters), vp (Extended Tofts), and vp (Patlak) could differentiate grade III and IV gliomas (P textural features of any DCE-MRI parameter maps could discriminate between subtypes of grade II and III gliomas (P features revealed relatively lower inter-observer agreement. No significant correlation was found between microvascular density and textural features, compared with a moderate correlation found between cellular proliferation index and those features. Textural features of DCE-MRI parameter maps displayed a good ability in glioma grading. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1099-1111. © 2017 International Society for Magnetic Resonance in Medicine.

  4. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2010-01-01

    have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

  5. Red and processed meat consumption and risk of glioma in adults: A systematic review and meta-analysis of observational studies

    Directory of Open Access Journals (Sweden)

    Parvane Saneei

    2015-01-01

    Full Text Available 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

  6. Whole-brain activity maps reveal stereotyped, distributed networks for visuomotor behavior.

    Science.gov (United States)

    Portugues, Ruben; Feierstein, Claudia E; Engert, Florian; Orger, Michael B

    2014-03-19

    Most behaviors, even simple innate reflexes, are mediated by circuits of neurons spanning areas throughout the brain. However, in most cases, the distribution and dynamics of firing patterns of these neurons during behavior are not known. We imaged activity, with cellular resolution, throughout the whole brains of zebrafish performing the optokinetic response. We found a sparse, broadly distributed network that has an elaborate but ordered pattern, with a bilaterally symmetrical organization. Activity patterns fell into distinct clusters reflecting sensory and motor processing. By correlating neuronal responses with an array of sensory and motor variables, we find that the network can be clearly divided into distinct functional modules. Comparing aligned data from multiple fish, we find that the spatiotemporal activity dynamics and functional organization are highly stereotyped across individuals. These experiments systematically reveal the functional architecture of neural circuits underlying a sensorimotor behavior in a vertebrate brain. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Identification of molecular pathways facilitating glioma cell invasion in situ.

    Directory of Open Access Journals (Sweden)

    Ido Nevo

    Full Text Available Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

  8. The value of intraoperative sonography in low grade glioma surgery.

    Science.gov (United States)

    Petridis, Athanasios K; Anokhin, Maxim; Vavruska, Jan; Mahvash, Mehran; Scholz, Martin

    2015-04-01

    There is a number of different methods to localize a glioma intraoperatively. Neuronavigation, intraoperative MRI, 5-aminolevulinic acid, as well as intraoperative sonography. Every method has its advantages and disadvantages. Low grade gliomas do not show a specific signal with 5-aminolevulinic acid and are difficult to distinguish macroscopically from normal tissue. In the present study we stress out the importance of intraoperative diagnostic ultrasound for localization of low grade gliomas. We retrospectively evaluated the charts and MRIs of 34 patients with low grade gliomas operated in our department from 2011 until December 2014. The efficacy of ultrasound as an intraoperative navigational tool was assessed. In 15 patients ultrasound was used and in 19 not. Only histologically proven low grades gliomas (astrocytomas grade II) were evaluated. In none of the patients where ultrasound (combined with neuronavigation) was used (N=15) to find the tumors, the target was missed, whereas the exclusive use of neuronavigation missed the target in 5 of 19 cases of small subcortical low grade gliomas. Intraoperative ultrasound is an excellent tool in localizing low grade gliomas intraoperatively. It is an inexpensive, real time neuronavigational tool, which overcomes brain shift. Even when identifying the tumors with ultrasound is very reliable, the extend of resection and the decision to remove any residual tumor with the help of ultrasound is at the moment unreliable. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Glioma epidemiology in the central Tunisian population: 1993-2012.

    Science.gov (United States)

    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.

  10. Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part I. Treatment modalities of radiation therapy

    International Nuclear Information System (INIS)

    Kortmann, R.D.; Timmermann, B.; Plasswilm, L.; Paulsen, F.; Jeremic, B.; Kay, S.; Bamberg, M.; Taylor, R.E.; Scarzello, G.; Gnekow, A.K.; Dieckmann, K.

    2003-01-01

    Background: Treatment of childhood low-grade gliomas is a challenging issue owing to their low incidence and the lack of consensus about ''optimal'' treatment approach. Material and Methods: Reports in the literature spanning 60 years of radiation therapy, including orthovoltage, megavoltage and recently modern high-precision treatments, were reviewed with respect to visual function, survival, prognostic factors, dose prescriptions, target volumes, and treatment techniques. Based on these experiences, future strategies in the management of childhood low-grade glioma are presented. Results: Evaluation of published reports is difficult because of inconsistencies in data presentation, relatively short follow-up in some series and failure to present findings and results in a comparable way. Even with the shortcomings of the reports available in the literature, primarily concerning indications, age at treatment, dose response, timing and use of ''optimal'' treatment fields, radiation therapy continues to play an important role in the management of these tumors achieving long-term survival rates up to 80% or more. Particularly in gliomas of the visual pathway, high local tumor control and improved or stable function is achieved in approximately 90% of cases. Data on dose-response relationships recommend dose prescriptions between 45 and 54 Gy with standard fractionation. There is consensus now to employ radiation therapy in older children in case of progressive disease only, regardless of tumor location and histologic subtype. In younger children, the role of radiotherapy is unclear. Recent advances in treatment techniques, such as 3-D treatment planning and various ''high-precision'' treatments achieved promising initial outcome, however with limited patient numbers and short follow-ups. Conclusions: Radiation therapy is an effective treatment modality in children with low-grade glioma regarding tumor control and improvement and/or preservation of neurologic function or

  11. Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

    Science.gov (United States)

    Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

    2017-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.

  12. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury.

    Science.gov (United States)

    Dennis, Emily L; Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

    2016-05-01

    Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1-6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI.

  13. Revealing topological organization of human brain functional networks with resting-state functional near infrared spectroscopy.

    Science.gov (United States)

    Niu, Haijing; Wang, Jinhui; Zhao, Tengda; Shu, Ni; He, Yong

    2012-01-01

    The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics. We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques. Our results confirmed the feasibility and validity of using graph-theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders.

  14. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury

    Science.gov (United States)

    Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M.; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C.; Thompson, Paul M.; Asarnow, Robert F.

    2016-01-01

    Abstract Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1–6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI. PMID:26393494

  15. Metabolomics reveals metabolic alterations by intrauterine growth restriction in the fetal rabbit brain.

    Directory of Open Access Journals (Sweden)

    Erwin van Vliet

    Full Text Available Intrauterine Growth Restriction (IUGR due to placental insufficiency occurs in 5-10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development.At gestation day 25, IUGR was induced in two New Zealand rabbits by 40-50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR.IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty acid profiles and oxidative stress

  16. Inter-species activity correlations reveal functional correspondences between monkey and human brain areas

    Science.gov (United States)

    Mantini, Dante; Hasson, Uri; Betti, Viviana; Perrucci, Mauro G.; Romani, Gian Luca; Corbetta, Maurizio; Orban, Guy A.; Vanduffel, Wim

    2012-01-01

    Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. In cases where functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions. Here we describe a method to examine functional correspondences across species. Without making spatial assumptions, we assess similarities in sensory-driven functional magnetic resonance imaging responses between monkey (Macaca mulatta) and human brain areas by means of temporal correlation. Using natural vision data, we reveal regions for which functional processing has shifted to topologically divergent locations during evolution. We conclude that substantial evolution-driven functional reorganizations have occurred, not always consistent with cortical expansion processes. This novel framework for evaluating changes in functional architecture is crucial to building more accurate evolutionary models. PMID:22306809

  17. Metabolic connectivity mapping reveals effective connectivity in the resting human brain.

    Science.gov (United States)

    Riedl, Valentin; Utz, Lukas; Castrillón, Gabriel; Grimmer, Timo; Rauschecker, Josef P; Ploner, Markus; Friston, Karl J; Drzezga, Alexander; Sorg, Christian

    2016-01-12

    Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using "eyes open" versus "eyes closed" conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.

  18. Species-Specific Mechanisms of Neuron Subtype Specification Reveal Evolutionary Plasticity of Amniote Brain Development

    Directory of Open Access Journals (Sweden)

    Tadashi Nomura

    2018-03-01

    Full Text Available Summary: Highly ordered brain architectures in vertebrates consist of multiple neuron subtypes with specific neuronal connections. However, the origin of and evolutionary changes in neuron specification mechanisms remain unclear. Here, we report that regulatory mechanisms of neuron subtype specification are divergent in developing amniote brains. In the mammalian neocortex, the transcription factors (TFs Ctip2 and Satb2 are differentially expressed in layer-specific neurons. In contrast, these TFs are co-localized in reptilian and avian dorsal pallial neurons. Multi-potential progenitors that produce distinct neuronal subtypes commonly exist in the reptilian and avian dorsal pallium, whereas a cis-regulatory element of avian Ctip2 exhibits attenuated transcription suppressive activity. Furthermore, the neuronal subtypes distinguished by these TFs are not tightly associated with conserved neuronal connections among amniotes. Our findings reveal the evolutionary plasticity of regulatory gene functions that contribute to species differences in neuronal heterogeneity and connectivity in developing amniote brains. : Neuronal heterogeneity is essential for assembling intricate neuronal circuits. Nomura et al. find that species-specific transcriptional mechanisms underlie diversities of excitatory neuron subtypes in mammalian and non-mammalian brains. Species differences in neuronal subtypes and connections suggest functional plasticity of regulatory genes for neuronal specification during amniote brain evolution. Keywords: Ctip2, Satb2, multi-potential progenitors, transcriptional regulation, neuronal connectivity

  19. Alterations in Normal Aging Revealed by Cortical Brain Network Constructed Using IBASPM.

    Science.gov (United States)

    Li, Wan; Yang, Chunlan; Shi, Feng; Wang, Qun; Wu, Shuicai; Lu, Wangsheng; Li, Shaowu; Nie, Yingnan; Zhang, Xin

    2018-04-16

    Normal aging has been linked with the decline of cognitive functions, such as memory and executive skills. One of the prominent approaches to investigate the age-related alterations in the brain is by examining the cortical brain connectome. IBASPM is a toolkit to realize individual atlas-based volume measurement. Hence, this study seeks to determine what further alterations can be revealed by cortical brain networks formed by IBASPM-extracted regional gray matter volumes. We found the reduced strength of connections between the superior temporal pole and middle temporal pole in the right hemisphere, global hubs as the left fusiform gyrus and right Rolandic operculum in the young and aging groups, respectively, and significantly reduced inter-module connection of one module in the aging group. These new findings are consistent with the phenomenon of normal aging mentioned in previous studies and suggest that brain network built with the IBASPM could provide supplementary information to some extent. The individualization of morphometric features extraction deserved to be given more attention in future cortical brain network research.

  20. Radiosensitivity and TP 53, EGFR amplification and LOH10 analysis of primary glioma cell cultures

    NARCIS (Netherlands)

    Gerlach, Bärbel; Harder, Anna H.; Hulsebos, Theo J. M.; Leenstra, Sieger; Slotman, Berend J.; Vandertop, W. Peter; Hartmann, Karl-Axel; Sminia, Peter

    2002-01-01

    Aim: Determination of in-vitro radiosensitivity and genetic alterations of cell cultures derived from human glioma biopsy tissue and established glioma cell lines. Material and Methods: Fresh brain tumor specimens of six patients were processed to early passage cell cultures. In addition the cell

  1. Identification of Predictive Response Markers and Novel Treatment Targets for Gliomas

    NARCIS (Netherlands)

    L. Erdem-Eraslan (Lale)

    2016-01-01

    markdownabstractGliomas are the most frequent primary brain tumors in adults. Despite multimodality treatment strategies, the survival of patients with a diffuse glioma remains poor. There has been an increasing use of molecular markers to assist diagnosis and predict prognosis and response to

  2. Structural studies of human glioma pathogenesis-related protein 1

    Energy Technology Data Exchange (ETDEWEB)

    Asojo, Oluwatoyin A., E-mail: oasojo@unmc.edu [College of Medicine, Nebraska Medical Center, Omaha, NE 68198-6495 (United States); Koski, Raymond A.; Bonafé, Nathalie [L2 Diagnostics LLC, 300 George Street, New Haven, CT 06511 (United States); College of Medicine, Nebraska Medical Center, Omaha, NE 68198-6495 (United States)

    2011-10-01

    Structural analysis of a truncated soluble domain of human glioma pathogenesis-related protein 1, a membrane protein implicated in the proliferation of aggressive brain cancer, is presented. Human glioma pathogenesis-related protein 1 (GLIPR1) is a membrane protein that is highly upregulated in brain cancers but is barely detectable in normal brain tissue. GLIPR1 is composed of a signal peptide that directs its secretion, a conserved cysteine-rich CAP (cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 proteins) domain and a transmembrane domain. GLIPR1 is currently being investigated as a candidate for prostate cancer gene therapy and for glioblastoma targeted therapy. Crystal structures of a truncated soluble domain of the human GLIPR1 protein (sGLIPR1) solved by molecular replacement using a truncated polyalanine search model of the CAP domain of stecrisp, a snake-venom cysteine-rich secretory protein (CRISP), are presented. The correct molecular-replacement solution could only be obtained by removing all loops from the search model. The native structure was refined to 1.85 Å resolution and that of a Zn{sup 2+} complex was refined to 2.2 Å resolution. The latter structure revealed that the putative binding cavity coordinates Zn{sup 2+} similarly to snake-venom CRISPs, which are involved in Zn{sup 2+}-dependent mechanisms of inflammatory modulation. Both sGLIPR1 structures have extensive flexible loop/turn regions and unique charge distributions that were not observed in any of the previously reported CAP protein structures. A model is also proposed for the structure of full-length membrane-bound GLIPR1.

  3. Intraoperative Cerebral Glioma Characterization with Contrast Enhanced Ultrasound

    Directory of Open Access Journals (Sweden)

    Francesco Prada

    2014-01-01

    Full Text Available Background. Contrast enhanced ultrasound (CEUS is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. Aim. To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. Methods. We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. Results. We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. Conclusion. Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors’ biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy.

  4. CD147 and glioma: a meta-analysis.

    Science.gov (United States)

    Li, Hui; Xi, Zhouhuan; Dai, Xuejiao; Wu, Wenyue; Li, Yanwen; Liu, Yanting; Zhang, Hanwen

    2017-08-01

    Gliomas are the most common primary brain tumors. This meta-analysis aimed to systematically evaluate the relationship between CD147 expression in tissues and the clinicopathological features of patients with glioma. We searched PubMed (1966-2016), EMBASE (1980-2016), Cochrane Library (1996-2016), Web of Science (1945-2016), China National Knowledge Infrastructure (1982-2016), and Wan Fang databases (1988-2016). Quality assessment of the literature was performed using the Newcastle-Ottawa Scale, with Revman 5.3 and Stata 14.0 for analysis. In total, 1806 glioma patients from 19 studies were included, and patients with CD147 overexpression had poorer overall survival [hazard ratio (HR) = 2.211, P CD147 expression when comparing glioma tissues versus non-cancerous brain tissues (OR 20.42; 95% CI 13.94-29.91; P CD147 expression did not differ based on patient's age (young vs. old, P = 0.89) or gender (female vs. male, P = 0.57). CD147 expression may be a potential prognostic biomarker for poorer overall and relapse-free survival, and may affect the 5-year survival rate in glioma patients. CD147 expression is also closely correlated with poor clinical characteristics in glioma patients.

  5. Utility of multiparametric 3-T MRI for glioma characterization

    International Nuclear Information System (INIS)

    Roy, Bhaswati; Gupta, Rakesh K.; Maudsley, Andrew A.; Sheriff, Sulaiman; Awasthi, Rishi; Mohakud, Sudipta; Gu, Meng; Spielman, Daniel M.; Husain, Nuzhat; Behari, Sanjay; Pandey, Chandra M.; Rathore, Ram K.S.; Alger, Jeffry R.

    2013-01-01

    Accurate grading of cerebral glioma using conventional structural imaging techniques remains challenging due to the relatively poor sensitivity and specificity of these methods. The purpose of this study was to evaluate the relative sensitivity and specificity of structural magnetic resonance imaging and MR measurements of perfusion, diffusion, and whole-brain spectroscopic parameters for glioma grading. Fifty-six patients with radiologically suspected untreated glioma were studied with T1- and T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, diffusion tensor imaging, and volumetric whole-brain MR spectroscopic imaging. Receiver-operating characteristic analysis was performed using the relative cerebral blood volume (rCBV), apparent diffusion coefficient, fractional anisotropy, and multiple spectroscopic parameters to determine optimum thresholds for tumor grading and to obtain the sensitivity, specificity, and positive and negative predictive values for identifying high-grade gliomas. Logistic regression was performed to analyze all the parameters together. The rCBV individually classified glioma as low and high grade with a sensitivity and specificity of 100 and 88 %, respectively, based on a threshold value of 3.34. On combining all parameters under consideration, the classification was achieved with 2 % error and sensitivity and specificity of 100 and 96 %, respectively. Individually, CBV measurement provides the greatest diagnostic performance for predicting glioma grade; however, the most accurate classification can be achieved by combining all of the imaging parameters. (orig.)

  6. Loss of heterozygosity of TRIM3 in malignant gliomas

    Directory of Open Access Journals (Sweden)

    Dolder Béatrice

    2009-02-01

    Full Text Available Abstract Background Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3 encodes a structural homolog of Drosophila brain tumor (brat implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ... Methods Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. Results Our analysis identifies LOH in 17 cases (24% of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. Conclusion Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene.

  7. TCGA_LowerGradeGliomas

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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 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.

  9. Increased Expression of microRNA-17 Predicts Poor Prognosis in Human Glioma

    Directory of Open Access Journals (Sweden)

    Shengkui Lu

    2012-01-01

    Full Text Available Aim. To investigate the clinical significance of microRNA-17 (miR-17 expression in human gliomas. Methods. Quantitative real-time polymerase chain reaction (qRT-PCR analysis was used to characterize the expression patterns of miR-17 in 108 glioma and 20 normal brain tissues. The associations of miR-17 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. Results. Compared with normal brain tissues, miR-17 expression was significantly higher in glioma tissues (P<0.001. In addition, the increased expression of miR-17 in glioma was significantly associated with advanced pathological grade (P=0.006 and low Karnofsky performance score (KPS, P=0.01. Moreover, Kaplan-Meier survival and Cox regression analyses showed that miR-17 overexpression (P=0.008 and advanced pathological grade (P=0.02 were independent factors predicting poor prognosis for gliomas. Furthermore, subgroup analyses showed that miR-17 expression was significantly associated with poor overall survival in glioma patients with high pathological grades (for grade III~IV: P<0.001. Conclusions. Our data offer the convinced evidence that the increased expression of miR-17 may have potential value for predicting poor prognosis in glioma patients with high pathological grades, indicating that miR-17 may contribute to glioma progression and be a candidate therapeutic target for this disease.

  10. Resting-state brain networks revealed by granger causal connectivity in frogs.

    Science.gov (United States)

    Xue, Fei; Fang, Guangzhan; Yue, Xizi; Zhao, Ermi; Brauth, Steven E; Tang, Yezhong

    2016-10-15

    Resting-state networks (RSNs) refer to the spontaneous brain activity generated under resting conditions, which maintain the dynamic connectivity of functional brain networks for automatic perception or higher order cognitive functions. Here, Granger causal connectivity analysis (GCCA) was used to explore brain RSNs in the music frog (Babina daunchina) during different behavioral activity phases. The results reveal that a causal network in the frog brain can be identified during the resting state which reflects both brain lateralization and sexual dimorphism. Specifically (1) ascending causal connections from the left mesencephalon to both sides of the telencephalon are significantly higher than those from the right mesencephalon, while the right telencephalon gives rise to the strongest efferent projections among all brain regions; (2) causal connections from the left mesencephalon in females are significantly higher than those in males and (3) these connections are similar during both the high and low behavioral activity phases in this species although almost all electroencephalograph (EEG) spectral bands showed higher power in the high activity phase for all nodes. The functional features of this network match important characteristics of auditory perception in this species. Thus we propose that this causal network maintains auditory perception during the resting state for unexpected auditory inputs as resting-state networks do in other species. These results are also consistent with the idea that females are more sensitive to auditory stimuli than males during the reproductive season. In addition, these results imply that even when not behaviorally active, the frogs remain vigilant for detecting external stimuli. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Revealing the cerebello-ponto-hypothalamic pathway in the human brain.

    Science.gov (United States)

    Kamali, Arash; Karbasian, Niloofar; Rabiei, Pejman; Cano, Andres; Riascos, Roy F; Tandon, Nitin; Arevalo, Octavio; Ocasio, Laura; Younes, Kyan; Khayat-Khoei, Mahsa; Mirbagheri, Saeedeh; Hasan, Khader M

    2018-04-16

    The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain. Copyright © 2018. Published by Elsevier B.V.

  12. Multifrequency magnetic resonance elastography of the brain reveals tissue degeneration in neuromyelitis optica spectrum disorder

    International Nuclear Information System (INIS)

    Streitberger, Kaspar-Josche; Fehlner, Andreas; Sack, Ingolf; Pache, Florence; Lacheta, Anna; Papazoglou, Sebastian; Brandt, Alexander; Bellmann-Strobl, Judith; Ruprecht, Klemens; Braun, Juergen; Paul, Friedemann; Wuerfel, Jens

    2017-01-01

    Application of multifrequency magnetic resonance elastography (MMRE) of the brain parenchyma in patients with neuromyelitis optica spectrum disorder (NMOSD) compared to age matched healthy controls (HC). 15 NMOSD patients and 17 age- and gender-matched HC were examined using MMRE. Two three-dimensional viscoelastic parameter maps, the magnitude G* and phase angle φ of the complex shear modulus were reconstructed by simultaneous inversion of full wave-field data in 1.9-mm isotropic resolution at 7 harmonic drive frequencies from 30 to 60 Hz. In NMOSD patients, a significant reduction of G* was observed within the white matter fraction (p = 0.017), predominantly within the thalamic regions (p = 0.003), compared to HC. These parameters exceeded the reduction in brain volume measured in patients versus HC (p = 0.02 whole-brain volume reduction). Volumetric differences in white matter fraction and the thalami were not detectable between patients and HC. However, phase angle φ was decreased in patients within the white matter (p = 0.03) and both thalamic regions (p = 0.044). MMRE reveals global tissue degeneration with accelerated softening of the brain parenchyma in patients with NMOSD. The predominant reduction of stiffness is found within the thalamic region and related white matter tracts, presumably reflecting Wallerian degeneration. (orig.)

  13. Multifrequency magnetic resonance elastography of the brain reveals tissue degeneration in neuromyelitis optica spectrum disorder

    Energy Technology Data Exchange (ETDEWEB)

    Streitberger, Kaspar-Josche [Charite - Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany); Charite - Universitaetsmedizin Berlin, Department of Neurology with Experimental Neurology, Berlin (Germany); Fehlner, Andreas; Sack, Ingolf [Charite - Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany); Pache, Florence [Charite - Universitaetsmedizin Berlin, Department of Neurology with Experimental Neurology, Berlin (Germany); Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Lacheta, Anna; Papazoglou, Sebastian; Brandt, Alexander [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Bellmann-Strobl, Judith [Max Delbrueck Center for Molecular Medicine and Charite - Universitaetsmedizin Berlin, Experimental and Clinical Research Center, Berlin (Germany); Ruprecht, Klemens [Charite - Universitaetsmedizin Berlin, Department of Neurology with Experimental Neurology, Berlin (Germany); Braun, Juergen [Charite - Universitaetsmedizin Berlin, Institute of Medical Informatics, Berlin (Germany); Paul, Friedemann [Charite - Universitaetsmedizin Berlin, Department of Neurology with Experimental Neurology, Berlin (Germany); Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Max Delbrueck Center for Molecular Medicine and Charite - Universitaetsmedizin Berlin, Experimental and Clinical Research Center, Berlin (Germany); Wuerfel, Jens [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Max Delbrueck Center for Molecular Medicine and Charite - Universitaetsmedizin Berlin, Experimental and Clinical Research Center, Berlin (Germany); Medical Image Analysis Center (MIAC AG), Basel (Switzerland)

    2017-05-15

    Application of multifrequency magnetic resonance elastography (MMRE) of the brain parenchyma in patients with neuromyelitis optica spectrum disorder (NMOSD) compared to age matched healthy controls (HC). 15 NMOSD patients and 17 age- and gender-matched HC were examined using MMRE. Two three-dimensional viscoelastic parameter maps, the magnitude G* and phase angle φ of the complex shear modulus were reconstructed by simultaneous inversion of full wave-field data in 1.9-mm isotropic resolution at 7 harmonic drive frequencies from 30 to 60 Hz. In NMOSD patients, a significant reduction of G* was observed within the white matter fraction (p = 0.017), predominantly within the thalamic regions (p = 0.003), compared to HC. These parameters exceeded the reduction in brain volume measured in patients versus HC (p = 0.02 whole-brain volume reduction). Volumetric differences in white matter fraction and the thalami were not detectable between patients and HC. However, phase angle φ was decreased in patients within the white matter (p = 0.03) and both thalamic regions (p = 0.044). MMRE reveals global tissue degeneration with accelerated softening of the brain parenchyma in patients with NMOSD. The predominant reduction of stiffness is found within the thalamic region and related white matter tracts, presumably reflecting Wallerian degeneration. (orig.)

  14. Common brain regions underlying different arithmetic operations as revealed by conjunct fMRI-BOLD activation.

    Science.gov (United States)

    Fehr, Thorsten; Code, Chris; Herrmann, Manfred

    2007-10-03

    The issue of how and where arithmetic operations are represented in the brain has been addressed in numerous studies. Lesion studies suggest that a network of different brain areas are involved in mental calculation. Neuroimaging studies have reported inferior parietal and lateral frontal activations during mental arithmetic using tasks of different complexities and using different operators (addition, subtraction, etc.). Indeed, it has been difficult to compare brain activation across studies because of the variety of different operators and different presentation modalities used. The present experiment examined fMRI-BOLD activity in participants during calculation tasks entailing different arithmetic operations -- addition, subtraction, multiplication and division -- of different complexities. Functional imaging data revealed a common activation pattern comprising right precuneus, left and right middle and superior frontal regions during all arithmetic operations. All other regional activations were operation specific and distributed in prominently frontal, parietal and central regions when contrasting complex and simple calculation tasks. The present results largely confirm former studies suggesting that activation patterns due to mental arithmetic appear to reflect a basic anatomical substrate of working memory, numerical knowledge and processing based on finger counting, and derived from a network originally related to finger movement. We emphasize that in mental arithmetic research different arithmetic operations should always be examined and discussed independently of each other in order to avoid invalid generalizations on arithmetics and involved brain areas.

  15. Activation of AMP-activated protein kinase by kainic acid mediates brain-derived neurotrophic factor expression through a NF-kappaB dependent mechanism in C6 glioma cells

    International Nuclear Information System (INIS)

    Yoon, Hana; Oh, Young Taek; Lee, Jung Yeon; Choi, Ji Hyun; Lee, Ju Hie; Baik, Hyung Hwan; Kim, Sung Soo; Choe, Wonchae; Yoon, Kyung-Sik; Ha, Joohun; Kang, Insug

    2008-01-01

    AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. Kainic acid (KA), a prototype excitotoxin is known to induce brain-derived neurotrophic factor (BDNF) in brain. In this study, we examined the role of AMPK in KA-induced BDNF expression in C6 glioma cells. We showed that KA and KA receptor agonist induced activation of AMPK and KA-induced AMPK activation was blocked by inhibition of Ca 2+ /calmodulin-dependent protein kinase kinase (CaMKK) β. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPKα1 blocked KA-induced BDNF mRNA and protein expression. Inhibition of AMPK blocked KA-induced phosphorylation of CaMKII and I kappaB kinase (IKK) in C6 cells. Finally, we showed that inhibition of AMPK reduced DNA binding and transcriptional activation of nuclear factor-kappaB (NF-κB) in KA-treated cells. These results suggest that AMPK mediates KA-induced BDNF expression by regulating NF-κB activation

  16. Deep sequencing analysis of the developing mouse brain reveals a novel microRNA

    Directory of Open Access Journals (Sweden)

    Piltz Sandra

    2011-04-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are small non-coding RNAs that can exert multilevel inhibition/repression at a post-transcriptional or protein synthesis level during disease or development. Characterisation of miRNAs in adult mammalian brains by deep sequencing has been reported previously. However, to date, no small RNA profiling of the developing brain has been undertaken using this method. We have performed deep sequencing and small RNA analysis of a developing (E15.5 mouse brain. Results We identified the expression of 294 known miRNAs in the E15.5 developing mouse brain, which were mostly represented by let-7 family and other brain-specific miRNAs such as miR-9 and miR-124. We also discovered 4 putative 22-23 nt miRNAs: mm_br_e15_1181, mm_br_e15_279920, mm_br_e15_96719 and mm_br_e15_294354 each with a 70-76 nt predicted pre-miRNA. We validated the 4 putative miRNAs and further characterised one of them, mm_br_e15_1181, throughout embryogenesis. Mm_br_e15_1181 biogenesis was Dicer1-dependent and was expressed in E3.5 blastocysts and E7 whole embryos. Embryo-wide expression patterns were observed at E9.5 and E11.5 followed by a near complete loss of expression by E13.5, with expression restricted to a specialised layer of cells within the developing and early postnatal brain. Mm_br_e15_1181 was upregulated during neurodifferentiation of P19 teratocarcinoma cells. This novel miRNA has been identified as miR-3099. Conclusions We have generated and analysed the first deep sequencing dataset of small RNA sequences of the developing mouse brain. The analysis revealed a novel miRNA, miR-3099, with potential regulatory effects on early embryogenesis, and involvement in neuronal cell differentiation/function in the brain during late embryonic and early neonatal development.

  17. Sustained Angiopoietin-2 Expression Disrupts Vessel Formation and Inhibits Glioma Growth

    Directory of Open Access Journals (Sweden)

    Ok-Hee Lee

    2006-05-01

    Full Text Available Systematic analyses of the expression of angiogenic regulators in cancer models should yield useful information for the development of novel therapies for malignant gliomas. In this study, we analyzed tumor growth, vascularization, and angiopoietin-2 (Ang2 expression during the development of U-87 MG xenografts. We found that tumoral angiogenesis in this model follows a multistage process characterized by avascular, prolific peripheral angiogenesis, and late vascular phases. On day 4, we observed an area of central necrosis, a peripheral ring of Ang2-positive glioma cells, and reactive Ang2-positive vascular structures in the tumor/brain interface. When the tumor had developed a vascular network, Ang2 was expressed only in peripheral vascular structures. Because Ang2 expression was downmodulated in the late stages of development, probably to maintain a stable tumoral vasculature, we next studied whether sustained Ang2 expression might impair vascular development and, ultimately, tumor growth. Ang2 prevented the formation of capillary-like structures and impaired angiogenesis in a chorioallantoic membrane chicken model. Finally, we tested the effect of sustained Ang2 expression on U-87 MG xenograff development. Ang2 significantly prolonged the survival of intracranial U-87 MG tumor-bearing animals. Examination of Ang2treated xenograffs revealed areas of tumor necrosis and vascular damage. We therefore conclude that deregulated Ang2 expression during gliomagenesis hindered successful angiogenesis and that therapies that sustain Ang2 expression might be effective against malignant gliomas.

  18. [Identification of emotions in patients with low-grade gliomas versus cerebrovascular accidents].

    Science.gov (United States)

    du Boullay, V; Plaza, M; Capelle, L; Chaby, L

    2013-03-01

    Facial and vocal emotions contribute to sustain efficient social relationships. Brain disease may impair their identification. In the case of slow-growth tumors (Low Grade Gliomas [LGG]) or sudden stroke (cerebrovascular accidents [CVA]), the lesions induce contrasted plasticity and reorganisation processes. We compared the facial, vocal and intermodal identification of six emotions (happiness, fear, angriness, sadness, disgust and neutral) of three groups: patients with LGG before and after tumor resection, patients with CVA and control subjects. In LGG patients, the results revealed less efficient performances after tumor resection and in CVA patients weak performances regarding negative emotions. The intermodal condition (simultaneous visual and vocal association) improved performances in all groups and enabled equivalent performance in CVA subjects compared with control subjects. The intergroup differences may be related to variable brain plasticity as a function of type and rapidity of brain injury. Intermodal processing appears to be a compensatory condition. Copyright © 2012. Published by Elsevier Masson SAS.

  19. Aberrant Signaling Pathways in Glioma

    International Nuclear Information System (INIS)

    Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

    2011-01-01

    Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

  20. In vivo intracellular oxygen dynamics in murine brain glioma and immunotherapeutic response of cytotoxic T cells observed by fluorine-19 magnetic resonance imaging.

    Directory of Open Access Journals (Sweden)

    Jia Zhong

    Full Text Available Noninvasive biomarkers of anti-tumoral efficacy are of great importance to the development of therapeutic agents. Tumor oxygenation has been shown to be an important indicator of therapeutic response. We report the use of intracellular labeling of tumor cells with perfluorocarbon (PFC molecules, combined with quantitative ¹⁹F spin-lattice relaxation rate (R₁ measurements, to assay tumor cell oxygen dynamics in situ. In a murine central nervous system (CNS GL261 glioma model, we visualized the impact of Pmel-1 cytotoxic T cell immunotherapy, delivered intravenously, on intracellular tumor oxygen levels. GL261 glioma cells were labeled ex vivo with PFC and inoculated into the mouse striatum. The R₁ of ¹⁹F labeled cells was measured using localized single-voxel magnetic resonance spectroscopy, and the absolute intracellular partial pressure of oxygen (pO₂ was ascertained. Three days after tumor implantation, mice were treated with 2×10⁷ cytotoxic T cells intravenously. At day five, a transient spike in pO₂ was observed indicating an influx of T cells into the CNS and putative tumor cell apoptosis. Immunohistochemistry and quantitative flow cytometry analysis confirmed that the pO₂ was causally related to the T cells infiltration. Surprisingly, the pO₂ spike was detected even though few (∼4×10⁴ T cells actually ingress into the CNS and with minimal tumor shrinkage. These results indicate the high sensitivity of this approach and its utility as a non-invasive surrogate biomarker of anti-cancer immunotherapeutic response in preclinical models.

  1. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain?

    International Nuclear Information System (INIS)

    Hermanto, Ulrich; Frija, Erik K.; Lii, MingFwu J.; Chang, Eric L.; Mahajan, Anita; Woo, Shiao Y.

    2007-01-01

    Purpose: To determine whether intensity-modulated radiotherapy (IMRT) treatment increases the total integral dose of nontarget tissue relative to the conventional three-dimensional conformal radiotherapy (3D-CRT) technique for high-grade gliomas. Methods and Materials: Twenty patients treated with 3D-CRT for glioblastoma multiforme were selected for a comparative dosimetric evaluation with IMRT. Original target volumes, organs at risk (OAR), and dose-volume constraints were used for replanning with IMRT. Predicted isodose distributions, cumulative dose-volume histograms of target volumes and OAR, normal tissue integral dose, target coverage, dose conformity, and normal tissue sparing with 3D-CRT and IMRT planning were compared. Statistical analyses were performed to determine differences. Results: In all 20 patients, IMRT maintained equivalent target coverage, improved target conformity (conformity index [CI] 95% 1.52 vs. 1.38, p mean by 19.8% and D max by 10.7%), optic chiasm (D mean by 25.3% and D max by 22.6%), right optic nerve (D mean by 37.3% and D max by 28.5%), and left optic nerve (D mean by 40.6% and D max by 36.7%), p ≤ 0.01. This was achieved without increasing the total nontarget integral dose by greater than 0.5%. Overall, total integral dose was reduced by 7-10% with IMRT, p < 0.001, without significantly increasing the 0.5-5 Gy low-dose volume. Conclusions: These results indicate that IMRT treatment for high-grade gliomas allows for improved target conformity, better critical tissue sparing, and importantly does so without increasing integral dose and the volume of normal tissue exposed to low doses of radiation

  2. The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption

    International Nuclear Information System (INIS)

    Yasui, Hironobu; Asanuma, Taketoshi; Kino, Junichi; Yamamori, Tohru; Meike, Shunsuke; Nagane, Masaki; Kubota, Nobuo; Kuwabara, Mikinori; Inanami, Osamu

    2013-01-01

    Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB). Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [ 14 C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth. Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [ 14 C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas. Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects

  3. “...those left behind.” Biology and Oncology of Invasive Glioma Cells

    Directory of Open Access Journals (Sweden)

    Michael E Berens

    1999-08-01

    Full Text Available Although significant technical advances in surgical and radiation treatment for brain tumors have emerged in recent years, their impact on clinical outcome for patients has been disappointing. A fundamental source of the management challenge presented by glioma patients is the insidious propensity of the malignant cells to invade into adjacent normal brain. Invasive tumor cells escape surgical removal and geographically dodge lethal radiation exposure. Recent improved understanding of the biochemistry and molecular determinants of glioma cell invasion provide valuable insight to the underlying biological features of the disease, as well as illuminating possible new therapeutic targets. Heightened commitment to migrate and invade is accompanied by a glioma cell's reduced proliferative activity. The microenvironmental manipulations coincident to invasion and migration may also impact the glioma cell's response to cytotoxic treatments. These collateral aspects of the glioma cell invasive phenotype should be further explored and exploited as novel antiglioma therapies.

  4. Nasal Glioma: Case report

    Directory of Open Access Journals (Sweden)

    Ozgur Surmelioglu

    2011-02-01

    Full Text Available Nasal gliomas are rare, benign, congenital tumors that are thought to be result of abnormality in embryonic development. Three types of clinical presentations have been recognized; extranasal, intranasal and combined. Clinically, these masses are non-pulsatile, gray or purple lesions that obstruct the nasal cavity and cause deformity extranasaly. Histologically, they are made up of astrocytic cells, fibrous and vascular connective tissue that is covered with nasal respiratory mucosa. Treatment of the nasal glioma requires a multidisciplinary approach including an radiologist, neurosurgeon and otorhinolaryngologist. Radiological investigation should be performed to describe intracranial extension. In this case, a 2 years old boy with nasal mass that was diagnosed as nasal glioma is reported. . [Cukurova Med J 2011; 36(1.000: 34-36

  5. Nasal Glioma: Case report

    Directory of Open Access Journals (Sweden)

    Ozgur Surmelioglu

    2011-03-01

    Full Text Available Nasal gliomas are rare, benign, congenital tumors that are thought to be result of abnormality in embryonic development. Three types of clinical presentations have been recognized; extranasal, intranasal and combined. Clinically, these masses are non-pulsatile, gray or purple lesions that obstruct the nasal cavity and cause deformity extranasaly. Histologically, they are made up of astrocytic cells, fibrous and vascular connective tissue that is covered with nasal respiratory mucosa. Treatment of the nasal glioma requires a multidisciplinary approach including an radiologist, neurosurgeon and otorhinolaryngologist. Radiological investigation should be performed to describe intracranial extension. In this case, a 2 years old boy with nasal mass that was diagnosed as nasal glioma is reported. . [Cukurova Med J 2011; 36(1: 34-36

  6. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogeno...... of the solutions used in the study nor was it present as a residual material in blank HPLC runs. CONCLUSIONS: Morphine is present in human gliomas, suggesting that it may exert an action that effects tumour physiology/pathology.......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  7. CURRENT APPROACHES TO CHEMORADIOTHERAPY FOR MALIGNANT GLIOMAS

    Directory of Open Access Journals (Sweden)

    Ye. L. Choinzonov

    2014-01-01

    Full Text Available High-grade malignant gliomas (WHO grade G III–IV account for more than 50% of all primary brain tumors. Despite aggressive treatment, survival rates are still very low with a median reported survival of no more than 1.5 years.Radiation therapy is an integral part of the combined treatment, but often does not influence lethally on resistant tumor cells. Thereby, in recent decades there has been an active search for novel approaches to the treatment of malignant gliomas (chemotherapeutic drugs, biological modifiers, local hyperthermia. Experimental data showed that the effect of high temperatures has both a direct damaging effect on tumor cells and a sensitizing effect. Significant advantages are achieved when the complex treatment of different malignant tumorsincludes local hyperthermia. However data on the treatment of patients with primary and recurrent gliomas G III–IV using local hyperthermia are scarce.The literature review is given in the article provides an overview of the existing treatment methods for brain tumors.

  8. Extra-Neural Metastases of Malignant Gliomas: Myth or Reality?

    Energy Technology Data Exchange (ETDEWEB)

    Beauchesne, Patrick [Neuro-Oncology, CHU de NANCY, Hôpital Central, CO n°34, 54035 Nancy Cedex (France)

    2011-01-27

    Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years— despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases.

  9. Extra-Neural Metastases of Malignant Gliomas: Myth or Reality?

    International Nuclear Information System (INIS)

    Beauchesne, Patrick

    2011-01-01

    Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years— despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases

  10. Clinical characteristics associated with the intracranial dissemination of gliomas.

    Science.gov (United States)

    Cai, Xu; Qin, Jun-Jie; Hao, Shu-Yu; Li, Huan; Zeng, Chun; Sun, Sheng-Jun; Yu, Lan-Bing; Gao, Zhi-Xian; Xie, Jian

    2018-03-01

    Glioma is the most common malignant tumor of the brain and the intracranial dissemination of gliomas is the late stage of the development of the tumor. However, there is little research in literature on the occurrence of intracranial dissemination of gliomas. In order to provide a reference for clinical work, we carried out this study on intracranial dissemination of glioma. A total of 629 patients with gliomas received tumor resection by the same surgeon from August 2010 to September 2015 were included in this study. The authors performed a retrospective review of the patients and the information regarding clinical features, histopathological results, molecular pathologic results and clinical outcomes was collected and analyzed. In this retrospective study, we found that the intracranial dissemination phenomenon occurred in 53 patients (8.43%). We analyzed the clinical characteristics of patients and found that the age at diagnosis (P = 0.011), WHO grade of the tumor (P dissemination. The higher grade of the tumor, the more prone to disseminate. Deletion of 1p/19q had no significant correlation with the intracranial dissemination. MMP9, Ki-67, and EGFR were highly expressed in tumor cells that caused dissemination, and the level of Ki-67 expression had significance in statistics (P 40 years), high pathological grade, invasion of the corpus callosum and high levels of Ki-67 expression were risk factors associated with the intracranial dissemination of gliomas. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Gene expression of manganese superoxide dismutase in human glioma cells

    Directory of Open Access Journals (Sweden)

    Novi S. Hardiany

    2010-02-01

    Full Text Available Aim This study analyze the MnSOD gene expression as endogenous antioxidant in human glioma cells compared with leucocyte cells as control.Methods MnSOD gene expression of 20 glioma patients was analyzed by measuring the relative expression of mRNA and enzyme activity of MnSOD in brain and leucocyte cells. The relative expression of mRNA MnSOD was determined by using quantitative Real Time RT-PCR and the enzyme activity of MnSOD using biochemical kit assay (xantine oxidase inhibition. Statistic analysis for mRNA and enzyme activity of MnSOD was performed using Kruskal Wallis test.Results mRNA of MnSOD in glioma cells of 70% sample was 0.015–0.627 lower, 10% was 1.002-1.059 and 20% was 1.409-6.915 higher than in leucocyte cells. Also the specific activity of MnSOD enzyme in glioma cells of 80% sample showed 0,064-0,506 lower and 20% sample was 1.249-2.718 higher than in leucocyte cells.Conclusion MnSOD gene expression in human glioma cells are significantly lower than its expression in leucocytes cells. (Med J Indones 2010; 19:21-5Keywords : MnSOD, glioma, gene expression

  12. Ring enhancement in recurrent gliomas

    International Nuclear Information System (INIS)

    Ogashiwa, Motohide; Takeuchi, Kazuo; Akai, Keiichiro

    1981-01-01

    The clinical courses,CT scans, and postmortem reports for 6 glioma patients treated by surgery, radiation, and chemotherapy were reviewed. They underwent reoperation and/or retreatment with radiation or chemotherapy for recurrent tumors. CT scans taken at the time of recurrence or about one month prior to death showed ring enhancement of varied size and form after intensive treatment. The cases were examined histologically in correlation with the CT features and divided into two groups based on the pathological findings in the centers surrounded by areas of ring enhancement. The 1st group demonstrated a large necrotic area in the center, and the 2nd group, a cystic tumor. Tumor cells were found to have spread throughout the high-density areas around the necrotic area or cyst. However, gross differentiation between tumor and necrosis was difficult. In addition to an increase in cellularity, all cases demonstrated vascular proliferation, and dilatation of vessels in the sulci or sulci adjacent to gyri invaded by the tumor. The contrast enhancement corresponded well with the vascular proliferation in these areas. It is concluded that vascular proliferation or dilatation of vessels in and around the tumor is an important factor in demonstrating high-density areas in ring enhancement, while a cyst or necrosis in the tumor center is revealed as a low-density area in the CT scan of recurrent gliomas. (author)

  13. Ring enhancement in recurrent gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Ogashiwa, M; Takeuchi, K; Akai, K [Kyorin Univ., Mitaka, Tokyo (Japan). School of Medicine

    1981-08-01

    The clinical courses,CT scans, and postmortem reports for 6 glioma patients treated by surgery, radiation, and chemotherapy were reviewed. They underwent reoperation and/or retreatment with radiation or chemotherapy for recurrent tumors. CT scans taken at the time of recurrence or about one month prior to death showed ring enhancement of varied size and form after intensive treatment. The cases were examined histologically in correlation with the CT features and divided into two groups based on the pathological findings in the centers surrounded by areas of ring enhancement. The 1st group demonstrated a large necrotic area in the center, and the 2nd group, a cystic tumor. Tumor cells were found to have spread throughout the high-density areas around the necrotic area or cyst. However, gross differentiation between tumor and necrosis was difficult. In addition to an increase in cellularity, all cases demonstrated vascular proliferation, and dilatation of vessels in the sulci or sulci adjacent to gyri invaded by the tumor. The contrast enhancement corresponded well with the vascular proliferation in these areas. It is concluded that vascular proliferation or dilatation of vessels in and around the tumor is an important factor in demonstrating high-density areas in ring enhancement, while a cyst or necrosis in the tumor center is revealed as a low-density area in the CT scan of recurrent gliomas.

  14. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    Science.gov (United States)

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex.

    Science.gov (United States)

    Guadalupe, Tulio; Mathias, Samuel R; vanErp, Theo G M; Whelan, Christopher D; Zwiers, Marcel P; Abe, Yoshinari; Abramovic, Lucija; Agartz, Ingrid; Andreassen, Ole A; Arias-Vásquez, Alejandro; Aribisala, Benjamin S; Armstrong, Nicola J; Arolt, Volker; Artiges, Eric; Ayesa-Arriola, Rosa; Baboyan, Vatche G; Banaschewski, Tobias; Barker, Gareth; Bastin, Mark E; Baune, Bernhard T; Blangero, John; Bokde, Arun L W; Boedhoe, Premika S W; Bose, Anushree; Brem, Silvia; Brodaty, Henry; Bromberg, Uli; Brooks, Samantha; Büchel, Christian; Buitelaar, Jan; Calhoun, Vince D; Cannon, Dara M; Cattrell, Anna; Cheng, Yuqi; Conrod, Patricia J; Conzelmann, Annette; Corvin, Aiden; Crespo-Facorro, Benedicto; Crivello, Fabrice; Dannlowski, Udo; de Zubicaray, Greig I; de Zwarte, Sonja M C; Deary, Ian J; Desrivières, Sylvane; Doan, Nhat Trung; Donohoe, Gary; Dørum, Erlend S; Ehrlich, Stefan; Espeseth, Thomas; Fernández, Guillén; Flor, Herta; Fouche, Jean-Paul; Frouin, Vincent; Fukunaga, Masaki; Gallinat, Jürgen; Garavan, Hugh; Gill, Michael; Suarez, Andrea Gonzalez; Gowland, Penny; Grabe, Hans J; Grotegerd, Dominik; Gruber, Oliver; Hagenaars, Saskia; Hashimoto, Ryota; Hauser, Tobias U; Heinz, Andreas; Hibar, Derrek P; Hoekstra, Pieter J; Hoogman, Martine; Howells, Fleur M; Hu, Hao; Hulshoff Pol, Hilleke E; Huyser, Chaim; Ittermann, Bernd; Jahanshad, Neda; Jönsson, Erik G; Jurk, Sarah; Kahn, Rene S; Kelly, Sinead; Kraemer, Bernd; Kugel, Harald; Kwon, Jun Soo; Lemaitre, Herve; Lesch, Klaus-Peter; Lochner, Christine; Luciano, Michelle; Marquand, Andre F; Martin, Nicholas G; Martínez-Zalacaín, Ignacio; Martinot, Jean-Luc; Mataix-Cols, David; Mather, Karen; McDonald, Colm; McMahon, Katie L; Medland, Sarah E; Menchón, José M; Morris, Derek W; Mothersill, Omar; Maniega, Susana Munoz; Mwangi, Benson; Nakamae, Takashi; Nakao, Tomohiro; Narayanaswaamy, Janardhanan C; Nees, Frauke; Nordvik, Jan E; Onnink, A Marten H; Opel, Nils; Ophoff, Roel; Paillère Martinot, Marie-Laure; Papadopoulos Orfanos, Dimitri; Pauli, Paul; Paus, Tomáš; Poustka, Luise; Reddy, Janardhan Yc; Renteria, Miguel E; Roiz-Santiáñez, Roberto; Roos, Annerine; Royle, Natalie A; Sachdev, Perminder; Sánchez-Juan, Pascual; Schmaal, Lianne; Schumann, Gunter; Shumskaya, Elena; Smolka, Michael N; Soares, Jair C; Soriano-Mas, Carles; Stein, Dan J; Strike, Lachlan T; Toro, Roberto; Turner, Jessica A; Tzourio-Mazoyer, Nathalie; Uhlmann, Anne; Hernández, Maria Valdés; van den Heuvel, Odile A; van der Meer, Dennis; van Haren, Neeltje E M; Veltman, Dick J; Venkatasubramanian, Ganesan; Vetter, Nora C; Vuletic, Daniella; Walitza, Susanne; Walter, Henrik; Walton, Esther; Wang, Zhen; Wardlaw, Joanna; Wen, Wei; Westlye, Lars T; Whelan, Robert; Wittfeld, Katharina; Wolfers, Thomas; Wright, Margaret J; Xu, Jian; Xu, Xiufeng; Yun, Je-Yeon; Zhao, JingJing; Franke, Barbara; Thompson, Paul M; Glahn, David C; Mazoyer, Bernard; Fisher, Simon E; Francks, Clyde

    2017-10-01

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

  16. Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

    Science.gov (United States)

    Godin, Antoine G.; Varela, Juan A.; Gao, Zhenghong; Danné, Noémie; Dupuis, Julien P.; Lounis, Brahim; Groc, Laurent; Cognet, Laurent

    2017-03-01

    The brain is a dynamic structure with the extracellular space (ECS) taking up almost a quarter of its volume. Signalling molecules, neurotransmitters and nutrients transit via the ECS, which constitutes a key microenvironment for cellular communication and the clearance of toxic metabolites. The spatial organization of the ECS varies during sleep, development and aging and is probably altered in neuropsychiatric and degenerative diseases, as inferred from electron microscopy and macroscopic biophysical investigations. Here we show an approach to directly observe the local ECS structures and rheology in brain tissue using super-resolution imaging. We inject single-walled carbon nanotubes into rat cerebroventricles and follow the near-infrared emission of individual nanotubes as they diffuse inside the ECS for tens of minutes in acute slices. Because of the interplay between the nanotube geometry and the ECS local environment, we can extract information about the dimensions and local viscosity of the ECS. We find a striking diversity of ECS dimensions down to 40 nm, and as well as of local viscosity values. Moreover, by chemically altering the extracellular matrix of the brains of live animals before nanotube injection, we reveal that the rheological properties of the ECS are affected, but these alterations are local and inhomogeneous at the nanoscale.

  17. A functional genomics screen in planarians reveals regulators of whole-brain regeneration

    Science.gov (United States)

    Roberts-Galbraith, Rachel H; Brubacher, John L; Newmark, Phillip A

    2016-01-01

    Planarians regenerate all body parts after injury, including the central nervous system (CNS). We capitalized on this distinctive trait and completed a gene expression-guided functional screen to identify factors that regulate diverse aspects of neural regeneration in Schmidtea mediterranea. Our screen revealed molecules that influence neural cell fates, support the formation of a major connective hub, and promote reestablishment of chemosensory behavior. We also identified genes that encode signaling molecules with roles in head regeneration, including some that are produced in a previously uncharacterized parenchymal population of cells. Finally, we explored genes downregulated during planarian regeneration and characterized, for the first time, glial cells in the planarian CNS that respond to injury by repressing several transcripts. Collectively, our studies revealed diverse molecules and cell types that underlie an animal’s ability to regenerate its brain. DOI: http://dx.doi.org/10.7554/eLife.17002.001 PMID:27612384

  18. Resistance to Two Heterologous Neurotropic Oncolytic Viruses, Semliki Forest Virus and Vaccinia Virus, in Experimental Glioma

    Science.gov (United States)

    Le Boeuf, Fabrice; Lemay, Chantal; De Silva, Naomi; Diallo, Jean-Simon; Cox, Julie; Becker, Michelle; Choi, Youngmin; Ananth, Abhirami; Sellers, Clara; Breton, Sophie; Roy, Dominic; Falls, Theresa; Brun, Jan; Hemminki, Akseli; Hinkkanen, Ari; Bell, John C.

    2013-01-01

    Attenuated Semliki Forest virus (SFV) may be suitable for targeting malignant glioma due to its natural neurotropism, but its replication in brain tumor cells may be restricted by innate antiviral defenses. We attempted to facilitate SFV replication in glioma cells by combining it with vaccinia virus, which is capable of antagonizing such defenses. Surprisingly, we found parenchymal mouse brain tumors to be refractory to both viruses. Also, vaccinia virus appears to be sensitive to SFV-induced antiviral interference. PMID:23221568

  19. Recent adaptive events in human brain revealed by meta-analysis of positively selected genes.

    Directory of Open Access Journals (Sweden)

    Yue Huang

    Full Text Available BACKGROUND AND OBJECTIVES: Analysis of positively-selected genes can help us understand how human evolved, especially the evolution of highly developed cognitive functions. However, previous works have reached conflicting conclusions regarding whether human neuronal genes are over-represented among genes under positive selection. METHODS AND RESULTS: We divided positively-selected genes into four groups according to the identification approaches, compiling a comprehensive list from 27 previous studies. We showed that genes that are highly expressed in the central nervous system are enriched in recent positive selection events in human history identified by intra-species genomic scan, especially in brain regions related to cognitive functions. This pattern holds when different datasets, parameters and analysis pipelines were used. Functional category enrichment analysis supported these findings, showing that synapse-related functions are enriched in genes under recent positive selection. In contrast, immune-related functions, for instance, are enriched in genes under ancient positive selection revealed by inter-species coding region comparison. We further demonstrated that most of these patterns still hold even after controlling for genomic characteristics that might bias genome-wide identification of positively-selected genes including gene length, gene density, GC composition, and intensity of negative selection. CONCLUSION: Our rigorous analysis resolved previous conflicting conclusions and revealed recent adaptation of human brain functions.

  20. Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

    Science.gov (United States)

    Harro, Jaanus; Kanarik, Margus; Kaart, Tanel; Matrov, Denis; Kõiv, Kadri; Mällo, Tanel; Del Río, Joaquin; Tordera, Rosa M; Ramirez, Maria J

    2014-07-01

    The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Differential expression of centrosomal proteins at different stages of human glioma

    International Nuclear Information System (INIS)

    Loh, Joon-Khim; Lieu, Ann-Shung; Chou, Chia-Hua; Lin, Fang-Yi; Wu, Chia-Hung; Howng, Sheng-Long; Chio, Chung-Ching; Hong, Yi-Ren

    2010-01-01

    High-grade gliomas have poor prognosis, requiring aggressive treatment. The aim of this study is to explore mitotic and centrosomal dysregulation in gliomas, which may provide novel targets for treatment. A case-control study was performed using 34 resected gliomas, which were separated into low- and high-grade groups. Normal human brain tissue was used as a control. Using immunohistochemical analysis, immunofluorescent microscopy, and RT-PCR, detection of centrins 1 and 2, γ-tubulin, hNinein, Aurora A, and Aurora B, expression was performed. Analysis of the GBM8401 glioma cell line was also undertaken to complement the in vivo studies. In high-grade gliomas, the cells had greater than two very brightly staining centrioles within large, atypical nuclei, and moderate-to-strong Aurora A staining. Comparing with normal human brain tissue, most of the mRNAs expression in gliomas for centrosomal structural proteins, including centrin 3, γ-tubulin, and hNinein isoforms 1, 2, 5 and 6, Aurora A and Aurora B were elevated. The significant different expression was observed between high- and low-grade glioma in both γ-tubulin and Aurora A mRNA s. In the high-grade glioma group, 78.6% of the samples had higher than normal expression of γ-tubulin mRNA, which was significantly higher than in the low-grade glioma group (18.2%, p < 0.05). Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas. Therefore, these results are clinically useful for glioma staging as well as the development of novel treatments strategies

  2. Differential expression of centrosomal proteins at different stages of human glioma

    Directory of Open Access Journals (Sweden)

    Lin Fang-Yi

    2010-06-01

    Full Text Available Abstract Background High-grade gliomas have poor prognosis, requiring aggressive treatment. The aim of this study is to explore mitotic and centrosomal dysregulation in gliomas, which may provide novel targets for treatment. Methods A case-control study was performed using 34 resected gliomas, which were separated into low- and high-grade groups. Normal human brain tissue was used as a control. Using immunohistochemical analysis, immunofluorescent microscopy, and RT-PCR, detection of centrins 1 and 2, γ-tubulin, hNinein, Aurora A, and Aurora B, expression was performed. Analysis of the GBM8401 glioma cell line was also undertaken to complement the in vivo studies. Results In high-grade gliomas, the cells had greater than two very brightly staining centrioles within large, atypical nuclei, and moderate-to-strong Aurora A staining. Comparing with normal human brain tissue, most of the mRNAs expression in gliomas for centrosomal structural proteins, including centrin 3, γ-tubulin, and hNinein isoforms 1, 2, 5 and 6, Aurora A and Aurora B were elevated. The significant different expression was observed between high- and low-grade glioma in both γ-tubulin and Aurora A mRNA s. In the high-grade glioma group, 78.6% of the samples had higher than normal expression of γ-tubulin mRNA, which was significantly higher than in the low-grade glioma group (18.2%, p Conclusions Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas. Therefore, these results are clinically useful for glioma staging as well as the development of novel treatments strategies.

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

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jianguo [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China); Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Sun, Jie; Yang, Liu; Yan, Yaohua; Shi, Wei; Shi, Jinlong; Huang, Qingfeng; Chen, Jian [Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Lan, Qing, E-mail: lanqingsj@163.com [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China)

    2015-10-09

    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 release 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.

  4. The role of drebrin in glioma migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Terakawa, Yuzo [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka (Japan); Agnihotri, Sameer; Golbourn, Brian; Nadi, Mustafa; Sabha, Nesrin; Smith, Christian A. [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Croul, Sidney E. [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Division of Neuropathology, University Health Network, Department of Laboratory Medicine and Pathobiology (Canada); Rutka, James T., E-mail: james.rutka@sickkids.ca [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Department of Surgery, University of Toronto, Toronto, Ontario (Canada)

    2013-02-15

    Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172 GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility. - Highlights: ► Drebrin is an actin-binding protein aberrantly expressed in several cancers. ► Role of drebrin in glioma cell morphology and motility is previously unknown. ► We demonstrate that drebrin is expressed in 40% of glioblastoma specimens. ► Drebrin plays a significant role in modulating glioma cell migration and invasion.

  5. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  6. Mitochondrial Dysfunction in Gliomas

    Czech Academy of Sciences Publication Activity Database

    Katsetos, C.D.; Anni, H.; Dráber, Pavel

    2013-01-01

    Roč. 20, č. 3 (2013), s. 216-227 ISSN 1071-9091 R&D Projects: GA MŠk LH12050 Institutional support: RVO:68378050 Keywords : gliomas * mitochondrial dysfunction * microtubule proteins Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.883, year: 2013

  7. MRI of Mouse Models for Gliomas Shows Similarities to Humans and Can Be Used to Identify Mice for Preclinical Trials

    Directory of Open Access Journals (Sweden)

    Jason A. Koutcher

    2002-01-01

    Full Text Available Magnetic resonance imaging (MRI has been utilized for screening and detecting brain tumors in mice based upon their imaging characteristics appearance and their pattern of enhancement. Imaging of these tumors reveals many similarities to those observed in humans with identical pathology. Specifically, high-grade murine gliomas have histologic characteristics of glioblastoma multiforme (GBM with contrast enhancement after intravenous administration of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA, implying disruption of the blood-brain barrier in these tumors. In contrast, low-grade murine oligodendrogliomas do not reveal contrast enhancement, similar to human tumors. MRI can be used to identify mice with brain neoplasms as inclusion criteria in preclinical trials.

  8. Glioma Indian scenario: Is there a human leucocyte antigen association?

    Science.gov (United States)

    Shankarkumar, U; Sridharan, B

    2011-07-01

    The central nervous system tumors are a rare neoplasm with little knowledge with Human Leukocyte Antigen (HLA) involvement. Primary brain tumors are cancers that originate in brain classified according to their appearance under a microscope as low grade (grade I and II) with diffuse astrocytomas, pliocytic astrocytomas, oligodendrogliomas, gangliogliomas, and mixed gliomas as common subtypes and high grade (grade III and IV). HLA associations in common glioma are reported from other parts of the world. The normal cancer treatment is surgery, followed by radiotherapy, and chemotherapy; nowadays immunotherapy is advised. HLA distribution in a Glioma patient was done based on serology and molecular techniques. The immune response gene studies have implicated the HLA allele association in most of the common diseases from India. Considerable variations are noted in HLA association with cancers; hence, we have summarized the HLA involvement in Glioma with respect to the literature. HLA A*030101, A*310102, B*350101, B*4406, Cw*040101, Cw*070101, DRB1*070101, and DRB1*1001. Ethnic diversity and HLA polymorphism precipitate differential immune response genes involved in variable disease manifestations. Therefore, caste-specific HLA allelic specificity needs to be identified, which may help in early identification of the associated HLA allele and establishing clinical practices among glioma patients.

  9. Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

    Directory of Open Access Journals (Sweden)

    Moonsup Jeong

    Full Text Available Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI. Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl-1-nitrosourea (BCNU, a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.

  10. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    International Nuclear Information System (INIS)

    Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

    2011-01-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  11. Cortical GABAergic excitation contributes to epileptic activities around human glioma

    Science.gov (United States)

    Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

    2015-01-01

    Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

  12. Artificial selection on relative brain size in the guppy reveals costs and benefits of evolving a larger brain.

    Science.gov (United States)

    Kotrschal, Alexander; Rogell, Björn; Bundsen, Andreas; Svensson, Beatrice; Zajitschek, Susanne; Brännström, Ioana; Immler, Simone; Maklakov, Alexei A; Kolm, Niclas

    2013-01-21

    The large variation in brain size that exists in the animal kingdom has been suggested to have evolved through the balance between selective advantages of greater cognitive ability and the prohibitively high energy demands of a larger brain (the "expensive-tissue hypothesis"). Despite over a century of research on the evolution of brain size, empirical support for the trade-off between cognitive ability and energetic costs is based exclusively on correlative evidence, and the theory remains controversial. Here we provide experimental evidence for costs and benefits of increased brain size. We used artificial selection for large and small brain size relative to body size in a live-bearing fish, the guppy (Poecilia reticulata), and found that relative brain size evolved rapidly in response to divergent selection in both sexes. Large-brained females outperformed small-brained females in a numerical learning assay designed to test cognitive ability. Moreover, large-brained lines, especially males, developed smaller guts, as predicted by the expensive-tissue hypothesis, and produced fewer offspring. We propose that the evolution of brain size is mediated by a functional trade-off between increased cognitive ability and reproductive performance and discuss the implications of these findings for vertebrate brain evolution. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Cognitive impairments in patients with low grade gliomas and high grade gliomas

    Directory of Open Access Journals (Sweden)

    Eliane C. Miotto

    2011-08-01

    Full Text Available OBJECTIVE: The relationship between brain tumors and cognitive deficits is well established in the literature. However, studies investigating the cognitive status in low and high-grade gliomas patients are scarce, particularly in patients with average or lower educational level. This study aimed at investigating the cognitive functioning in a sample of patients with low and high-grade gliomas before surgical intervention. METHOD: The low-grade (G1, n=19 and high-grade glioma (G2, n=8 patients underwent a detailed neuropsychological assessment of memory, executive functions, visuo-perceptive and visuo-spatial abilities, intellectual level and language. RESULTS: There was a significant impairment on verbal and visual episodic memory, executive functions including mental flexibility, nominal and categorical verbal fluency and speed of information processing in G2. G1 showed only specific deficits on verbal and visual memory recall, mental flexibility and processing speed. CONCLUSION: These findings demonstrated different levels of impairments in the executive and memory domains in patients with low and high grade gliomas.

  14. K -shell decomposition reveals hierarchical cortical organization of the human brain

    International Nuclear Information System (INIS)

    Lahav, Nir; Ksherim, Baruch; Havlin, Shlomo; Ben-Simon, Eti; Maron-Katz, Adi; Cohen, Reuven

    2016-01-01

    In recent years numerous attempts to understand the human brain were undertaken from a network point of view. A network framework takes into account the relationships between the different parts of the system and enables to examine how global and complex functions might emerge from network topology. Previous work revealed that the human brain features ‘small world’ characteristics and that cortical hubs tend to interconnect among themselves. However, in order to fully understand the topological structure of hubs, and how their profile reflect the brain’s global functional organization, one needs to go beyond the properties of a specific hub and examine the various structural layers that make up the network. To address this topic further, we applied an analysis known in statistical physics and network theory as k-shell decomposition analysis. The analysis was applied on a human cortical network, derived from MRI/DSI data of six participants. Such analysis enables us to portray a detailed account of cortical connectivity focusing on different neighborhoods of inter-connected layers across the cortex. Our findings reveal that the human cortex is highly connected and efficient, and unlike the internet network contains no isolated nodes. The cortical network is comprised of a nucleus alongside shells of increasing connectivity that formed one connected giant component, revealing the human brain’s global functional organization. All these components were further categorized into three hierarchies in accordance with their connectivity profile, with each hierarchy reflecting different functional roles. Such a model may explain an efficient flow of information from the lowest hierarchy to the highest one, with each step enabling increased data integration. At the top, the highest hierarchy (the nucleus) serves as a global interconnected collective and demonstrates high correlation with consciousness related regions, suggesting that the nucleus might serve as a

  15. Microglia immunophenotyping in gliomas

    Science.gov (United States)

    Annovazzi, Laura; Mellai, Marta; Bovio, Enrica; Mazzetti, Samanta; Pollo, Bianca; Schiffer, Davide

    2018-01-01

    Microglia, once assimilated to peripheral macrophages, in gliomas has long been discussed and currently it is hypothesized to play a pro-tumor role in tumor progression. Uncertain between M1 and M2 polarization, it exchanges signals with glioma cells to create an immunosuppressive microenvironment and stimulates cell proliferation and migration. Four antibodies are currently used for microglia/macrophage identification in tissues that exhibit different cell forms and cell localization. The aim of the present work was to describe the distribution of the different cell forms and to deduce their significance on the basis of what is known on their function from the literature. Normal resting microglia, reactive microglia, intermediate and bumpy forms and macrophage-like cells can be distinguished by Iba1, CD68, CD16 and CD163 and further categorized by CD11b, CD45, c-MAF and CD98. The number of microglia/macrophages strongly increased from normal cortex and white matter to infiltrating and solid tumors. The ramified microglia accumulated in infiltration areas of both high- and low-grade gliomas, when hypertrophy and hyperplasia occur. In solid tumors, intermediate and bumpy forms prevailed and there is a large increase of macrophage-like cells in glioblastoma. The total number of microglia cells did not vary among the three grades of malignancy, but macrophage-like cells definitely prevailed in high-grade gliomas and frequently expressed CD45 and c-MAF. CD98+ cells were present. Microglia favors tumor progression, but many aspects suggest that the phagocytosing function is maintained. CD98+ cells can be the product of fusion, but also of phagocytosis. Microglia correlated with poorer survival in glioblastoma, when considering CD163+ cells, whereas it did not change prognosis in isocitrate dehydrogenase-mutant low grade gliomas. PMID:29399160

  16. Transcriptomic analyses reveal novel genes with sexually dimorphic expression in the zebrafish gonad and brain.

    Directory of Open Access Journals (Sweden)

    Rajini Sreenivasan

    Full Text Available BACKGROUND: Our knowledge on zebrafish reproduction is very limited. We generated a gonad-derived cDNA microarray from zebrafish and used it to analyze large-scale gene expression profiles in adult gonads and other organs. METHODOLOGY/PRINCIPAL FINDINGS: We have identified 116638 gonad-derived zebrafish expressed sequence tags (ESTs, 21% of which were isolated in our lab. Following in silico normalization, we constructed a gonad-derived microarray comprising 6370 unique, full-length cDNAs from differentiating and adult gonads. Labeled targets from adult gonad, brain, kidney and 'rest-of-body' from both sexes were hybridized onto the microarray. Our analyses revealed 1366, 881 and 656 differentially expressed transcripts (34.7% novel that showed highest expression in ovary, testis and both gonads respectively. Hierarchical clustering showed correlation of the two gonadal transcriptomes and their similarities to those of the brains. In addition, we have identified 276 genes showing sexually dimorphic expression both between the brains and between the gonads. By in situ hybridization, we showed that the gonadal transcripts with the strongest array signal intensities were germline-expressed. We found that five members of the GTP-binding septin gene family, from which only one member (septin 4 has previously been implicated in reproduction in mice, were all strongly expressed in the gonads. CONCLUSIONS/SIGNIFICANCE: We have generated a gonad-derived zebrafish cDNA microarray and demonstrated its usefulness in identifying genes with sexually dimorphic co-expression in both the gonads and the brains. We have also provided the first evidence of large-scale differential gene expression between female and male brains of a teleost. Our microarray would be useful for studying gonad development, differentiation and function not only in zebrafish but also in related teleosts via cross-species hybridizations. Since several genes have been shown to play similar

  17. Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

    Directory of Open Access Journals (Sweden)

    Gregory K Friedman

    2013-02-01

    Full Text Available While glioblastoma multiforme (GBM is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed ‘glioma stem cells’ (GSCs, ‘glioma progenitor cells’, or ‘glioma-initiating cells', which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGGs must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses, genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oncolytic herpes simplex virus (HSV.

  18. Electrical brain responses in language-impaired children reveal grammar-specific deficits.

    Directory of Open Access Journals (Sweden)

    Elisabeth Fonteneau

    2008-03-01

    Full Text Available Scientific and public fascination with human language have included intensive scrutiny of language disorders as a new window onto the biological foundations of language and its evolutionary origins. Specific language impairment (SLI, which affects over 7% of children, is one such disorder. SLI has received robust scientific attention, in part because of its recent linkage to a specific gene and loci on chromosomes and in part because of the prevailing question regarding the scope of its language impairment: Does the disorder impact the general ability to segment and process language or a specific ability to compute grammar? Here we provide novel electrophysiological data showing a domain-specific deficit within the grammar of language that has been hitherto undetectable through behavioural data alone.We presented participants with Grammatical(G-SLI, age-matched controls, and younger child and adult controls, with questions containing syntactic violations and sentences containing semantic violations. Electrophysiological brain responses revealed a selective impairment to only neural circuitry that is specific to grammatical processing in G-SLI. Furthermore, the participants with G-SLI appeared to be partially compensating for their syntactic deficit by using neural circuitry associated with semantic processing and all non-grammar-specific and low-level auditory neural responses were normal.The findings indicate that grammatical neural circuitry underlying language is a developmentally unique system in the functional architecture of the brain, and this complex higher cognitive system can be selectively impaired. The findings advance fundamental understanding about how cognitive systems develop and all human language is represented and processed in the brain.

  19. Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

    Science.gov (United States)

    Tikka, Saara; Monogioudi, Evanthia; Gotsopoulos, Athanasios; Soliymani, Rabah; Pezzini, Francesco; Scifo, Enzo; Uusi-Rauva, Kristiina; Tyynelä, Jaana; Baumann, Marc; Jalanko, Anu; Simonati, Alessandro; Lalowski, Maciej

    2016-03-01

    Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood

  20. Lost for emotion words: What motor and limbic brain activity reveals about autism and semantic theory

    Science.gov (United States)

    Moseley, Rachel L.; Shtyrov, Yury; Mohr, Bettina; Lombardo, Michael V.; Baron-Cohen, Simon; Pulvermüller, Friedemann

    2015-01-01

    Autism spectrum conditions (ASC) are characterised by deficits in understanding and expressing emotions and are frequently accompanied by alexithymia, a difficulty in understanding and expressing emotion words. Words are differentially represented in the brain according to their semantic category and these difficulties in ASC predict reduced activation to emotion-related words in limbic structures crucial for affective processing. Semantic theories view ‘emotion actions’ as critical for learning the semantic relationship between a word and the emotion it describes, such that emotion words typically activate the cortical motor systems involved in expressing emotion actions such as facial expressions. As ASC are also characterised by motor deficits and atypical brain structure and function in these regions, motor structures would also be expected to show reduced activation during emotion-semantic processing. Here we used event-related fMRI to compare passive processing of emotion words in comparison to abstract verbs and animal names in typically-developing controls and individuals with ASC. Relatively reduced brain activation in ASC for emotion words, but not matched control words, was found in motor areas and cingulate cortex specifically. The degree of activation evoked by emotion words in the motor system was also associated with the extent of autistic traits as revealed by the Autism Spectrum Quotient. We suggest that hypoactivation of motor and limbic regions for emotion word processing may underlie difficulties in processing emotional language in ASC. The role that sensorimotor systems and their connections might play in the affective and social-communication difficulties in ASC is discussed. PMID:25278250

  1. Enhancing the discrimination accuracy between metastases, gliomas and meningiomas on brain MRI by volumetric textural features and ensemble pattern recognition methods.

    Science.gov (United States)

    Georgiadis, Pantelis; Cavouras, Dionisis; Kalatzis, Ioannis; Glotsos, Dimitris; Athanasiadis, Emmanouil; Kostopoulos, Spiros; Sifaki, Koralia; Malamas, Menelaos; Nikiforidis, George; Solomou, Ekaterini

    2009-01-01

    Three-dimensional (3D) texture analysis of volumetric brain magnetic resonance (MR) images has been identified as an important indicator for discriminating among different brain pathologies. The purpose of this study was to evaluate the efficiency of 3D textural features using a pattern recognition system in the task of discriminating benign, malignant and metastatic brain tissues on T1 postcontrast MR imaging (MRI) series. The dataset consisted of 67 brain MRI series obtained from patients with verified and untreated intracranial tumors. The pattern recognition system was designed as an ensemble classification scheme employing a support vector machine classifier, specially modified in order to integrate the least squares features transformation logic in its kernel function. The latter, in conjunction with using 3D textural features, enabled boosting up the performance of the system in discriminating metastatic, malignant and benign brain tumors with 77.14%, 89.19% and 93.33% accuracy, respectively. The method was evaluated using an external cross-validation process; thus, results might be considered indicative of the generalization performance of the system to "unseen" cases. The proposed system might be used as an assisting tool for brain tumor characterization on volumetric MRI series.

  2. The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.

    Science.gov (United States)

    Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C; Ali, Almas; Tamarina, Natalia; Philipson, Louis H; Enquist, Lynn W; Myers, Martin G; Rhodes, Christopher J

    2016-09-01

    The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. © 2016 by the American Diabetes Association.

  3. PET Imaging Reveals Brain Metabolic Changes in Adolescent Rats Following Chronic Escalating Morphine Administration.

    Science.gov (United States)

    Chen, Qing; Hou, Haifeng; Feng, Jin; Zhang, Xiaohui; Chen, Yao; Wang, Jing; Ji, Jianfeng; He, Xiao; Wu, Hao; Zhang, Hong

    2018-04-10

    Non-medical use of prescription opioids, especially among adolescents, has been substantially increased in recent years. However, the neuromechanism remains largely unexplored. In the present study, we aimed to investigate the brain metabolic changes in adolescent rats following chronic escalating morphine administration using positron emission tomography (PET). 2-Deoxy-2-[ 18 F]Fluoro-D-glucose ([ 18 F]FDG) microPET imaging was performed, and statistical parametric mapping (SPM) was used for image analysis. Glucose transporter 3 (Glut-3), dopamine D 2 receptor (D 2 R), and Mμ-opioid receptor (μ-OR) were used for immunostaining analysis. Cerebral glucose metabolism was increased in the corpus callosum (CC) and right retrosplenial dysgranular cortex (rRSD), while it was decreased in the right ventral pallidum (rVP). The expressions of Glut-3, D 2 R, and μ-OR were increased in CC and rRSD, while they were decreased in rVP. Furthermore, glucose metabolism and Glut-3 expression were positively correlated with the expressions of D 2 R or μ-OR in CC, rRSD, and rVP. [ 18 F]FDG microPET brain imaging study in combination with immunohistological investigation revealed that CC, rRSD, and rVP were specifically involved in opioid dependence in adolescents. Our findings provided valuable insights into the neuromechanism of adolescent addiction of prescription opioids and might have important implications for the development of prevention and intervention approaches.

  4. Whole brain white matter changes revealed by multiple diffusion metrics in multiple sclerosis: A TBSS study

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yaou, E-mail: asiaeurope80@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Duan, Yunyun, E-mail: xiaoyun81.love@163.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); He, Yong, E-mail: yong.h.he@gmail.com [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China); Yu, Chunshui, E-mail: csyuster@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Wang, Jun, E-mail: jun_wang@bnu.edu.cn [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China); Huang, Jing, E-mail: sainthj@126.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Ye, Jing, E-mail: jingye.2007@yahoo.com.cn [Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Parizel, Paul M., E-mail: paul.parizel@ua.ac.be [Department of Radiology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Edegem, 8 Belgium (Belgium); Li, Kuncheng, E-mail: kunchengli55@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Shu, Ni, E-mail: nshu55@gmail.com [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China)

    2012-10-15

    Objective: To investigate whole brain white matter changes in multiple sclerosis (MS) by multiple diffusion indices, we examined patients with diffusion tensor imaging and utilized tract-based spatial statistics (TBSS) method to analyze the data. Methods: Forty-one relapsing-remitting multiple sclerosis (RRMS) patients and 41 age- and gender-matched normal controls were included in this study. Diffusion weighted images were acquired by employing a single-shot echo planar imaging sequence on a 1.5 T MR scanner. Voxel-wise analyses of multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed with TBSS. Results: The MS patients had significantly decreased FA (9.11%), increased MD (8.26%), AD (3.48%) and RD (13.17%) in their white matter skeletons compared with the controls. Through TBSS analyses, we found abnormal diffusion changes in widespread white matter regions in MS patients. Specifically, decreased FA, increased MD and increased RD were involved in whole-brain white matter, while several regions exhibited increased AD. Furthermore, white matter regions with significant correlations between the diffusion metrics and the clinical variables (the EDSS scores, disease durations and white matter lesion loads) in MS patients were identified. Conclusion: Widespread white matter abnormalities were observed in MS patients revealed by multiple diffusion metrics. The diffusion changes and correlations with clinical variables were mainly attributed to increased RD, implying the predominant role of RD in reflecting the subtle pathological changes in MS.

  5. Whole brain white matter changes revealed by multiple diffusion metrics in multiple sclerosis: A TBSS study

    International Nuclear Information System (INIS)

    Liu, Yaou; Duan, Yunyun; He, Yong; Yu, Chunshui; Wang, Jun; Huang, Jing; Ye, Jing; Parizel, Paul M.; Li, Kuncheng; Shu, Ni

    2012-01-01

    Objective: To investigate whole brain white matter changes in multiple sclerosis (MS) by multiple diffusion indices, we examined patients with diffusion tensor imaging and utilized tract-based spatial statistics (TBSS) method to analyze the data. Methods: Forty-one relapsing-remitting multiple sclerosis (RRMS) patients and 41 age- and gender-matched normal controls were included in this study. Diffusion weighted images were acquired by employing a single-shot echo planar imaging sequence on a 1.5 T MR scanner. Voxel-wise analyses of multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed with TBSS. Results: The MS patients had significantly decreased FA (9.11%), increased MD (8.26%), AD (3.48%) and RD (13.17%) in their white matter skeletons compared with the controls. Through TBSS analyses, we found abnormal diffusion changes in widespread white matter regions in MS patients. Specifically, decreased FA, increased MD and increased RD were involved in whole-brain white matter, while several regions exhibited increased AD. Furthermore, white matter regions with significant correlations between the diffusion metrics and the clinical variables (the EDSS scores, disease durations and white matter lesion loads) in MS patients were identified. Conclusion: Widespread white matter abnormalities were observed in MS patients revealed by multiple diffusion metrics. The diffusion changes and correlations with clinical variables were mainly attributed to increased RD, implying the predominant role of RD in reflecting the subtle pathological changes in MS

  6. Water diffusion closely reveals neural activity status in rat brain loci affected by anesthesia.

    Directory of Open Access Journals (Sweden)

    Yoshifumi Abe

    2017-04-01

    Full Text Available Diffusion functional MRI (DfMRI reveals neuronal activation even when neurovascular coupling is abolished, contrary to blood oxygenation level-dependent (BOLD functional MRI (fMRI. Here, we show that the water apparent diffusion coefficient (ADC derived from DfMRI increased in specific rat brain regions under anesthetic conditions, reflecting the decreased neuronal activity observed with local field potentials (LFPs, especially in regions involved in wakefulness. In contrast, BOLD signals showed nonspecific changes, reflecting systemic effects of the anesthesia on overall brain hemodynamics status. Electrical stimulation of the central medial thalamus nucleus (CM exhibiting this anesthesia-induced ADC increase led the animals to transiently wake up. Infusion in the CM of furosemide, a specific neuronal swelling blocker, led the ADC to increase further locally, although LFP activity remained unchanged, and increased the current threshold awakening the animals under CM electrical stimulation. Oppositely, induction of cell swelling in the CM through infusion of a hypotonic solution (-80 milliosmole [mOsm] artificial cerebrospinal fluid [aCSF] led to a local ADC decrease and a lower current threshold to wake up the animals. Strikingly, the local ADC changes produced by blocking or enhancing cell swelling in the CM were also mirrored remotely in areas functionally connected to the CM, such as the cingulate and somatosensory cortex. Together, those results strongly suggest that neuronal swelling is a significant mechanism underlying DfMRI.

  7. Glycogen distribution in the microwave-fixed mouse brain reveals heterogeneous astrocytic patterns.

    Science.gov (United States)

    Oe, Yuki; Baba, Otto; Ashida, Hitoshi; Nakamura, Kouichi C; Hirase, Hajime

    2016-09-01

    In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well-defined glycogen immunoreactive signals compared with the conventional periodic acid-Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3-CA1 and striatum had a 'patchy' appearance with glycogen-rich and glycogen-poor astrocytes appearing in alternation. The glycogen patches were more evident with large-molecule glycogen in young adult mice but they were hardly observable in aged mice (1-2 years old). Our results reveal brain region-dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes. GLIA 2016;64:1532-1545. © 2016 The Authors. Glia Published by Wiley Periodicals, Inc.

  8. Glycogen distribution in the microwave‐fixed mouse brain reveals heterogeneous astrocytic patterns

    Science.gov (United States)

    Baba, Otto; Ashida, Hitoshi; Nakamura, Kouichi C.

    2016-01-01

    In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well‐defined glycogen immunoreactive signals compared with the conventional periodic acid‐Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3‐CA1 and striatum had a ‘patchy’ appearance with glycogen‐rich and glycogen‐poor astrocytes appearing in alternation. The glycogen patches were more evident with large‐molecule glycogen in young adult mice but they were hardly observable in aged mice (1–2 years old). Our results reveal brain region‐dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes. GLIA 2016;64:1532–1545 PMID:27353480

  9. Diversity of sharp-wave–ripple LFP signatures reveals differentiated brain-wide dynamical events

    Science.gov (United States)

    Ramirez-Villegas, Juan F.; Logothetis, Nikos K.; Besserve, Michel

    2015-01-01

    Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

  10. Diversity of sharp-wave-ripple LFP signatures reveals differentiated brain-wide dynamical events.

    Science.gov (United States)

    Ramirez-Villegas, Juan F; Logothetis, Nikos K; Besserve, Michel

    2015-11-17

    Sharp-wave-ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R-triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions.

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

    Science.gov (United States)

    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

  12. Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03.

    Science.gov (United States)

    Lee, Eudocia Q; Puduvalli, Vinay K; Reid, Joel M; Kuhn, John G; Lamborn, Kathleen R; Cloughesy, Timothy F; Chang, Susan M; Drappatz, Jan; Yung, W K Alfred; Gilbert, Mark R; Robins, H Ian; Lieberman, Frank S; Lassman, Andrew B; McGovern, Renee M; Xu, Jihong; Desideri, Serena; Ye, Xiabu; Ames, Matthew M; Espinoza-Delgado, Igor; Prados, Michael D; Wen, Patrick Y

    2012-11-01

    A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles. In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. ©2012 AACR.

  13. Split-brain reveals separate but equal self-recognition in the two cerebral hemispheres.

    Science.gov (United States)

    Uddin, Lucina Q; Rayman, Jan; Zaidel, Eran

    2005-09-01

    To assess the ability of the disconnected cerebral hemispheres to recognize images of the self, a split-brain patient (an individual who underwent complete cerebral commissurotomy to relieve intractable epilepsy) was tested using morphed self-face images presented to one visual hemifield (projecting to one hemisphere) at a time while making "self/other" judgments. The performance of the right and left hemispheres of this patient as assessed by a signal detection method was not significantly different, though a measure of bias did reveal hemispheric differences. The right and left hemispheres of this patient independently and equally possessed the ability to self-recognize, but only the right hemisphere could successfully recognize familiar others. This supports a modular concept of self-recognition and other-recognition, separately present in each cerebral hemisphere.

  14. Discovery of methylfarnesoate as the annelid brain hormone reveals an ancient role of sesquiterpenoids in reproduction.

    Science.gov (United States)

    Schenk, Sven; Krauditsch, Christian; Frühauf, Peter; Gerner, Christopher; Raible, Florian

    2016-11-29

    Animals require molecular signals to determine when to divert resources from somatic functions to reproduction. This decision is vital in animals that reproduce in an all-or-nothing mode, such as bristle worms: females committed to reproduction spend roughly half their body mass for yolk and egg production; following mass spawning, the parents die. An enigmatic brain hormone activity suppresses reproduction. We now identify this hormone as the sesquiterpenoid methylfarnesoate. Methylfarnesoate suppresses transcript levels of the yolk precursor Vitellogenin both in cell culture and in vivo , directly inhibiting a central energy-costly step of reproductive maturation. We reveal that contrary to common assumptions, sesquiterpenoids are ancient animal hormones present in marine and terrestrial lophotrochozoans. In turn, insecticides targeting this pathway suppress vitellogenesis in cultured worm cells. These findings challenge current views of animal hormone evolution, and indicate that non-target species and marine ecosystems are susceptible to commonly used insect larvicides.

  15. Perspectives in Intraoperative Diagnostics of Human Gliomas

    Directory of Open Access Journals (Sweden)

    O. Tyurikova

    2015-01-01

    Full Text Available Amongst large a variety of oncological diseases, malignant gliomas represent one of the most severe types of tumors. They are also the most common type of the brain tumors and account for over half of the astrocytic tumors. According to different sources, the average life expectancy of patients with various glioblastomas varies between 10 and 12 months and that of patients with anaplastic astrocytic tumors between 20 and 24 months. Therefore, studies of the physiology of transformed glial cells are critical for the development of treatment methods. Modern medical approaches offer complex procedures, including the microsurgical tumor removal, radiotherapy, and chemotherapy, supplemented with photodynamic therapy and immunotherapy. The most radical of them is surgical resection, which allows removing the largest part of the tumor, reduces the intracranial hypertension, and minimizes the degree of neurological deficit. However, complete removal of the tumor remains impossible. The main limitations are insufficient visualization of glioma boundaries, due to its infiltrative growth, and the necessity to preserve healthy tissue. This review is devoted to the description of advantages and disadvantages of modern intraoperative diagnostics of human gliomas and highlights potential perspectives for development of their treatment.

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

    Science.gov (United States)

    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

  17. Response-predictive gene expression profiling of glioma progenitor cells in vitro.

    Directory of Open Access Journals (Sweden)

    Sylvia Moeckel

    Full Text Available High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a to enrich specimens for brain tumor initiating cells and (b to confront cells with a therapeutic agent before expression profiling.As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro.For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.

  18. Treating malignant glioma in Chinese patients: update on temozolomide

    Directory of Open Access Journals (Sweden)

    Chang L

    2014-02-01

    Full Text Available Liang Chang,1 Jun Su,1 Xiuzhi Jia,2,3 Huan Ren2,3 1Department of Neurosurgery, The Tumor Hospital of Harbin Medical University, 2Department of Immunology, Harbin Medical University, 3Key Lab Infection and Immunity, Heilongjiang Province, Harbin, People's Republic of China Abstract: Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive. The median survival of patients with newly diagnosed glioblastoma is only 12–14 months despite advanced therapeutic strategies. Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ, a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma. This review provides an update on the efficacy, mechanism of action, adverse reactions, and clinical role of TMZ in the treatment of malignant glioma in Chinese patients. Keywords: malignant glioma, chemotherapy, temozolomide, efficacy, side effect, People's Republic of China

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

    Science.gov (United States)

    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.

  20. Senescence from glioma stem cell differentiation promotes tumor growth

    International Nuclear Information System (INIS)

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  1. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  2. Investigation of enzyme-sensitive lipid nanoparticles for delivery of siRNA to blood–brain barrier and glioma cells

    DEFF Research Database (Denmark)

    Bruun, Jonas; Larsen, Trine Bjørnbo; Jølck, Rasmus Irming

    2015-01-01

    Clinical applications of siRNA for treating disorders in the central nervous system require development of systemic stable, safe, and effective delivery vehicles that are able to cross the impermeable blood–brain barrier (BBB). Engineering nanocarriers with low cellular interaction during systemi...

  3. Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area

    Directory of Open Access Journals (Sweden)

    Anna Luisa Di Stefano

    2014-01-01

    Full Text Available Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV, calculated with Dynamic Susceptibility Contrast (DSC Perfusion-Weighted Imaging (PWI, allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV. Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp., the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P=0.036. In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.

  4. Altered spontaneous brain activity in adolescent boys with pure conduct disorder revealed by regional homogeneity analysis.

    Science.gov (United States)

    Wu, Qiong; Zhang, Xiaocui; Dong, Daifeng; Wang, Xiang; Yao, Shuqiao

    2017-07-01

    Functional magnetic resonance imaging (fMRI) studies have revealed abnormal neural activity in several brain regions of adolescents with conduct disorder (CD) performing various tasks. However, little is known about the spontaneous neural activity in people with CD in a resting state. The aims of this study were to investigate CD-associated regional activity abnormalities and to explore the relationship between behavioral impulsivity and regional activity abnormalities. Resting-state fMRI (rs-fMRI) scans were administered to 28 adolescents with CD and 28 age-, gender-, and IQ-matched healthy controls (HCs). The rs-fMRI data were subjected to regional homogeneity (ReHo) analysis. ReHo can demonstrate the temporal synchrony of regional blood oxygen level-dependent signals and reflect the coordination of local neuronal activity facilitating similar goals or representations. Compared to HCs, the CD group showed increased ReHo bilaterally in the insula as well as decreased ReHo in the right inferior parietal lobule, right middle temporal gyrus and right fusiform gyrus, left anterior cerebellum anterior, and right posterior cerebellum. In the CD group, mean ReHo values in the left and the right insula correlated positively with Barratt Impulsivity Scale (BIS) total scores. The results suggest that CD is associated with abnormal intrinsic brain activity, mainly in the cerebellum and temporal-parietal-limbic cortices, regions that are related to emotional and cognitive processing. BIS scores in adolescents with CD may reflect severity of abnormal neuronal synchronization in the insula.

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

    Science.gov (United States)

    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.

  6. Cloning and characterization of human RTVP-1b, a novel splice variant of RTVP-1 in glioma cells

    International Nuclear Information System (INIS)

    Xiang Cunli; Sarid, Ronit; Cazacu, Simona; Finniss, Susan; Lee, Hae-Kyung; Ziv-Av, Amotz; Mikkelsen, Tom; Brodie, Chaya

    2007-01-01

    Here, we report the cloning and characterization of RTVP-1b, a novel splice variant of human RTVP-1, which was isolated from the U87 glioma cell line. Sequence analysis revealed that RTVP-1b contains an additional 71 base exon between exons 2 and 3 that is missing in RTVP-1, leading to a frame-shift and a different putative protein. The deduced protein was 237 amino acids in length, sharing the N-terminal 141 amino acids with RTVP-1. RT-PCR analysis demonstrated that RTVP-1b was expressed in a wide range of tissues and that its expression was different from that of RTVP-1. In contrast, RTVP-1 and RTVP-1b showed similar patterns of expression in astrocytic tumors; highly expressed in glioblastomas as compared to normal brains, low-grade astrocytomas and anaplastic oligodendrogliomas. Overexpression of RTVP-1b increased glioma cell proliferation but did not affect cell migration. Our results suggest that RTVP-1b represents a potential prognostic marker and therapeutic target in gliomas

  7. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

    NARCIS (Netherlands)

    Guadalupe, Tulio; Mathias, Samuel R.; vanErp, Theo G.M.; Whelan, Christopher D.; Zwiers, Marcel P.; Abe, Yoshinari; Abramovic, Lucija; Agartz, Ingrid; Andreassen, Ole A.; Arias-Vásquez, Alejandro; Aribisala, Benjamin S.; Armstrong, Nicola J.; Arolt, Volker; Artiges, Eric; Ayesa-Arriola, Rosa; Baboyan, Vatche G.; Banaschewski, Tobias; Barker, Gareth; Bastin, Mark E.; Baune, Bernhard T.; Blangero, John; Bokde, Arun L.W.; Boedhoe, Premika S.W.; Bose, Anushree; Brem, Silvia; Brodaty, Henry; Bromberg, Uli; Brooks, Samantha; Büchel, Christian; Buitelaar, Jan; Calhoun, Vince D.; Cannon, Dara M.; Cattrell, Anna; Cheng, Yuqi; Conrod, Patricia J.; Conzelmann, Annette; Corvin, Aiden; Crespo-Facorro, Benedicto; Crivello, Fabrice; Dannlowski, Udo; de Zubicaray, Greig I.; de Zwarte, Sonja M.C.; Deary, Ian J.; Desrivières, Sylvane; Doan, Nhat Trung; Donohoe, Gary; Dørum, Erlend S.; Ehrlich, Stefan; Espeseth, Thomas; Fernández, Guillén; Flor, Herta; Fouche, Jean Paul; Frouin, Vincent; Fukunaga, Masaki; Gallinat, Jürgen; Garavan, Hugh; Gill, Michael; Suarez, Andrea Gonzalez; Gowland, Penny; Grabe, Hans J.; Grotegerd, Dominik; Gruber, Oliver; Hagenaars, Saskia; Hashimoto, Ryota; Hauser, Tobias U.; Heinz, Andreas; Hibar, Derrek P.; Hoekstra, Pieter J.; Hoogman, Martine; Howells, Fleur M.; Hu, Hao; Hulshoff Pol, Hilleke E.; Huyser, Chaim; Ittermann, Bernd; Jahanshad, Neda; Jönsson, Erik G.; Jurk, Sarah; Kahn, Rene S.; Kelly, Sinead; Kraemer, Bernd; Kugel, Harald; Kwon, Jun Soo; Lemaitre, Herve; Lesch, Klaus Peter; Lochner, Christine; Luciano, Michelle; Marquand, Andre F.; Martin, Nicholas G.; Martínez-Zalacaín, Ignacio; Martinot, Jean Luc; Mataix-Cols, David; Mather, Karen; McDonald, Colm; McMahon, Katie L.; Medland, Sarah E.; Menchón, José M.; Morris, Derek W.; Mothersill, Omar; Maniega, Susana Munoz; Mwangi, Benson; Nakamae, Takashi; Nakao, Tomohiro; Narayanaswaamy, Janardhanan C.; Nees, Frauke; Nordvik, Jan E.; Onnink, A. Marten H.; Opel, Nils; Ophoff, Roel; Paillère Martinot, Marie Laure; Papadopoulos Orfanos, Dimitri; Pauli, Paul; Paus, Tomáš; Poustka, Luise; Reddy, Janardhan Yc; Renteria, Miguel E.; Roiz-Santiáñez, Roberto; Roos, Annerine; Royle, Natalie A.; Sachdev, Perminder; Sánchez-Juan, Pascual; Schmaal, Lianne; Schumann, Gunter; Shumskaya, Elena; Smolka, Michael N.; Soares, Jair C.; Soriano-Mas, Carles; Stein, Dan J.; Strike, Lachlan T.; Toro, Roberto; Turner, Jessica A.; Tzourio-Mazoyer, Nathalie; Uhlmann, Anne; Hernández, Maria Valdés; van den Heuvel, Odile A.; van der Meer, Dennis; van Haren, Neeltje E.M.; Veltman, Dick J.; Venkatasubramanian, Ganesan; Vetter, Nora C.; Vuletic, Daniella; Walitza, Susanne; Walter, Henrik; Walton, Esther; Wang, Zhen; Wardlaw, Joanna; Wen, Wei; Westlye, Lars T.; Whelan, Robert; Wittfeld, Katharina; Wolfers, Thomas; Wright, Margaret J.; Xu, Jian; Xu, Xiufeng; Yun, Je Yeon; Zhao, Jing Jing; Franke, Barbara; Thompson, Paul M.; Glahn, David C.; Mazoyer, Bernard; Fisher, Simon E.; Francks, Clyde

    2017-01-01

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain

  8. A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model.

    Science.gov (United States)

    Towner, Rheal A; Ihnat, Michael; Saunders, Debra; Bastian, Anja; Smith, Nataliya; Pavana, Roheeth Kumar; Gangjee, Aleem

    2015-07-17

    High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule. GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively. Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.

  9. Delayed radiation-induced necrosis of the brain stem

    International Nuclear Information System (INIS)

    Yukawa, Osamu; Kodama, Yasunori; Kyoda, Jun; Yuki, Kiyoshi; Taniguchi, Eiji; Katayama, Shoichi; Hiroi, Tadashi; Uozumi, Toru.

    1993-01-01

    A 46-year-old man had surgery for a mixed glioma of the frontotemporal lobe. Postoperatively he received 50 Gy of irradiation. Sixteen months later he developed left hemiparesis and left facial palsy. MRI revealed lesion brain stem and basal ganglia. Despite chemotherapy and an additional 50 Gy dose, the patient deteriorated. Autopsy revealed a wide spread radiation-induced necrosis in the right cerebral hemisphere, midbrain and pons. In radiation therapy, great care must be taken to protect the normal brain tissue. (author)

  10. Safety and reliability of the insertable Reveal XT recorder in patients undergoing 3 Tesla brain magnetic resonance imaging.

    Science.gov (United States)

    Haeusler, Karl Georg; Koch, Lydia; Ueberreiter, Juliane; Coban, Nalan; Safak, Erdal; Kunze, Claudia; Villringer, Kersten; Endres, Matthias; Schultheiss, Heinz-Peter; Fiebach, Jochen B; Schirdewan, Alexander

    2011-03-01

    Up to now there is little evidence about the safety and reliability of insertable cardiac monitors (ICMs) in patients undergoing magnetic resonance imaging (MRI). The purpose of this prospective single-center study (MACPAF; clinicaltrials.govNCT01061931), which we are currently performing, was to evaluate these issues for the ICM Reveal XT at a 3 Tesla MRI scanner in patients undergoing serial brain MRI. We present an interim analysis including 62 brain MRI examinations in 24 patients with paroxysmal atrial fibrillation bearing the Reveal XT. All patients were interviewed for potential ICM-associated clinical symptoms during and after MRI examination. According to the study protocol, data from the Reveal XT were transmitted before and after the MRI examination. All patients were clinically asymptomatic during the MRI procedure. Moreover, the reliability (ability to detect signals, battery status) of the Reveal XT was unaffected, except for one MRI-induced artifact that was recorded by the ICM, mimicking a narrow complex tachycardia, as similarly recorded in a further study patient bearing the forerunner ICM Reveal DX. No loss of ICM data was observed after the MRI examination. The 3 Tesla brain MRI scanning is safe for patients bearing the ICM Reveal XT and does not alloy reliability of the Reveal XT itself. MRI-induced artifacts occur rarely but have to be taken into account. Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  11. Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD.

    Science.gov (United States)

    Atasoy, Selen; Roseman, Leor; Kaelen, Mendel; Kringelbach, Morten L; Deco, Gustavo; Carhart-Harris, Robin L

    2017-12-15

    Recent studies have started to elucidate the effects of lysergic acid diethylamide (LSD) on the human brain but the underlying dynamics are not yet fully understood. Here we used 'connectome-harmonic decomposition', a novel method to investigate the dynamical changes in brain states. We found that LSD alters the energy and the power of individual harmonic brain states in a frequency-selective manner. Remarkably, this leads to an expansion of the repertoire of active brain states, suggestive of a general re-organization of brain dynamics given the non-random increase in co-activation across frequencies. Interestingly, the frequency distribution of the active repertoire of brain states under LSD closely follows power-laws indicating a re-organization of the dynamics at the edge of criticality. Beyond the present findings, these methods open up for a better understanding of the complex brain dynamics in health and disease.

  12. The Effect of Molecular Diagnostics on the Treatment of Glioma.

    Science.gov (United States)

    Bush, Nancy Ann Oberheim; Butowski, Nicholas

    2017-04-01

    This review summarizes the use of molecular diagnostics in glioma and its effect on the development of novel therapeutics and management decisions. Genomic and proteomic profiling of brain tumors has provided significant expansion of our understanding of oncogenesis, characterization, and prognostication of brain tumors. Molecular markers such as MGMT, EGFR, IDH, 1p19q, ATRX, TERT, FGFR-TACC, and BRAF are now being used to classify brain tumors as well as influence management decisions. Several of these markers are also being used as therapeutic targets. We review the use of several molecular diagnostics in gliomas and discuss their impact on drug development and clinical trial design. In the future, molecular characterization based on a specific genomic, proteomic as well as transcriptomes for bioformatics analysis will provide clinicians the ability to rationally select drugs with actionable targets for each patient.

  13. Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers.

    Science.gov (United States)

    Thelin, Eric Peter; Just, David; Frostell, Arvid; Häggmark-Månberg, Anna; Risling, Mårten; Svensson, Mikael; Nilsson, Peter; Bellander, Bo-Michael

    2018-03-15

    The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI. Sprague Dawley rats (n=73) received a 3mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O 2 ) or hypoxic (11% O 2 ) air mixture for 30min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data. We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1α, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins. Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

  14. Recovered neuronal viability revealed by Iodine-123-iomazenil SPECT following traumatic brain injury.

    Science.gov (United States)

    Koizumi, Hiroyasu; Fujisawa, Hirosuke; Kurokawa, Tetsu; Suehiro, Eiichi; Iwanaga, Hideyuki; Nakagawara, Jyoji; Suzuki, Michiyasu

    2010-10-01

    We evaluated cortical damages following traumatic brain injury (TBI) in the acute phase with [(123)I] iomazenil (IMZ) single photon emission computed tomography (SPECT). In all, 12 patients with cerebral contusion following TBI were recruited. All patients underwent IMZ SPECT within 1 week after TBI. To investigate the changes in distribution of IMZ in the cortex in the chronic phase, after conventional treatment, patients underwent IMZ SPECT again. A decrease in the accumulation of radioligand for the central benzodiazepine receptor in the cortex corresponding to the contusion revealed with computed tomography (CT) scans and magnetic resonance imaging (MRI) were shown on IMZ SPECT in the acute phase in all patients. In 9 of 12 patients (75%), images of IMZ SPECT obtained in the chronic phase of TBI showed that areas with a decreased distribution of IMZ were remarkably reduced in comparison with those obtained in the acute phase. Both CT scans and MRI showed a normal appearance of the cortex morphologically, where the binding potential of IMZ recovered in the chronic phase. Reduced binding potential of radioligand for the central benzodiazepine receptor is considered to be an irreversible reaction; however, in this study, IMZ accumulation in the cortex following TBI was recovered in the chronic phase in several patients. [(123)I] iomazenil SPECT may have a potential to disclose a reversible vulnerability of neurons following TBI.

  15. Brain Signals of Face Processing as Revealed by Event-Related Potentials

    Directory of Open Access Journals (Sweden)

    Ela I. Olivares

    2015-01-01

    Full Text Available We analyze the functional significance of different event-related potentials (ERPs as electrophysiological indices of face perception and face recognition, according to cognitive and neurofunctional models of face processing. Initially, the processing of faces seems to be supported by early extrastriate occipital cortices and revealed by modulations of the occipital P1. This early response is thought to reflect the detection of certain primary structural aspects indicating the presence grosso modo of a face within the visual field. The posterior-temporal N170 is more sensitive to the detection of faces as complex-structured stimuli and, therefore, to the presence of its distinctive organizational characteristics prior to within-category identification. In turn, the relatively late and probably more rostrally generated N250r and N400-like responses might respectively indicate processes of access and retrieval of face-related information, which is stored in long-term memory (LTM. New methods of analysis of electrophysiological and neuroanatomical data, namely, dynamic causal modeling, single-trial and time-frequency analyses, are highly recommended to advance in the knowledge of those brain mechanisms concerning face processing.

  16. Angiopep-2-conjugated poly(ethylene glycol-co-poly(ε-caprolactone polymersomes for dual-targeting drug delivery to glioma in rats

    Directory of Open Access Journals (Sweden)

    Lu F

    2017-03-01

    Full Text Available Fei Lu,1,2 Zhiyong Pang,2,3 Jingjing Zhao,2 Kai Jin,4 Haichun Li,2 Qiang Pang,2 Long Zhang,2 Zhiqing Pang2 1Department of Pharmacy, Xianju People’s Hospital, Xianju, Zhejiang, 2Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, 3Chongyang Center for Disease Control and Prevention, Xianning, Hubei, 4School of Life Science, Fudan University, Shanghai, People’s Republic of China Abstract: The blood–brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1, which is overexpressed in both blood–brain barrier and glioma cells. The polymersomes (PS were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX. The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was

  17. Regulation of DNA repair mechanism in human glioma xenograft cells both in vitro and in vivo in nude mice.

    Science.gov (United States)

    Ponnala, Shivani; Veeravalli, Krishna Kumar; Chetty, Chandramu; Dinh, Dzung H; Rao, Jasti S

    2011-01-01

    Glioblastoma Multiforme (GBM) is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR) are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ) repair mechanism plays a major role in double strand break (DSB) repair in mammalian cells. Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU) and MMP9-cathepsin B (pMC) shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls. Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential of MMP9, uPAR and cathepsin B shRNA in the treatment of glioma from clinical stand

  18. Regulation of DNA repair mechanism in human glioma xenograft cells both in vitro and in vivo in nude mice.

    Directory of Open Access Journals (Sweden)

    Shivani Ponnala

    Full Text Available Glioblastoma Multiforme (GBM is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ repair mechanism plays a major role in double strand break (DSB repair in mammalian cells.Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU and MMP9-cathepsin B (pMC shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls.Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential of MMP9, uPAR and cathepsin B shRNA in the treatment of glioma from

  19. The impact of dietary isoflavonoids on malignant brain tumors

    International Nuclear Information System (INIS)

    Sehm, Tina; Fan, Zheng; Weiss, Ruth; Schwarz, Marc; Engelhorn, Tobias; Hore, Nirjhar; Doerfler, Arnd; Buchfelder, Michael; Eyüpoglu, IIker Y; Savaskan, Nic E

    2014-01-01

    Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the body's response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose-dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose–response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor-implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor-induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state-of-the-art multimodal treatment approach

  20. Radiotherapy in supratentorial gliomas. A study of 821 cases

    International Nuclear Information System (INIS)

    Heesters, M.; Molenaar, W.; Go, G.K.

    2003-01-01

    Purpose: Analysis of the results of radiotherapy in a large group of cerebral gliomas with identification of prognostic factors and the outcome with respect to different decades of treatment. Patients and Methods: Two decades (1979-1999) of radiotherapy in supratentorial astrocytic and oligodendroglial tumors (n = 821) at the University Hospital Groningen were retrospectively evaluated. Prognostic factors for survival were analyzed. Two decades of radiotherapy treatment were compared with respect to radiotherapy dose and treatment-field design. Results: Glioblastoma multiforme, including gliosarcoma, was the most frequent supratentorial glioma (n = 442) with a poor survival, i.e., median survival time (MST) 7 months, especially in patients > 50 years of age and with poor performance. Patients with good performance were selected for radiotherapy with an optimum dose of 60 Gy local-field irradiation. However, in patients with poor prognosis, no radiotherapy was applied or a shorter treatment scheme was given. Anaplastic astrocytomas (n = 131) were treated in the same way as glioblastoma multiforme. Over time, a decrease in radiation dose (from 60 to 45 Gy) and from whole brain irradiation to local-field treatment was observed, following the literature. In low-grade gliomas, prognostic factors for survival were age, performance, and extent of resection. Gemistocytic astrocytoma (n = 15) had an inferior survival compared to astrocytoma (MST 46 vs. 54 months), but a superior survival compared to anaplastic astrocytoma (MST 10 months). The presence of an oligodendroglial component in a glioma implied a superior survival compared to the astrocytic gliomas. The inherent biology of the glioma is reflected by the study of recurrent tumors with progression to higher grades of malignancy in 32-40% and by the histology of recurrent oligodendroglial tumors. In comparing two decades of radiotherapy in gliomas, no differences in survival were observed despite the technological

  1. Radiotherapy in supratentorial gliomas. A study of 821 cases

    Energy Technology Data Exchange (ETDEWEB)

    Heesters, M. [Dept. of Radiotherapy, Groningen Univ. Hospital (Netherlands); Molenaar, W. [Dept. of Pathology, Groningen Univ. Hospital (Netherlands); Go, G.K. [Dept. of Neurosurgery, Groningen Univ. Hospital (Netherlands)

    2003-09-01

    Purpose: Analysis of the results of radiotherapy in a large group of cerebral gliomas with identification of prognostic factors and the outcome with respect to different decades of treatment. Patients and Methods: Two decades (1979-1999) of radiotherapy in supratentorial astrocytic and oligodendroglial tumors (n = 821) at the University Hospital Groningen were retrospectively evaluated. Prognostic factors for survival were analyzed. Two decades of radiotherapy treatment were compared with respect to radiotherapy dose and treatment-field design. Results: Glioblastoma multiforme, including gliosarcoma, was the most frequent supratentorial glioma (n = 442) with a poor survival, i.e., median survival time (MST) 7 months, especially in patients > 50 years of age and with poor performance. Patients with good performance were selected for radiotherapy with an optimum dose of 60 Gy local-field irradiation. However, in patients with poor prognosis, no radiotherapy was applied or a shorter treatment scheme was given. Anaplastic astrocytomas (n = 131) were treated in the same way as glioblastoma multiforme. Over time, a decrease in radiation dose (from 60 to 45 Gy) and from whole brain irradiation to local-field treatment was observed, following the literature. In low-grade gliomas, prognostic factors for survival were age, performance, and extent of resection. Gemistocytic astrocytoma (n = 15) had an inferior survival compared to astrocytoma (MST 46 vs. 54 months), but a superior survival compared to anaplastic astrocytoma (MST 10 months). The presence of an oligodendroglial component in a glioma implied a superior survival compared to the astrocytic gliomas. The inherent biology of the glioma is reflected by the study of recurrent tumors with progression to higher grades of malignancy in 32-40% and by the histology of recurrent oligodendroglial tumors. In comparing two decades of radiotherapy in gliomas, no differences in survival were observed despite the technological

  2. USE OF DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING FOR REVEALING HYPOXIC-ISCHEMIC BRAIN LESIONS IN NEONATES

    Directory of Open Access Journals (Sweden)

    E. V. Shimchenko

    2014-01-01

    Full Text Available The article presents advantages of use of diffusion-weighted magnetic resonance imaging (DW MRI for revealing hypoxic-ischemic brain lesions in neonates. The trial included 97 neonates with perinatal brain lesion who had been undergoing treatment at a resuscitation department or neonatal pathology department in the first month of life. The article shows high information value of diffusion-weighted images (DWI for diagnostics of hypoxic-ischemic lesions in comparison with regular standard modes. In the event of no structural brain lesions of neonates, pronounced increase in signal characteristics revealed by DWI indicated considerable pathophysiological alterations. Subsequently, children developed structural alterations in the form of cystic encephalomalacia with expansion of cerebrospinal fluid spaces manifested with pronounced neurological deficit. DW MRI has been offered as a method of prognosticating further neurological development of children on early stages. 

  3. Benefits of adjuvant chemotherapy in high-grade gliomas.

    Science.gov (United States)

    DeAngelis, Lisa M

    2003-12-01

    The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving >/=18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.

  4. Using R2* values to evaluate brain tumours on magnetic resonance imaging: Preliminary results

    International Nuclear Information System (INIS)

    Liu, Zhenghua; Liao, Haibo; Yin, Jianhua; Li, Yanfang

    2014-01-01

    To determine the usefulness of the R2* value in assessing the histopathological grade of glioma at magnetic resonance imaging and differentiating various brain tumours. Sixty-four patients with brain tumours underwent R2* mapping and diffusion-weighted imaging examinations. ANOVA was performed to analyse R2* values among four groups of glioma and among high-grade gliomas (grades III and IV), low-grade gliomas (grades I and II), meningiomas, and brain metastasis. Spearman's correlation coefficients were used to determine the relationships between the R2* values or apparent diffusion coefficient (ADC) and the histopathological grade of gliomas. R2* values of low- and high-grade gliomas were analysed with the receiver-operator characteristic curve. R2* values were significantly different among high-grade gliomas, low-grade gliomas, meningiomas, and brain metastasis, but not between grade I and grade II or between grade III and grade IV. The R2* value (18.73) of high-grade gliomas provided a very high sensitivity and specificity for differentiating low-grade gliomas. A strong correlation existed between the R2* value and the pathological grade of gliomas. R2* mapping is a useful sequence for determining grade of gliomas and in distinguishing benign from malignant tumours. R2* values are better than ADC for characterising gliomas. (orig.)

  5. Voxel-based clustered imaging by multiparameter diffusion tensor images for glioma grading.

    Science.gov (United States)

    Inano, Rika; Oishi, Naoya; Kunieda, Takeharu; Arakawa, Yoshiki; Yamao, Yukihiro; Shibata, Sumiya; Kikuchi, Takayuki; Fukuyama, Hidenao; Miyamoto, Susumu

    2014-01-01

    Gliomas are the most common intra-axial primary brain tumour; therefore, predicting glioma grade would influence therapeutic strategies. Although several methods based on single or multiple parameters from diagnostic images exist, a definitive method for pre-operatively determining glioma grade remains unknown. We aimed to develop an unsupervised method using multiple parameters from pre-operative diffusion tensor images for obtaining a clustered image that could enable visual grading of gliomas. Fourteen patients with low-grade gliomas and 19 with high-grade gliomas underwent diffusion tensor imaging and three-dimensional T1-weighted magnetic resonance imaging before tumour resection. Seven features including diffusion-weighted imaging, fractional anisotropy, first eigenvalue, second eigenvalue, third eigenvalue, mean diffusivity and raw T2 signal with no diffusion weighting, were extracted as multiple parameters from diffusion tensor imaging. We developed a two-level clustering approach for a self-organizing map followed by the K-means algorithm to enable unsupervised clustering of a large number of input vectors with the seven features for the whole brain. The vectors were grouped by the self-organizing map as protoclusters, which were classified into the smaller number of clusters by K-means to make a voxel-based diffusion tensor-based clustered image. Furthermore, we also determined if the diffusion tensor-based clustered image was really helpful for predicting pre-operative glioma grade in a supervised manner. The ratio of each class in the diffusion tensor-based clustered images was calculated from the regions of interest manually traced on the diffusion tensor imaging space, and the common logarithmic ratio scales were calculated. We then applied support vector machine as a classifier for distinguishing between low- and high-grade gliomas. Consequently, the sensitivity, specificity, accuracy and area under the curve of receiver operating characteristic

  6. Magnetic Resonance Fingerprinting of Adult Brain Tumors: Initial Experience

    Science.gov (United States)

    Badve, Chaitra; Yu, Alice; Dastmalchian, Sara; Rogers, Matthew; Ma, Dan; Jiang, Yun; Margevicius, Seunghee; Pahwa, Shivani; Lu, Ziang; Schluchter, Mark; Sunshine, Jeffrey; Griswold, Mark; Sloan, Andrew; Gulani, Vikas

    2016-01-01

    Background Magnetic resonance fingerprinting (MRF) allows rapid simultaneous quantification of T1 and T2 relaxation times. This study assesses the utility of MRF in differentiating between common types of adult intra-axial brain tumors. Methods MRF acquisition was performed in 31 patients with untreated intra-axial brain tumors: 17 glioblastomas, 6 WHO grade II lower-grade gliomas and 8 metastases. T1, T2 of the solid tumor (ST), immediate peritumoral white matter (PW), and contralateral white matter (CW) were summarized within each region of interest. Statistical comparisons on mean, standard deviation, skewness and kurtosis were performed using univariate Wilcoxon rank sum test across various tumor types. Bonferroni correction was used to correct for multiple comparisons testing. Multivariable logistic regression analysis was performed for discrimination between glioblastomas and metastases and area under the receiver operator curve (AUC) was calculated. Results Mean T2 values could differentiate solid tumor regions of lower-grade gliomas from metastases (mean±sd: 172±53ms and 105±27ms respectively, p =0.004, significant after Bonferroni correction). Mean T1 of PW surrounding lower-grade gliomas differed from PW around glioblastomas (mean±sd: 1066±218ms and 1578±331ms respectively, p=0.004, significant after Bonferroni correction). Logistic regression analysis revealed that mean T2 of ST offered best separation between glioblastomas and metastases with AUC of 0.86 (95% CI 0.69–1.00, p<0.0001). Conclusion MRF allows rapid simultaneous T1, T2 measurement in brain tumors and surrounding tissues. MRF based relaxometry can identify quantitative differences between solid-tumor regions of lower grade gliomas and metastases and between peritumoral regions of glioblastomas and lower grade gliomas. PMID:28034994

  7. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  8. Comparison of Dolphins' Body and Brain Measurements with Four Other Groups of Cetaceans Reveals Great Diversity.

    Science.gov (United States)

    Ridgway, Sam H; Carlin, Kevin P; Van Alstyne, Kaitlin R; Hanson, Alicia C; Tarpley, Raymond J

    2016-01-01

    We compared mature dolphins with 4 other groupings of mature cetaceans. With a large data set, we found great brain diversity among 5 different taxonomic groupings. The dolphins in our data set ranged in body mass from about 40 to 6,750 kg and in brain mass from 0.4 to 9.3 kg. Dolphin body length ranged from 1.3 to 7.6 m. In our combined data set from the 4 other groups of cetaceans, body mass ranged from about 20 to 120,000 kg and brain mass from about 0.2 to 9.2 kg, while body length varied from 1.21 to 26.8 m. Not all cetaceans have large brains relative to their body size. A few dolphins near human body size have human-sized brains. On the other hand, the absolute brain mass of some other cetaceans is only one-sixth as large. We found that brain volume relative to body mass decreases from Delphinidae to a group of Phocoenidae and Monodontidae, to a group of other odontocetes, to Balaenopteroidea, and finally to Balaenidae. We also found the same general trend when we compared brain volume relative to body length, except that the Delphinidae and Phocoenidae-Monodontidae groups do not differ significantly. The Balaenidae have the smallest relative brain mass and the lowest cerebral cortex surface area. Brain parts also vary. Relative to body mass and to body length, dolphins also have the largest cerebellums. Cortex surface area is isometric with brain size when we exclude the Balaenidae. Our data show that the brains of Balaenidae are less convoluted than those of the other cetaceans measured. Large vascular networks inside the cranial vault may help to maintain brain temperature, and these nonbrain tissues increase in volume with body mass and with body length ranging from 8 to 65% of the endocranial volume. Because endocranial vascular networks and other adnexa, such as the tentorium cerebelli, vary so much in different species, brain size measures from endocasts of some extinct cetaceans may be overestimates. Our regression of body length on endocranial

  9. MTSS1 is epigenetically regulated in glioma cells and inhibits glioma cell motility

    Directory of Open Access Journals (Sweden)

    Daniel Luxen

    2017-02-01

    Full Text Available Epigenetic silencing by DNA methylation in brain tumors has been reported for many genes, however, their function on pathogenesis needs to be evaluated. We investigated the MTSS1 gene, identified as hypermethylated by differential methylation hybridization (DMH. Fifty-nine glioma tissue samples and seven glioma cell lines were examined for hypermethylation of the MTSS1 promotor, MTSS1 expression levels and gene dosage. GBM cell lines were treated with demethylating agents and interrogated for functional consequences of MTSS1 expression after transient transfection. Hypermethylation was significantly associated with IDH1/2 mutation. Comparative SNP analysis indicates higher incidence of loss of heterozygosity of MTSS1 in anaplastic astrocytomas and secondary glioblastomas as well as hypermethylation of the remaining allele. Reversal of promoter hypermethylation results in an increased MTSS1 expression. Cell motility was significantly inhibited by MTSS1 overexpression without influencing cell growth or apoptosis. Immunofluorescence analysis of MTSS1 in human astrocytes indicates co-localization with actin filaments. MTSS1 is down-regulated by DNA methylation in glioblastoma cell lines and is part of the G-CIMP phenotype in primary glioma tissues. Our data on normal astrocytes suggest a function of MTSS1 at focal contact structures with an impact on migratory capacity but no influence on apoptosis or cellular proliferation.

  10. Monitoring Oxygen Levels in Orthotopic Human Glioma Xenograft Following Carbogen Inhalation and Chemotherapy by Implantable Resonator Based Oximetry

    Science.gov (United States)

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

    2014-01-01

    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 prognoses 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 approximately 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. PMID:25111969

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

    Science.gov (United States)

    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.

  12. Hypothalamic glioma masquerading as craniopharyngioma

    Directory of Open Access Journals (Sweden)

    Sameer Vyas

    2013-01-01

    Full Text Available Hypothalamic glioma account for 10-15% of supratentorial tumors in children. They usually present earlier (first 5 years of age than craniopharyngioma. Hypothalamic glioma poses a diagnostic dilemma with craniopharyngioma and other hypothalamic region tumors, when they present with atypical clinical or imaging patterns. Neuroimaging modalities especially MRI plays a very important role in scrutinizing the lesions in the hypothalamic region. We report a case of a hypothalamic glioma masquerading as a craniopharyngioma on imaging along with brief review of both the tumors.

  13. Water diffusion reveals networks that modulate multiregional morphological plasticity after repetitive brain stimulation.

    Science.gov (United States)

    Abe, Mitsunari; Fukuyama, Hidenao; Mima, Tatsuya

    2014-03-25

    Repetitive brain stimulation protocols induce plasticity in the stimulated site in brain slice models. Recent evidence from network models has indicated that additional plasticity-related changes occur in nonstimulated remote regions. Despite increasing use of brain stimulation protocols in experimental and clinical settings, the neural substrates underlying the additional effects in remote regions are unknown. Diffusion-weighted MRI (DWI) probes water diffusion and can be used to estimate morphological changes in cortical tissue that occur with the induction of plasticity. Using DWI techniques, we estimated morphological changes induced by application of repetitive transcranial magnetic stimulation (rTMS) over the left primary motor cortex (M1). We found that rTMS altered water diffusion in multiple regions including the left M1. Notably, the change in water diffusion was retained longest in the left M1 and remote regions that had a correlation of baseline fluctuations in water diffusion before rTMS. We conclude that synchronization of water diffusion at rest between stimulated and remote regions ensures retention of rTMS-induced changes in water diffusion in remote regions. Synchronized fluctuations in the morphology of cortical microstructures between stimulated and remote regions might identify networks that allow retention of plasticity-related morphological changes in multiple regions after brain stimulation protocols. These results increase our understanding of the effects of brain stimulation-induced plasticity on multiregional brain networks. DWI techniques could provide a tool to evaluate treatment effects of brain stimulation protocols in patients with brain disorders.

  14. Sparse coding reveals greater functional connectivity in female brains during naturalistic emotional experience.

    Directory of Open Access Journals (Sweden)

    Yudan Ren

    Full Text Available Functional neuroimaging is widely used to examine changes in brain function associated with age, gender or neuropsychiatric conditions. FMRI (functional magnetic resonance imaging studies employ either laboratory-designed tasks that engage the brain with abstracted and repeated stimuli, or resting state paradigms with little behavioral constraint. Recently, novel neuroimaging paradigms using naturalistic stimuli are gaining increasing attraction, as they offer an ecologically-valid condition to approximate brain function in real life. Wider application of naturalistic paradigms in exploring individual differences in brain function, however, awaits further advances in statistical methods for modeling dynamic and complex dataset. Here, we developed a novel data-driven strategy that employs group sparse representation to assess gender differences in brain responses during naturalistic emotional experience. Comparing to independent component analysis (ICA, sparse coding algorithm considers the intrinsic sparsity of neural coding and thus could be more suitable in modeling dynamic whole-brain fMRI signals. An online dictionary learning and sparse coding algorithm was applied to the aggregated fMRI signals from both groups, which was subsequently factorized into a common time series signal dictionary matrix and the associated weight coefficient matrix. Our results demonstrate that group sparse representation can effectively identify gender differences in functional brain network during natural viewing, with improved sensitivity and reliability over ICA-based method. Group sparse representation hence offers a superior data-driven strategy for examining brain function during naturalistic conditions, with great potential for clinical application in neuropsychiatric disorders.

  15. Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

    Science.gov (United States)

    Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith; Venkataraju, Kannan Umadevi; Bota, Mihail; García Del Molino, Luis Carlos; Fitzgerald, Greg; Ram, Keerthi; He, Miao; Levine, Jesse Maurica; Mitra, Partha; Huang, Z Josh; Wang, Xiao-Jing; Osten, Pavel

    2017-10-05

    The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Tricyclic Neovibsanin Scaffold Inhibits Glioma by Targeting Glioma ...

    African Journals Online (AJOL)

    Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. ... median survival time of mice bearing glioma to 34 days compared to 22 days in untreated mice. .... CX22 microscope (Olympus Corp, Inc, Tokyo,.

  17. Molecular subtypes of glioblastoma are relevant to lower grade glioma.

    Directory of Open Access Journals (Sweden)

    Xiaowei Guan

    Full Text Available Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas.Gene expression array, single nucleotide polymorphism (SNP array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson. Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP was assigned using prediction models by Fine et al.Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.

  18. Low intensity ultrasound promotes the sensitivity of rat brain glioma to Doxorubicin by down-regulating the expressions of p-glucoprotein and multidrug resistance protein 1 in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Zhen Zhang

    Full Text Available The overall prognosis for malignant glioma is extremely poor, and treatment options are limited in part because of multidrug resistant proteins. Our previous findings suggest low intensity ultrasound (LIUS can induce apoptosis of glioma cells. Given this finding, we were interested in determining if LIUS could help treat glioma by inhibiting multidrug resistant proteins, and if so, which pathways are involved. In this study, the toxicity sensitivity and multidrug resistance proteins of glioma induced by LIUS were investigated using CCK-8, immunohistochemistry, immunofluorency, and RT-PCR in tissue samples and cultured cells. LIUS inhibited increase of C6 cells in an intensity- and time-dependent manner. The toxicity sensitivity of C6 cells increased significantly after LIUS sonication (intensity of 142.0 mW/cm(2 or Doxorubicin (DOX at different concentration, particularly by the combination of LIUS sonication and DOX. The expressions of P-gp and MRP1 decreased significantly post-sonication at intensity of 142.0 mW/cm(2 both in vitro and in vivo. The expressions of p110 delta (PI3K, NF-κB-p65, Akt/PKB, and p-Akt/PKB were downregulated by LIUS sonication and DOX treatment separately or in combination at the same parameters in rat glioma. These results indicate that LIUS could increase the toxicity sensitivity of glioma by down-regulating the expressions of P-gp and MRP1, which might be mediated by the PI3K/Akt/NF-κB pathway.

  19. Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells.

    Science.gov (United States)

    Delwar, Zahid M; Avramidis, Dimitrios; Follin, Elna; Hua, Yan; Siden, Åke; Cruz, Mabel; Paulsson, Kajsa M; Yakisich, Juan Sebastian

    2012-08-01

    Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 μM:17.5 μM or 17.5 μM:10 μM was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.

  20. Brain classification reveals the right cerebellum as the best biomarker of dyslexia

    Directory of Open Access Journals (Sweden)

    Demonet Jean

    2009-06-01

    Full Text Available Abstract Background Developmental dyslexia is a specific cognitive disorder in reading acquisition that has genetic and neurological origins. Despite histological evidence for brain differences in dyslexia, we recently demonstrated that in large cohort of subjects, no differences between control and dyslexic readers can be found at the macroscopic level (MRI voxel, because of large variances in brain local volumes. In the present study, we aimed at finding brain areas that most discriminate dyslexic from control normal readers despite the large variance across subjects. After segmenting brain grey matter, normalizing brain size and shape and modulating the voxels' content, normal readers' brains were used to build a 'typical' brain via bootstrapped confidence intervals. Each dyslexic reader's brain was then classified independently at each voxel as being within or outside the normal range. We used this simple strategy to build a brain map showing regional percentages of differences between groups. The significance of this map was then assessed using a randomization technique. Results The right cerebellar declive and the right lentiform nucleus were the two areas that significantly differed the most between groups with 100% of the dyslexic subjects (N = 38 falling outside of the control group (N = 39 95% confidence interval boundaries. The clinical relevance of this result was assessed by inquiring cognitive brain-based differences among dyslexic brain subgroups in comparison to normal readers' performances. The strongest difference between dyslexic subgroups was observed between subjects with lower cerebellar declive (LCD grey matter volumes than controls and subjects with higher cerebellar declive (HCD grey matter volumes than controls. Dyslexic subjects with LCD volumes performed worse than subjects with HCD volumes in phonologically and lexicon related tasks. Furthermore, cerebellar and lentiform grey matter volumes interacted in dyslexic

  1. Graph Theoretical Analysis Reveals: Women's Brains Are Better Connected than Men's.

    Directory of Open Access Journals (Sweden)

    Balázs Szalkai

    Full Text Available Deep graph-theoretic ideas in the context with the graph of the World Wide Web led to the definition of Google's PageRank and the subsequent rise of the most popular search engine to date. Brain graphs, or connectomes, are being widely explored today. We believe that non-trivial graph theoretic concepts, similarly as it happened in the case of the World Wide Web, will lead to discoveries enlightening the structural and also the functional details of the animal and human brains. When scientists examine large networks of tens or hundreds of millions of vertices, only fast algorithms can be applied because of the size constraints. In the case of diffusion MRI-based structural human brain imaging, the effective vertex number of the connectomes, or brain graphs derived from the data is on the scale of several hundred today. That size facilitates applying strict mathematical graph algorithms even for some hard-to-compute (or NP-hard quantities like vertex cover or balanced minimum cut. In the present work we have examined brain graphs, computed from the data of the Human Connectome Project, recorded from male and female subjects between ages 22 and 35. Significant differences were found between the male and female structural brain graphs: we show that the average female connectome has more edges, is a better expander graph, has larger minimal bisection width, and has more spanning trees than the average male connectome. Since the average female brain weighs less than the brain of males, these properties show that the female brain has better graph theoretical properties, in a sense, than the brain of males. It is known that the female brain has a smaller gray matter/white matter ratio than males, that is, a larger white matter/gray matter ratio than the brain of males; this observation is in line with our findings concerning the number of edges, since the white matter consists of myelinated axons, which, in turn, roughly correspond to the connections

  2. Investigation of enzyme-sensitive lipid nanoparticles for delivery of siRNA to blood–brain barrier and glioma cells

    Directory of Open Access Journals (Sweden)

    Bruun J

    2015-09-01

    Full Text Available Jonas Bruun,1 Trine B Larsen,1 Rasmus I Jølck,1 Rasmus Eliasen,1 René Holm,2 Torben Gjetting,1 Thomas L Andresen11Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Technical University of Denmark, DTU Nanotech, Lyngby, Denmark; 2H Lundbeck A/S, Biologics and Pharmaceutical Science, Valby, DenmarkAbstract: Clinical applications of siRNA for treating disorders in the central nervous system require development of systemic stable, safe, and effective delivery vehicles that are able to cross the impermeable blood–brain barrier (BBB. Engineering nanocarriers with low cellular interaction during systemic circulation, but with high uptake in targeted cells, is a great challenge and is further complicated by the BBB. As a first step in obtaining such a delivery system, this study aims at designing a lipid nanoparticle (LNP able to efficiently encapsulate siRNA by a combination of titratable cationic lipids. The targeted delivery is obtained through the design of a two-stage system where the first step is conjugation of angiopep to the surface of the LNP for targeting the low-density lipoprotein receptor-related protein-1 expressed on the BBB. Second, the positively charged LNPs are masked with a negatively charged PEGylated (poly(ethylene glycol cleavable lipopeptide, which contains a recognition sequence for matrix metalloproteinases (MMPs, a class of enzymes often expressed in the tumor microenvironment and inflammatory BBB conditions. Proteolytic cleavage induces PEG release, including the release of four glutamic acid residues, providing a charge switch that triggers a shift of the LNP charge from weakly negative to positive, thus favoring cellular endocytosis and release of siRNA for high silencing efficiency. This work describes the development of this two-stage nanocarrier-system and evaluates the performance in brain endothelial and glioblastoma cells with respect to uptake and gene silencing efficiency. The

  3. Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain.

    Directory of Open Access Journals (Sweden)

    Jacqueline C Lieblein-Boff

    Full Text Available Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510 were excluded. In addition, moderate correlations with xenobiotic relationships (2 or those driven by single outliers (3 were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region-specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.

  4. Comparative magnetic resonance imaging findings between gliomas and presumed cerebrovascular accidents in dogs.

    Science.gov (United States)

    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).

  5. Histogram analysis of T2*-based pharmacokinetic imaging in cerebral glioma grading.

    Science.gov (United States)

    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.

  6. EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.

    Directory of Open Access Journals (Sweden)

    Li Tian

    Full Text Available 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.

  7. EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.

    Science.gov (United States)

    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.

  8. Computer-Aided Grading of Gliomas Combining Automatic Segmentation and Radiomics

    Directory of Open Access Journals (Sweden)

    Wei Chen

    2018-01-01

    Full Text Available Gliomas are the most common primary brain tumors, and the objective grading is of great importance for treatment. This paper presents an automatic computer-aided diagnosis of gliomas that combines automatic segmentation and radiomics, which can improve the diagnostic ability. The MRI data containing 220 high-grade gliomas and 54 low-grade gliomas are used to evaluate our system. A multiscale 3D convolutional neural network is trained to segment whole tumor regions. A wide range of radiomic features including first-order features, shape features, and texture features is extracted. By using support vector machines with recursive feature elimination for feature selection, a CAD system that has an extreme gradient boosting classifier with a 5-fold cross-validation is constructed for the grading of gliomas. Our CAD system is highly effective for the grading of gliomas with an accuracy of 91.27%, a weighted macroprecision of 91.27%, a weighted macrorecall of 91.27%, and a weighted macro-F1 score of 90.64%. This demonstrates that the proposed CAD system can assist radiologists for high accurate grading of gliomas and has the potential for clinical applications.

  9. Sequential Administration of Carbon Nanotubes and Near Infrared Radiation for the Treatment of Gliomas

    Directory of Open Access Journals (Sweden)

    Tiago eSantos

    2014-07-01

    Full Text Available The objective was to use carbon nanotubes (CNT coupled with near infrared radiation (NIR to induce hyperthermia, as a novel non-ionizing radiation treatment for primary brain tumors, glioblastoma multiforme (GBM. In this study we report the therapeutic potential of hyperthermia-induced thermal ablation using the sequential administration of carbon nanotubes and NIR. In vitro studies were performed using glioma tumor cell lines (U251, U87, LN229, T98G. Glioma cells were incubated with CNTs for 24 hours followed by exposure to NIR for 10 minutes. Glioma cells preferentially internalized CNTs, which upon NIR exposure, generated heat, causing necrotic cell death. There were minimal effects to normal cells, which correlate to their minimal uptake of CNTs. Furthermore, this protocol caused cell death to glioma cancer stem cells, and drug-resistant as well as drug-sensitive glioma cells. This sequential hyperthermia therapy was effective in vivo, in the rodent tumor model resulting in tumor shrinkage and no recurrence after only one treatment. In conclusion, this sequence of selective CNT administration followed by NIR activation provides a new approach to the treatment of glioma, particularly drug-resistant gliomas.

  10. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

    Science.gov (United States)

    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.

  11. Spinal metastases of malignant gliomas

    International Nuclear Information System (INIS)

    Materlik, B.; Steidle-Katic, U.; Feyerabend, T.; Richter, E.; Wauschkuhn, B.

    1998-01-01

    Purpose: Extracranial metastases of malignant gliomas are rare. We report 2 cases with spinal metastases in patients suffering from glioma. Patients and Method: Two patients (33 and 57 years old) developed spinal canal metastases of a glioblastoma multiforme and anaplastic astrocytoma Grade III respectively 25 and 9 months after surgical resection and radiotherapy. Both metastases were confirmed pathohistologically. Results: Intraspinal metastases were irradiated with a total dose of 12.6 Gy and 50 Gy. Treatment withdrawal was necessary in one patient due to reduced clinical condition. Regression of neurological symptoms was observed in the second patient. Conclusions: Spinal spread of malignant glioma should be considered during care and follow-up in glioma patients with spinal symptoms. (orig.) [de

  12. PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation

    KAUST Repository

    Hou, Xu

    2015-03-12

    Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)\\'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.

  13. PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation

    KAUST Repository

    Hou, Xu; Liu, Yaohua; Liu, Huailei; Chen, Xin; Liu, Min; Che, Hui; Guo, Fei; Wang, Chunlei; Zhang, Daming; Wu, Jianing; Chen, Xiaofeng; Shen, Chen; Li, Chenguang; Peng, Fei; Bi, Yunke; Yang, Zhuowen; Yang, Guang; Ai, Jing; Gao, Xin; Zhao, Shiguang

    2015-01-01

    Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.

  14. Retinoids in the treatment of glioma: a new perspective.

    Science.gov (United States)

    Mawson, Anthony R

    2012-01-01

    Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners) in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α (RARα) and reduced expression of retinoic acid receptor-β (RARβ). This suggests a potential new treatment strategy for gliomas, possibly even at a late stage of the disease, ie, to combine the use of a RARα antagonist and a RARβ agonist. According to this hypothesis, the RARα antagonist would be expected to inhibit RAR

  15. Retinoids in the treatment of glioma: a new perspective

    International Nuclear Information System (INIS)

    Mawson, Anthony R

    2012-01-01

    Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners) in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α (RARα) and reduced expression of retinoic acid receptor-β (RARβ). This suggests a potential new treatment strategy for gliomas, possibly even at a late stage of the disease, ie, to combine the use of a RARα antagonist and a RARβ agonist. According to this hypothesis, the RARα antagonist would be expected to inhibit RAR

  16. Innate immune functions of microglia isolated from human glioma patients

    Directory of Open Access Journals (Sweden)

    Grimm Elizabeth

    2006-03-01

    Full Text Available Abstract Background Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM. Methods GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. Results GIM expressed significant levels of Toll-like receptors (TLRs, however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. Conclusion We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.

  17. Brain damages in ketamine addicts as revealed by magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Chunmei eWang

    2013-07-01

    Full Text Available Ketamine, a known antagonist of N-methyl-D-aspartic (NMDA glutamate receptors, had been used as an anesthetic particularly for pediatric or for cardiac patients. Unfortunately, ketamine has become an abusive drug in many parts of the world while chronic and prolonged usage led to damages of many organs including the brain. However, no studies on possible damages in the brains induced by chronic ketamine abuse have been documented in the human via neuroimaging. This paper described for the first time via employing magnetic resonance imaging (MRI the changes in ketamine addicts of 0.5 to 12 years and illustrated the possible brain regions susceptible to ketamine abuse. Twenty-one ketamine addicts were recruited and the results showed that the lesions in the brains of ketamine addicts were located in many regions which appeared 2-4 years after ketamine addiction. Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts. Such study confirmed that many brain regions in the human were susceptible to chronic ketamine injury and presented a diffuse effect of ketamine on the brain which might differ from other central nervous system (CNS drugs, such as cocaine, heroin and methamphetamine.

  18. Hierarchical Neural Representation of Dreamed Objects Revealed by Brain Decoding with Deep Neural Network Features.

    Science.gov (United States)

    Horikawa, Tomoyasu; Kamitani, Yukiyasu

    2017-01-01

    Dreaming is generally thought to be generated by spontaneous brain activity during sleep with patterns common to waking experience. This view is supported by a recent study demonstrating that dreamed objects can be predicted from brain activity during sleep using statistical decoders trained with stimulus-induced brain activity. However, it remains unclear whether and how visual image features associated with dreamed objects are represented in the brain. In this study, we used a deep neural network (DNN) model for object recognition as a proxy for hierarchical visual feature representation, and DNN features for dreamed objects were analyzed with brain decoding of fMRI data collected during dreaming. The decoders were first trained with stimulus-induced brain activity labeled with the feature values of the stimulus image from multiple DNN layers. The decoders were then used to decode DNN features from the dream fMRI data, and the decoded features were compared with the averaged features of each object category calculated from a large-scale image database. We found that the feature values decoded from the dream fMRI data positively correlated with those associated with dreamed object categories at mid- to high-level DNN layers. Using the decoded features, the dreamed object category could be identified at above-chance levels by matching them to the averaged features for candidate categories. The results suggest that dreaming recruits hierarchical visual feature representations associated with objects, which may support phenomenal aspects of dream experience.

  19. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

    Science.gov (United States)

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM.

  20. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Qiu eXiangzhe

    2016-05-01

    Full Text Available Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM. However, the DM-related changes in the topological properties in functional brain networks are almost unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs, followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized shortest path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing the functional evidence for the abnormalities of brain networks in DM.

  1. Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951

    NARCIS (Netherlands)

    Erdem-Eraslan, L.; Gravendeel, L.A.; Rooi, J. de; Eilers, P.H.; Idbaih, A.; Spliet, W.G.; Dunnen, W. den; Teepen, J.L.; Wesseling, P.; Sillevis Smitt, P.A.; Kros, J.M.; Gorlia, T.; Bent, M.J. van den; French, P.J.

    2013-01-01

    PURPOSE: Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a

  2. A treatment planning and delivery comparison of volumetric modulated arc therapy with or without flattening filter for gliomas, brain metastases, prostate, head/neck and early stage lung cancer

    DEFF Research Database (Denmark)

    Gasic, Daniel; Ohlhues, Lars; Brodin, N. Patrik

    2014-01-01

    generated using STD- and FFF-VMAT for both 6 MV and 10 MV, and were compared with respect to plan quality, monitor units and delivery time using Wilcoxon signed rank tests. RESULTS: For H&N and high-grade gliomas, there was a significant difference in homogeneity index in favor for STD-VMAT (p

  3. Structural brain abnormalities in women with subclinical depression, as revealed by voxel-based morphometry and diffusion tensor imaging.

    Science.gov (United States)

    Hayakawa, Yayoi K; Sasaki, Hiroki; Takao, Hidemasa; Mori, Harushi; Hayashi, Naoto; Kunimatsu, Akira; Aoki, Shigeki; Ohtomo, Kuni

    2013-01-25

    Brain structural changes accompany major depressive disorder, but whether subclinical depression is accompanied by similar changes in brain volume and white matter integrity is unknown. By using voxel-based morphometry (VBM) of the gray matter and tract-specific analysis based on diffusion tensor imaging (DTI) of the white matter, we explored the extent to which abnormalities could be identified in specific brain structures of healthy adults with subclinical depression. The subjects were 21 community-dwelling adults with subclinical depression, as measured by their Center for Epidemiologic Studies Depression Scale (CES-D) scores. They were not demented and had no neurological or psychiatric history. We collected brain magnetic resonance images of the patients and of 21 matched control subjects, and we used VBM to analyze the differences in regional gray matter volume between the two groups. Moreover, we examined the white matter integrity by using tract-specific analysis based on the gray matter volume changes revealed by VBM. VBM revealed that the volumes of both anterior cingulate gyri and the right rectal gyrus were smaller in subclinically depressed women than in control women. Calculation of DTI measures in the anterior cingulum bundle revealed a positive correlation between CES-D scale score and radial diffusivity in the right anterior cingulum in subclinically depressed women. The small sample size limits the stability of the reported findings. Gray matter volume reduction and white matter integrity change in specific frontal brain regions may be associated with depressive symptoms in women, even at a subclinical level. Copyright © 2012 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  5. KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

    Directory of Open Access Journals (Sweden)

    Wang Y

    2018-01-01

    Full Text Available Yiwei Wang,1 Jin Zang,1 Dongyong Zhang,2 Zhenxiang Sun,1 Bo Qiu,2 Xiaojie Wang1 1Department of Human Anatomy, Shenyang Medical College, Huanggu District, Shenyang City, 2Department of Neurosurgery, First Affiliated Hospital of China Medical University, Heping District, Shenyang City, Liaoning Province, ChinaBackground: Gliomas are one of the most lethal cancers in the human central nervous system. Despite clinical treatment advancements, the prognosis of patients with glioma remains poor. KDM2B is a histone lysine demethylase, which has been observed in multiple tumors. But the concrete role of KDM2B in gliomas remains to be further illustrated.Methods: The KDM2B expression in gliomas was detected with immunohistochemistry and Western blot assay. Furthermore, knockdown of KDM2B in U87 and U251 glioma cell lines, the proliferation capacity was evaluated by cell viability assay, colon formation assay and flow cytometry in vitro. Western blot assay was used to analyze the p21, EZH2 and cyclinD1 changes followed by knockdown of KDM2B.Results: KDM2B was upregulated in tissues of glioma patients, and the expression was correlated to cancer progression. Downregulation of KDM2B in U87 and U251 glioma cell lines inhibited cell proliferation and arrested cell cycle in G0/G1 phase. In addition, silencing KDM2B promoted the upregulation of p21 while reduced the expression of EZH2 and cyclinD1.Conclusion: Taken together, our results revealed that KDM2B might influence gliomas growth and act as a novel therapeutic target for glioma patients.Keywords: EZH2, glioma, KDM2B, P21

  6. Aberrant rhythmic expression of cryptochrome2 regulates the radiosensitivity of rat gliomas.

    Science.gov (United States)

    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.

  7. In vivo detection of c-Met expression in a rat C6 glioma model.

    Science.gov (United States)

    Towner, R A; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

    2008-01-01

    The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.

  8. Total magnitude of diffusion tensor imaging as an effective tool for the differentiation of glioma

    Energy Technology Data Exchange (ETDEWEB)

    Smitha, Karavallil A., E-mail: mithamahesh@gmail.com [Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram (India); Gupta, Arun kumar, E-mail: gupta209@gmail.com [Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neuro Sciences, Bangalore (India); Jayasree, Ramapurath S., E-mail: jayashreemenon@gmail.com [Biophotonics and Imaging Laboratory, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram (India)

    2013-05-15

    Objectives: The study aims to evaluate the difference in diffusion properties between high grade glioma and low grade glioma by measuring the total magnitude of diffusion tensor (L), and its isotropic (p) and anisotropic (q) components. Methods: The diffusion tensor parameters p, q, L and FA from the tumor area, adjacent area to the tumor and corresponding contra lateral normal area of 30 high grade glioma and 49 low grade glioma were calculated. Chi square analysis was done to find the changes in age and sex. One Way ANOVA was performed to compare the mean and ROC curve analysis to confirm the discriminative sensitivity. Results: Major variation in the mean values of p, L and FA was observed in different brain areas considered. Variation in the p and L values between low grade and high grade glioma were statistically significant (p < 0.001) and their ROC curve analysis yielded 93.9% and 91.8% sensitivity and 53.3% specificity respectively. Conclusion: Measurement of the isotropic component p and the total value of diffusion tensor L can be effectively correlated with different grades of glioma and can be used to study the diffusion properties of tumor affected brain.

  9. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

    Science.gov (United States)

    Zhu, Xiao-Hong; Lu, Ming; Lee, Byeong-Yeul; Ugurbil, Kamil; Chen, Wei

    2015-01-01

    NAD is an essential metabolite that exists in NAD+ or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD+/NADH redox state and modulating cellular signaling processes through the activity of the NAD+-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD+ and NADH contents and the NAD+/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD+, total NAD contents, and NAD+/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ. PMID:25730862

  10. Decreased expression of LATS1 is correlated with the progression and prognosis of glioma

    Directory of Open Access Journals (Sweden)

    Ji Tianhai

    2012-08-01

    Full Text Available Abstract Background LATS1 is a tumor suppressor genes implicated in the pathogenesis of certain types of tumors, but its role is not known in human glioma. Methods Using real-time PCR and immunohistochemistry, we detected the mRNA and protein expression of LATS1 in glioma. The effect of LATS1 on cell growth and invasion were investigated. Results We found that mRNA and protein of LATS1 expression is significantly downregulated in glioma compared with normal control brain tissues. Furthermore, reduced LATS1 expression was markedly negatively correlated with WHO grade and KPS (p Conclusion These results indicate that LATS1 is an important candidate tumor suppressor and its downregulated expression may contribute to glioma progression.

  11. Differentiation of grade II/III and grade IV glioma by combining ''T1 contrast-enhanced brain perfusion imaging'' and susceptibility-weighted quantitative imaging

    International Nuclear Information System (INIS)

    Saini, Jitender; Gupta, Pradeep Kumar; Gupta, Rakesh Kumar; Sahoo, Prativa; Singh, Anup; Patir, Rana; Ahlawat, Suneeta; Beniwal, Manish; Thennarasu, K.; Santosh, Vani

    2018-01-01

    MRI is a useful method for discriminating low- and high-grade glioma using perfusion MRI and susceptibility-weighted imaging (SWI). The purpose of this study is to evaluate the usefulness of T1-perfusion MRI and SWI in discriminating among grade II, III, and IV gliomas. T1-perfusion MRI was used to measure relative cerebral blood volume (rCBV) in 129 patients with glioma (70 grade IV, 33 grade III, and 26 grade II tumors). SWI was also used to measure the intratumoral susceptibility signal intensity (ITSS) scores for each tumor in these patients. rCBV and ITSS values were compared to seek differences between grade II vs. grade III, grade III vs. grade IV, and grade III+II vs. grade IV tumors. Significant differences in rCBV values of the three grades of the tumors were noted and pairwise comparisons showed significantly higher rCBV values in grade IV tumors as compared to grade III tumors, and similarly increased rCBV was seen in the grade III tumors as compared to grade II tumors (p < 0.001). Grade IV gliomas showed significantly higher ITSS scores on SWI as compared to grade III tumors (p < 0.001) whereas insignificant difference was seen on comparing ITSS scores of grade III with grade II tumors. Combining the rCBV and ITSS resulted in significant improvement in the discrimination of grade III from grade IV tumors. The combination of rCBV values derived from T1-perfusion MRI and SWI derived ITSS scores improves the diagnostic accuracy for discrimination of grade III from grade IV gliomas. (orig.)

  12. Differentiation of grade II/III and grade IV glioma by combining ''T1 contrast-enhanced brain perfusion imaging'' and susceptibility-weighted quantitative imaging

    Energy Technology Data Exchange (ETDEWEB)

    Saini, Jitender [National Institute of Mental Health and Neurosciences, Neuroimaging and Interventional Radiology, Bangalore (India); Gupta, Pradeep Kumar; Gupta, Rakesh Kumar [Fortis Memorial Research Institute, Department of Radiology and Imaging, Gurugram (India); Sahoo, Prativa [Philips Health System, Philips India Limited, Bangalore (India); Beckman Research Institute, Mathematical Oncology, Duarte, CA (United States); Singh, Anup [Indian Institute of Technology Delhi, Center for Biomedical Engineering, Delhi (India); Patir, Rana [Fortis Memorial Research Institute, Department of Neurosurgery, Gurugram (India); Ahlawat, Suneeta [Fortis Memorial Research Institute, SRL Diagnostics, Gurugram (India); Beniwal, Manish [National Institute of Mental Health and Neurosciences, Department of Neurosurgery, Bangalore (India); Thennarasu, K. [National Institute of Mental Health and Neurosciences, Department of Biostatistics, Bangalore (India); Santosh, Vani [National Institute of Mental Health and Neurosciences, Department of Neuropathology, Bangalore (India)

    2018-01-15

    MRI is a useful method for discriminating low- and high-grade glioma using perfusion MRI and susceptibility-weighted imaging (SWI). The purpose of this study is to evaluate the usefulness of T1-perfusion MRI and SWI in discriminating among grade II, III, and IV gliomas. T1-perfusion MRI was used to measure relative cerebral blood volume (rCBV) in 129 patients with glioma (70 grade IV, 33 grade III, and 26 grade II tumors). SWI was also used to measure the intratumoral susceptibility signal intensity (ITSS) scores for each tumor in these patients. rCBV and ITSS values were compared to seek differences between grade II vs. grade III, grade III vs. grade IV, and grade III+II vs. grade IV tumors. Significant differences in rCBV values of the three grades of the tumors were noted and pairwise comparisons showed significantly higher rCBV values in grade IV tumors as compared to grade III tumors, and similarly increased rCBV was seen in the grade III tumors as compared to grade II tumors (p < 0.001). Grade IV gliomas showed significantly higher ITSS scores on SWI as compared to grade III tumors (p < 0.001) whereas insignificant difference was seen on comparing ITSS scores of grade III with grade II tumors. Combining the rCBV and ITSS resulted in significant improvement in the discrimination of grade III from grade IV tumors. The combination of rCBV values derived from T1-perfusion MRI and SWI derived ITSS scores improves the diagnostic accuracy for discrimination of grade III from grade IV gliomas. (orig.)

  13. Monoamine oxidase A (MAO A) inhibitors decrease glioma progression

    Science.gov (United States)

    Vaikari, Vijaya Pooja; Kota, Rajesh; Chen, Kevin; Yeh, Tzu-Shao; Jhaveri, Niyati; Groshen, Susan L.; Olenyuk, Bogdan Z.; Chen, Thomas C.; Hofman, Florence M.; Shih, Jean C.

    2016-01-01

    Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis. PMID:26871599

  14. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Luisa Ciobanu

    Full Text Available During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine. We showed that the brain/vessels contrast in T(2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.

  15. Human Brain Organoids on a Chip Reveal the Physics of Folding.

    Science.gov (United States)

    Karzbrun, Eyal; Kshirsagar, Aditya; Cohen, Sidney R; Hanna, Jacob H; Reiner, Orly

    2018-05-01

    Human brain wrinkling has been implicated in neurodevelopmental disorders and yet its origins remain unknown. Polymer gel models suggest that wrinkling emerges spontaneously due to compression forces arising during differential swelling, but these ideas have not been tested in a living system. Here, we report the appearance of surface wrinkles during the in vitro development and self-organization of human brain organoids in a micro-fabricated compartment that supports in situ imaging over a timescale of weeks. We observe the emergence of convolutions at a critical cell density and maximal nuclear strain, which are indicative of a mechanical instability. We identify two opposing forces contributing to differential growth: cytoskeletal contraction at the organoid core and cell-cycle-dependent nuclear expansion at the organoid perimeter. The wrinkling wavelength exhibits linear scaling with tissue thickness, consistent with balanced bending and stretching energies. Lissencephalic (smooth brain) organoids display reduced convolutions, modified scaling and a reduced elastic modulus. Although the mechanism here does not include the neuronal migration seen in in vivo , it models the physics of the folding brain remarkably well. Our on-chip approach offers a means for studying the emergent properties of organoid development, with implications for the embryonic human brain.

  16. Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.

    Science.gov (United States)

    Kielar, Catherine; Sawiak, Stephen J; Navarro Negredo, Paloma; Tse, Desmond H Y; Morton, A Jennifer

    2012-01-01

    Complexins (Cplxs) are small, soluble, regulatory proteins that bind reversibly to the SNARE complex and modulate synaptic vesicle release. Cplx1 knockout mice (Cplx1(-/-)) have the earliest known onset of ataxia seen in a mouse model, although hitherto no histopathology has been described in these mice. Nevertheless, the profound neurological phenotype displayed by Cplx1(-/-) mutants suggests that significant functional abnormalities must be present in these animals. In this study, MRI was used to automatically detect regions where structural differences were not obvious when using a traditional histological approach. Tensor-based morphometry of Cplx1(-/-) mouse brains showed selective volume loss from the thalamus and cerebellum. Stereological analysis of Cplx1(-/-) and Cplx1(+/+) mice brain slices confirmed the volume loss in the thalamus as well as loss in some lobules of the cerebellum. Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/-) mice when compared to Cplx1(+/+) animals. Our study is the first to describe pathological changes in Cplx1(-/-) mouse brain. We suggest that the ataxia in Cplx1(-/-) mice is likely to be due to pathological changes in both cerebellum and thalamus. Reduced levels of Cplx proteins have been reported in brains of patients with neurodegenerative diseases. Therefore, understanding the effects of Cplx depletion in brains from Cplx1(-/-) mice may also shed light on the mechanisms underlying pathophysiology in disorders in which loss of Cplx1 occurs.

  17. Clinical study on eating disorders. Brain atrophy revealed by cranial computed tomography scans

    Energy Technology Data Exchange (ETDEWEB)

    Nishiwaki, Shinichi

    1988-06-01

    Cranial computed tomography (CT) scans were reviewed in 34 patients with anorexia nervosa (Group I) and 22 with bulimia (Group II) to elucidate the cause and pathological significance of morphological brain alterations. The findings were compared with those from 47 normal women. The incidence of brain atrophy was significantly higher in Group I (17/34, 50%) and Group II (11/22, 50%) than the control group (3/47, 6%). In Group I, there was a significant increase in the left septum-caudate distance, the maximum width of interhemispheric fissure, the width of the both-side Sylvian fissures adjacent to the skull, and the maximum width of the third ventricle. A significant increase in the maximum width of interhemispheric fissure and the width of the left-side Sylvian fissure adjacent to the skull were noted as well in Group II. Ventricular brain ratios were significantly higher in Groups I and II than the control group (6.76 and 7.29 vs 4.55). Brain atrophy did not correlate with age, body weight, malnutrition, eating behavior, depression, thyroid function, EEG findings, or intelligence scale. In Group I, serum cortisol levels after the administration of dexamethasone were correlated with ventricular brain ratio. (Namekawa, K) 51 refs.

  18. Human brain organoids on a chip reveal the physics of folding

    Science.gov (United States)

    Karzbrun, Eyal; Kshirsagar, Aditya; Cohen, Sidney R.; Hanna, Jacob H.; Reiner, Orly

    2018-05-01

    Human brain wrinkling has been implicated in neurodevelopmental disorders and yet its origins remain unknown. Polymer gel models suggest that wrinkling emerges spontaneously due to compression forces arising during differential swelling, but these ideas have not been tested in a living system. Here, we report the appearance of surface wrinkles during the in vitro development and self-organization of human brain organoids in a microfabricated compartment that supports in situ imaging over a timescale of weeks. We observe the emergence of convolutions at a critical cell density and maximal nuclear strain, which are indicative of a mechanical instability. We identify two opposing forces contributing to differential growth: cytoskeletal contraction at the organoid core and cell-cycle-dependent nuclear expansion at the organoid perimeter. The wrinkling wavelength exhibits linear scaling with tissue thickness, consistent with balanced bending and stretching energies. Lissencephalic (smooth brain) organoids display reduced convolutions, modified scaling and a reduced elastic modulus. Although the mechanism here does not include the neuronal migration seen in vivo, it models the physics of the folding brain remarkably well. Our on-chip approach offers a means for studying the emergent properties of organoid development, with implications for the embryonic human brain.

  19. Tensor-based morphometry and stereology reveal brain pathology in the complexin1 knockout mouse.

    Directory of Open Access Journals (Sweden)

    Catherine Kielar

    Full Text Available Complexins (Cplxs are small, soluble, regulatory proteins that bind reversibly to the SNARE complex and modulate synaptic vesicle release. Cplx1 knockout mice (Cplx1(-/- have the earliest known onset of ataxia seen in a mouse model, although hitherto no histopathology has been described in these mice. Nevertheless, the profound neurological phenotype displayed by Cplx1(-/- mutants suggests that significant functional abnormalities must be present in these animals. In this study, MRI was used to automatically detect regions where structural differences were not obvious when using a traditional histological approach. Tensor-based morphometry of Cplx1(-/- mouse brains showed selective volume loss from the thalamus and cerebellum. Stereological analysis of Cplx1(-/- and Cplx1(+/+ mice brain slices confirmed the volume loss in the thalamus as well as loss in some lobules of the cerebellum. Finally, stereology was used to show that there was loss of cerebellar granule cells in Cplx1(-/- mice when compared to Cplx1(+/+ animals. Our study is the first to describe pathological changes in Cplx1(-/- mouse brain. We suggest that the ataxia in Cplx1(-/- mice is likely to be due to pathological changes in both cerebellum and thalamus. Reduced levels of Cplx proteins have been reported in brains of patients with neurodegenerative diseases. Therefore, understanding the effects of Cplx depletion in brains from Cplx1(-/- mice may also shed light on the mechanisms underlying pathophysiology in disorders in which loss of Cplx1 occurs.

  20. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI

    International Nuclear Information System (INIS)

    Ciobanu, Luisa; Reynaud, Olivier; Le Bihan, Denis; Uhrig, Lynn; Jarraya, Bechir

    2012-01-01

    During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T2'*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7 T and 17.2 T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine). We showed that the brain/vessels contrast in T2'*- weighted images at 17.2 T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7 T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation. (authors)

  1. Role of Inflammation and Oxidative Stress Mediators in Gliomas

    Directory of Open Access Journals (Sweden)

    Alfredo Conti

    2010-04-01

    Full Text Available Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

  2. Role of Inflammation and Oxidative Stress Mediators in Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Conti, Alfredo, E-mail: alfredo.conti@unime.it; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed [Department of Neuroscience and Department of Oncology, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, 98125, Messina (Italy)

    2010-04-26

    Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

  3. Role of Inflammation and Oxidative Stress Mediators in Gliomas

    International Nuclear Information System (INIS)

    Conti, Alfredo; Gulì, Carlo; La Torre, Domenico; Tomasello, Chiara; Angileri, Filippo F.; Aguennouz, M’Hammed

    2010-01-01

    Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment

  4. TRIM8 downregulation in glioma affects cell proliferation and it is associated with patients survival

    International Nuclear Information System (INIS)

    Micale, Lucia; Fusco, Carmela; Fontana, Andrea; Barbano, Raffaela; Augello, Bartolomeo; De Nittis, Pasquelena; Copetti, Massimiliano; Pellico, Maria Teresa; Mandriani, Barbara; Cocciadiferro, Dario; Parrella, Paola; Fazio, Vito Michele; Dimitri, Lucia Maria Cecilia; D’Angelo, Vincenzo; Novielli, Chiara; Larizza, Lidia; Daga, Antonio; Merla, Giuseppe

    2015-01-01

    Human gliomas are a heterogeneous group of primary malignant brain tumors whose molecular pathogenesis is not yet solved. In this regard, a major research effort has been directed at identifying novel specific glioma-associated genes. Here, we investigated the effect of TRIM8 gene in glioma. TRIM8 transcriptional level was profiled in our own glioma cases collection by qPCR and confirmed in the independent TCGA glioma cohort. The association between TRIM8 expression and Overall Survival and Progression-free Survival in TCGA cohort was determined by using uni-multivariable Cox regression analysis. The effect of TRIM8 on patient glioma cell proliferation was evaluated by performing MTT and clonogenic assays. The mechanisms causing the reduction of TRIM8 expression were explored by using qPCR and in vitro assays. We showed that TRIM8 expression correlates with unfavorable clinical outcome in glioma patients. We found that a restored TRIM8 expression induced a significant reduction of clonogenic potential in U87MG and patient’s glioblastoma cells. Finally we provide experimental evidences showing that miR-17 directly targets the 3′ UTR of TRIM8 and post-transcriptionally represses the expression of TRIM8. Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients. The online version of this article (doi:10.1186/s12885-015-1449-9) contains supplementary material, which is available to authorized users

  5. Cell proliferation in the Drosophila adult brain revealed by clonal analysis and bromodeoxyuridine labelling

    Directory of Open Access Journals (Sweden)

    Brand Andrea H

    2009-03-01

    Full Text Available Abstract Background The production of new neurons during adulthood and their subsequent integration into a mature central nervous system have been shown to occur in all vertebrate species examined to date. However, the situation in insects is less clear and, in particular, it has been reported that there is no proliferation in the Drosophila adult brain. Results We report here, using clonal analysis and 5'-bromo-2'-deoxyuridine (BrdU labelling, that cell proliferation does occur in the Drosophila adult brain. The majority of clones cluster on the ventrolateral side of the antennal lobes, as do the BrdU-positive cells. Of the BrdU-labelled cells, 86% express the glial gene reversed polarity (repo, and 14% are repo negative. Conclusion We have observed cell proliferation in the Drosophila adult brain. The dividing cells may be adult stem cells, generating glial and/or non-glial cell types.

  6. Use of statins and risk of glioma

    DEFF Research Database (Denmark)

    Gaist, David; Andersen, L; Hallas, Jesper

    2013-01-01

    Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting.......Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting....

  7. Imaging of adult brainstem gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Purohit, Bela, E-mail: purohitbela@yahoo.co.in; Kamli, Ali A.; Kollias, Spyros S.

    2015-04-15

    Highlights: •BSG are classified on MRI into diffuse low-grade, malignant, focal tectal and exophytic subtypes. •Their prognosis and treatment is variable and is almost similar to adult supratentorial gliomas. •This article illustrates the imaging of adult BSGs on MRI and FET-PET. •We also describe prognostic factors and the treatment options of these tumours. -- Abstract: Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all intracranial neoplasms. They are often phenotypically low-grade as compared to their more common paediatric counterparts. Since brainstem biopsies are rarely performed, these tumours are commonly classified according to their MR imaging characteristics into 4 subgroups: (a) diffuse intrinsic low-grade gliomas, (b) enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic gliomas/other subtypes. The prognosis and treatment is variable for the different types and is almost similar to adult supratentorial gliomas. Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to the exophytic subtypes. Review of previous literature shows that the detailed imaging of adult BSGs has not received significant attention. This review illustrates in detail the imaging features of adult BSGs using conventional and advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as well as {sup 18}F-fluoro-ethyl-tyrosine positron emission tomography ({sup 18}F-FET/PET). We have discussed the pertinent differences between childhood and adult BSGs, imaging mimics, prognostic factors and briefly reviewed the treatment options of these tumours.

  8. 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.

    Science.gov (United States)

    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

  9. Perceptual Shift in Bilingualism: Brain Potentials Reveal Plasticity in Pre-Attentive Colour Perception

    Science.gov (United States)

    Athanasopoulos, Panos; Dering, Benjamin; Wiggett, Alison; Kuipers, Jan-Rouke; Thierry, Guillaume

    2010-01-01

    The validity of the linguistic relativity principle continues to stimulate vigorous debate and research. The debate has recently shifted from the behavioural investigation arena to a more biologically grounded field, in which tangible physiological evidence for language effects on perception can be obtained. Using brain potentials in a colour…

  10. Three-dimensional textural analysis of brain images reveals distributed grey-matter abnormalities in schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Ganeshan, Balaji [University of Sussex, Falmer, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton (United Kingdom); University of Sussex, Falmer, Department of Engineering and Design, Brighton (United Kingdom); Miles, Kenneth A.; Critchley, Hugo D. [University of Sussex, Falmer, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton (United Kingdom); Young, Rupert C.D.; Chatwin, Christopher R. [University of Sussex, Falmer, Department of Engineering and Design, Brighton (United Kingdom); Gurling, Hugh M.D. [University College London, Department of Mental Health Sciences, London (United Kingdom)

    2010-04-15

    Three-dimensional (3-D) selective- and relative-scale texture analysis (TA) was applied to structural magnetic resonance (MR) brain images to quantify the presence of grey-matter (GM) and white-matter (WM) textural abnormalities associated with schizophrenia. Brain TA comprised volume filtration using the Laplacian of Gaussian filter to highlight fine, medium and coarse textures within GM and WM, followed by texture quantification. Relative TA (e.g. ratio of fine to medium) was also computed. T1-weighted MR whole-brain images from 32 participants with diagnosis of schizophrenia (n = 10) and healthy controls (n = 22) were examined. Five patients possessed marker alleles (SZ8) associated with schizophrenia on chromosome 8 in the pericentriolar material 1 gene while the remaining five had not inherited any of the alleles (SZ0). Filtered fine GM texture (mean grey-level intensity; MGI) most significantly differentiated schizophrenic patients from controls (P = 0.0058; area under the receiver-operating characteristic curve = 0.809, sensitivity = 90%, specificity = 70%). WM measurements did not distinguish the two groups. Filtered GM and WM textures (MGI) correlated with total GM and WM volume respectively. Medium-to-coarse GM entropy distinguished SZ0 from controls (P = 0.0069) while measures from SZ8 were intermediate between the two. 3-D TA of brain MR enables detection of subtle distributed morphological features associated with schizophrenia, determined partly by susceptibility genes. (orig.)

  11. Three-dimensional textural analysis of brain images reveals distributed grey-matter abnormalities in schizophrenia

    International Nuclear Information System (INIS)

    Ganeshan, Balaji; Miles, Kenneth A.; Critchley, Hugo D.; Young, Rupert C.D.; Chatwin, Christopher R.; Gurling, Hugh M.D.

    2010-01-01

    Three-dimensional (3-D) selective- and relative-scale texture analysis (TA) was applied to structural magnetic resonance (MR) brain images to quantify the presence of grey-matter (GM) and white-matter (WM) textural abnormalities associated with schizophrenia.